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Drug gets orphan designation for WM
The US Food and Drug Administration (FDA) has granted orphan drug designation for IMO-8400, an antagonist of the endosomal Toll-like receptors (TLRs) 7, 8 and 9, for the treatment of Waldenström’s macroglobulinemia (WM).
The designation provides the drug’s maker, Idera Pharmaceuticals, with certain incentives, including eligibility for federal grants, research and development tax credits, and 7 years of marketing exclusivity if the product is approved.
Preclinical studies have shown that, in WM and other B‐cell lymphomas characterized by the MYD88 L265P oncogenic mutation, TLR signaling is overactivated. And this enables tumor cell survival and proliferation.
About 90% of WM patients are reported to harbor the MYD88 L265P mutation.
In research presented at the 2014 AACR Annual Meeting, investigators showed that IMO-8400 decreased the viability of mutated WM cells and diffuse large B-cell lymphoma (DLBCL) cells in vitro. The drug also decreased tumor growth and prolonged survival in mice with MYD88 L265P-positive DLBCL.
Now, Idera is conducting a phase 1/2 trial (NCT02092909) of IMO-8400 in patients with WM who have a history of relapse or failure to respond to one or more prior therapies. The protocol includes 3 dose-escalation cohorts of IMO-8400 administered subcutaneously.
The trial’s independent data review committee has completed its review of 4-week safety data from the second dose cohort (1.2 mg/kg/week) and has determined that Idera may open enrollment in the third dose cohort (2.4 mg/kg/week).
Final 24-week safety and clinical activity data are anticipated in the second half of 2015.
Aside from WM, Idera is pursuing clinical development of IMO-8400 in DLBCL patients harboring the MYD88 L265P mutation and in rare autoimmune diseases, including dermatomyositis. 
The US Food and Drug Administration (FDA) has granted orphan drug designation for IMO-8400, an antagonist of the endosomal Toll-like receptors (TLRs) 7, 8 and 9, for the treatment of Waldenström’s macroglobulinemia (WM).
The designation provides the drug’s maker, Idera Pharmaceuticals, with certain incentives, including eligibility for federal grants, research and development tax credits, and 7 years of marketing exclusivity if the product is approved.
Preclinical studies have shown that, in WM and other B‐cell lymphomas characterized by the MYD88 L265P oncogenic mutation, TLR signaling is overactivated. And this enables tumor cell survival and proliferation.
About 90% of WM patients are reported to harbor the MYD88 L265P mutation.
In research presented at the 2014 AACR Annual Meeting, investigators showed that IMO-8400 decreased the viability of mutated WM cells and diffuse large B-cell lymphoma (DLBCL) cells in vitro. The drug also decreased tumor growth and prolonged survival in mice with MYD88 L265P-positive DLBCL.
Now, Idera is conducting a phase 1/2 trial (NCT02092909) of IMO-8400 in patients with WM who have a history of relapse or failure to respond to one or more prior therapies. The protocol includes 3 dose-escalation cohorts of IMO-8400 administered subcutaneously.
The trial’s independent data review committee has completed its review of 4-week safety data from the second dose cohort (1.2 mg/kg/week) and has determined that Idera may open enrollment in the third dose cohort (2.4 mg/kg/week).
Final 24-week safety and clinical activity data are anticipated in the second half of 2015.
Aside from WM, Idera is pursuing clinical development of IMO-8400 in DLBCL patients harboring the MYD88 L265P mutation and in rare autoimmune diseases, including dermatomyositis.
The US Food and Drug Administration (FDA) has granted orphan drug designation for IMO-8400, an antagonist of the endosomal Toll-like receptors (TLRs) 7, 8 and 9, for the treatment of Waldenström’s macroglobulinemia (WM).
The designation provides the drug’s maker, Idera Pharmaceuticals, with certain incentives, including eligibility for federal grants, research and development tax credits, and 7 years of marketing exclusivity if the product is approved.
Preclinical studies have shown that, in WM and other B‐cell lymphomas characterized by the MYD88 L265P oncogenic mutation, TLR signaling is overactivated. And this enables tumor cell survival and proliferation.
About 90% of WM patients are reported to harbor the MYD88 L265P mutation.
In research presented at the 2014 AACR Annual Meeting, investigators showed that IMO-8400 decreased the viability of mutated WM cells and diffuse large B-cell lymphoma (DLBCL) cells in vitro. The drug also decreased tumor growth and prolonged survival in mice with MYD88 L265P-positive DLBCL.
Now, Idera is conducting a phase 1/2 trial (NCT02092909) of IMO-8400 in patients with WM who have a history of relapse or failure to respond to one or more prior therapies. The protocol includes 3 dose-escalation cohorts of IMO-8400 administered subcutaneously.
The trial’s independent data review committee has completed its review of 4-week safety data from the second dose cohort (1.2 mg/kg/week) and has determined that Idera may open enrollment in the third dose cohort (2.4 mg/kg/week).
Final 24-week safety and clinical activity data are anticipated in the second half of 2015.
Aside from WM, Idera is pursuing clinical development of IMO-8400 in DLBCL patients harboring the MYD88 L265P mutation and in rare autoimmune diseases, including dermatomyositis.
Certain cancers primarily result from ‘bad luck’
in the bone marrow
Scientists have created a statistical model that measures the proportion of cancer incidence, across many tissue types, caused mainly by random mutations that occur when stem cells divide.
By their measure, two-thirds of adult cancers—including certain leukemias—can be explained primarily by “bad luck,” when these random mutations occur in genes that can drive cancer growth.
The remaining third are due to environmental factors and inherited genes.
“All cancers are caused by a combination of bad luck, the environment, and heredity, and we’ve created a model that may help quantify how much of these three factors contribute to cancer development,” said Bert Vogelstein, MD, of the Johns Hopkins University School of Medicine.
Dr Vogelstein and Cristian Tomasetti, PhD, also of the Johns Hopkins University School of Medicine, detailed these findings in Science.
The pair came to their conclusions by searching the scientific literature for information on the cumulative number of stem cell divisions in 31 tissue types during an average individual’s lifetime.
The researchers knew that cancer arises when tissue-specific stem cells make random mistakes, or mutations. But the actual contribution of these random mistakes to cancer incidence, in comparison to the contribution of hereditary or environmental factors, was unclear.
To sort out the role of random mutations in cancer risk, the team charted the number of stem cell divisions in 31 tissues and compared these rates with the lifetime risks of cancer in the same tissues among Americans.
From this data scatterplot, Drs Tomasetti and Vogelstein determined the correlation between the total number of stem cell divisions and cancer risk to be 0.804. Mathematically, the closer this value is to 1, the more stem cell divisions and cancer risk are correlated.
“Our study shows, in general, that a change in the number of stem cell divisions in a tissue type is highly correlated with a change in the incidence of cancer in that same tissue,” Dr Vogelstein said.
One example is in colon tissue, which undergoes 4 times more stem cell divisions than small intestine tissue in humans. Likewise, colon cancer is much more prevalent than small intestinal cancer.
“You could argue that the colon is exposed to more environmental factors than the small intestine, which increases the potential rate of acquired mutations,” Dr Tomasetti said.
However, the scientists observed the opposite in mouse colons, which had a lower number of stem cell divisions than in their small intestines. In mice, cancer incidence is lower in the colon than in the small intestine. The researchers believe this supports the role of the total number of stem cell divisions in the development of cancer.
Using statistical theory, the pair calculated how much of the variation in cancer risk can be explained by the number of stem cell divisions, which is 0.804 squared, or, in percentage form, approximately 65%.
Finally, the scientists classified the types of cancers they studied into two groups. They calculated which cancer types had an incidence predicted by the number of stem cell divisions and which had higher incidence.
They found that 22 cancer types—including acute myeloid leukemia and chronic lymphocytic leukemia—could be largely explained by the “bad luck” factor of random DNA mutations during cell division.
The other 9 cancer types had incidences higher than predicted by “bad luck” and were presumably due to a combination of bad luck plus environmental or inherited factors.
“We found that the types of cancer that had higher risk than predicted by the number of stem cell divisions were precisely the ones you’d expect, including lung cancer, which is linked to smoking; skin cancer, linked to sun exposure; and forms of cancers associated with hereditary syndromes,” Dr Vogelstein said.
“This study shows that you can add to your risk of getting cancers by smoking or other poor lifestyle factors. However, many forms of cancer are due largely to the bad luck of acquiring a mutation in a cancer driver gene regardless of lifestyle and heredity factors. The best way to eradicate these cancers will be through early detection, when they are still curable by surgery.”
The researchers noted that some cancers, such as breast and prostate cancer, were not included in the report because the team was unable to find reliable stem cell division rates in the scientific literature.
They hope other scientists will help refine their statistical model by finding more precise stem cell division rates.
in the bone marrow
Scientists have created a statistical model that measures the proportion of cancer incidence, across many tissue types, caused mainly by random mutations that occur when stem cells divide.
By their measure, two-thirds of adult cancers—including certain leukemias—can be explained primarily by “bad luck,” when these random mutations occur in genes that can drive cancer growth.
The remaining third are due to environmental factors and inherited genes.
“All cancers are caused by a combination of bad luck, the environment, and heredity, and we’ve created a model that may help quantify how much of these three factors contribute to cancer development,” said Bert Vogelstein, MD, of the Johns Hopkins University School of Medicine.
Dr Vogelstein and Cristian Tomasetti, PhD, also of the Johns Hopkins University School of Medicine, detailed these findings in Science.
The pair came to their conclusions by searching the scientific literature for information on the cumulative number of stem cell divisions in 31 tissue types during an average individual’s lifetime.
The researchers knew that cancer arises when tissue-specific stem cells make random mistakes, or mutations. But the actual contribution of these random mistakes to cancer incidence, in comparison to the contribution of hereditary or environmental factors, was unclear.
To sort out the role of random mutations in cancer risk, the team charted the number of stem cell divisions in 31 tissues and compared these rates with the lifetime risks of cancer in the same tissues among Americans.
From this data scatterplot, Drs Tomasetti and Vogelstein determined the correlation between the total number of stem cell divisions and cancer risk to be 0.804. Mathematically, the closer this value is to 1, the more stem cell divisions and cancer risk are correlated.
“Our study shows, in general, that a change in the number of stem cell divisions in a tissue type is highly correlated with a change in the incidence of cancer in that same tissue,” Dr Vogelstein said.
One example is in colon tissue, which undergoes 4 times more stem cell divisions than small intestine tissue in humans. Likewise, colon cancer is much more prevalent than small intestinal cancer.
“You could argue that the colon is exposed to more environmental factors than the small intestine, which increases the potential rate of acquired mutations,” Dr Tomasetti said.
However, the scientists observed the opposite in mouse colons, which had a lower number of stem cell divisions than in their small intestines. In mice, cancer incidence is lower in the colon than in the small intestine. The researchers believe this supports the role of the total number of stem cell divisions in the development of cancer.
Using statistical theory, the pair calculated how much of the variation in cancer risk can be explained by the number of stem cell divisions, which is 0.804 squared, or, in percentage form, approximately 65%.
Finally, the scientists classified the types of cancers they studied into two groups. They calculated which cancer types had an incidence predicted by the number of stem cell divisions and which had higher incidence.
They found that 22 cancer types—including acute myeloid leukemia and chronic lymphocytic leukemia—could be largely explained by the “bad luck” factor of random DNA mutations during cell division.
The other 9 cancer types had incidences higher than predicted by “bad luck” and were presumably due to a combination of bad luck plus environmental or inherited factors.
“We found that the types of cancer that had higher risk than predicted by the number of stem cell divisions were precisely the ones you’d expect, including lung cancer, which is linked to smoking; skin cancer, linked to sun exposure; and forms of cancers associated with hereditary syndromes,” Dr Vogelstein said.
“This study shows that you can add to your risk of getting cancers by smoking or other poor lifestyle factors. However, many forms of cancer are due largely to the bad luck of acquiring a mutation in a cancer driver gene regardless of lifestyle and heredity factors. The best way to eradicate these cancers will be through early detection, when they are still curable by surgery.”
The researchers noted that some cancers, such as breast and prostate cancer, were not included in the report because the team was unable to find reliable stem cell division rates in the scientific literature.
They hope other scientists will help refine their statistical model by finding more precise stem cell division rates.
in the bone marrow
Scientists have created a statistical model that measures the proportion of cancer incidence, across many tissue types, caused mainly by random mutations that occur when stem cells divide.
By their measure, two-thirds of adult cancers—including certain leukemias—can be explained primarily by “bad luck,” when these random mutations occur in genes that can drive cancer growth.
The remaining third are due to environmental factors and inherited genes.
“All cancers are caused by a combination of bad luck, the environment, and heredity, and we’ve created a model that may help quantify how much of these three factors contribute to cancer development,” said Bert Vogelstein, MD, of the Johns Hopkins University School of Medicine.
Dr Vogelstein and Cristian Tomasetti, PhD, also of the Johns Hopkins University School of Medicine, detailed these findings in Science.
The pair came to their conclusions by searching the scientific literature for information on the cumulative number of stem cell divisions in 31 tissue types during an average individual’s lifetime.
The researchers knew that cancer arises when tissue-specific stem cells make random mistakes, or mutations. But the actual contribution of these random mistakes to cancer incidence, in comparison to the contribution of hereditary or environmental factors, was unclear.
To sort out the role of random mutations in cancer risk, the team charted the number of stem cell divisions in 31 tissues and compared these rates with the lifetime risks of cancer in the same tissues among Americans.
From this data scatterplot, Drs Tomasetti and Vogelstein determined the correlation between the total number of stem cell divisions and cancer risk to be 0.804. Mathematically, the closer this value is to 1, the more stem cell divisions and cancer risk are correlated.
“Our study shows, in general, that a change in the number of stem cell divisions in a tissue type is highly correlated with a change in the incidence of cancer in that same tissue,” Dr Vogelstein said.
One example is in colon tissue, which undergoes 4 times more stem cell divisions than small intestine tissue in humans. Likewise, colon cancer is much more prevalent than small intestinal cancer.
“You could argue that the colon is exposed to more environmental factors than the small intestine, which increases the potential rate of acquired mutations,” Dr Tomasetti said.
However, the scientists observed the opposite in mouse colons, which had a lower number of stem cell divisions than in their small intestines. In mice, cancer incidence is lower in the colon than in the small intestine. The researchers believe this supports the role of the total number of stem cell divisions in the development of cancer.
Using statistical theory, the pair calculated how much of the variation in cancer risk can be explained by the number of stem cell divisions, which is 0.804 squared, or, in percentage form, approximately 65%.
Finally, the scientists classified the types of cancers they studied into two groups. They calculated which cancer types had an incidence predicted by the number of stem cell divisions and which had higher incidence.
They found that 22 cancer types—including acute myeloid leukemia and chronic lymphocytic leukemia—could be largely explained by the “bad luck” factor of random DNA mutations during cell division.
The other 9 cancer types had incidences higher than predicted by “bad luck” and were presumably due to a combination of bad luck plus environmental or inherited factors.
“We found that the types of cancer that had higher risk than predicted by the number of stem cell divisions were precisely the ones you’d expect, including lung cancer, which is linked to smoking; skin cancer, linked to sun exposure; and forms of cancers associated with hereditary syndromes,” Dr Vogelstein said.
“This study shows that you can add to your risk of getting cancers by smoking or other poor lifestyle factors. However, many forms of cancer are due largely to the bad luck of acquiring a mutation in a cancer driver gene regardless of lifestyle and heredity factors. The best way to eradicate these cancers will be through early detection, when they are still curable by surgery.”
The researchers noted that some cancers, such as breast and prostate cancer, were not included in the report because the team was unable to find reliable stem cell division rates in the scientific literature.
They hope other scientists will help refine their statistical model by finding more precise stem cell division rates.
New data added to obinutuzumab label
Credit: Bill Branson
The US Food and Drug Administration (FDA) has approved a supplemental biologics license application for obinutuzumab (Gazyva) in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL).
The approval adds to the drug’s label data from stage 2 of the CLL11 study, which showed that obinutuzumab plus chlorambucil offers significant clinical improvements when compared head-to-head with rituximab plus chlorambucil.
This includes progression-free survival (PFS), complete response (CR), and minimal residual disease (MRD) data from stage 2 of the study. In addition, overall survival data was added from stage 1, in which researchers compared obinutuzumab plus chlorambucil to chlorambucil alone.
The label now reflects that obinutuzumab plus chlorambucil improved PFS compared to rituximab plus chlorambucil. The median PFS was 26.7 months and 14.9 months, respectively (hazard ratio=0.42, P<0.0001).
Additionally, obinutuzumab plus chlorambucil nearly tripled the CR rate when compared to rituximab plus chlorambucil. The CR rates were 26.1% and 8.8%, respectively.
Of the patients who achieved a CR with or without complete recovery from abnormal blood cell counts, 19% (18/94) of patients in the obinutuzumab arm and 6% (2/34) in the rituximab arm were MRD negative in the bone marrow.
Forty-one percent (39/94) of patients in the obinutuzumab arm and 12% (4/34) in the rituximab arm were MRD-negative in the peripheral blood.
At nearly 2 years, the rate of death was 9% (22/238) for patients who received obinutuzumab plus chlorambucil and 20% (24/118) for those who received chlorambucil alone (hazard ratio=0.41). The median overall survival has not yet been reached.
About obinutuzumab
Obinutuzumab is an engineered monoclonal antibody designed to attach to CD20 on B cells. The drug attacks targeted cells both directly and together with the body’s immune system.
The prescribing information for obinutuzumab includes warnings that the drug can cause serious or life-threatening side effects. These include hepatitis B reactivation, progressive multifocal leukoencephalopathy, infusion reactions, tumor lysis syndrome, infections, and neutropenia.
The most common side effects of the drug are infusion reactions, neutropenia, thrombocytopenia, anemia, fever, cough, nausea, and diarrhea.
Obinutuzumab was FDA-approved for use in combination with chlorambucil to treat previously untreated CLL in November 2013. The drug (which is known as Gazyvaro in Europe) was approved by the European Commission for the same indication in July 2014.
Obinutuzumab was discovered by Roche Glycart AG, an independent research unit of Roche. In the US, the drug is part of a collaboration between Genentech and Biogen Idec.
Credit: Bill Branson
The US Food and Drug Administration (FDA) has approved a supplemental biologics license application for obinutuzumab (Gazyva) in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL).
The approval adds to the drug’s label data from stage 2 of the CLL11 study, which showed that obinutuzumab plus chlorambucil offers significant clinical improvements when compared head-to-head with rituximab plus chlorambucil.
This includes progression-free survival (PFS), complete response (CR), and minimal residual disease (MRD) data from stage 2 of the study. In addition, overall survival data was added from stage 1, in which researchers compared obinutuzumab plus chlorambucil to chlorambucil alone.
The label now reflects that obinutuzumab plus chlorambucil improved PFS compared to rituximab plus chlorambucil. The median PFS was 26.7 months and 14.9 months, respectively (hazard ratio=0.42, P<0.0001).
Additionally, obinutuzumab plus chlorambucil nearly tripled the CR rate when compared to rituximab plus chlorambucil. The CR rates were 26.1% and 8.8%, respectively.
Of the patients who achieved a CR with or without complete recovery from abnormal blood cell counts, 19% (18/94) of patients in the obinutuzumab arm and 6% (2/34) in the rituximab arm were MRD negative in the bone marrow.
Forty-one percent (39/94) of patients in the obinutuzumab arm and 12% (4/34) in the rituximab arm were MRD-negative in the peripheral blood.
At nearly 2 years, the rate of death was 9% (22/238) for patients who received obinutuzumab plus chlorambucil and 20% (24/118) for those who received chlorambucil alone (hazard ratio=0.41). The median overall survival has not yet been reached.
About obinutuzumab
Obinutuzumab is an engineered monoclonal antibody designed to attach to CD20 on B cells. The drug attacks targeted cells both directly and together with the body’s immune system.
The prescribing information for obinutuzumab includes warnings that the drug can cause serious or life-threatening side effects. These include hepatitis B reactivation, progressive multifocal leukoencephalopathy, infusion reactions, tumor lysis syndrome, infections, and neutropenia.
The most common side effects of the drug are infusion reactions, neutropenia, thrombocytopenia, anemia, fever, cough, nausea, and diarrhea.
Obinutuzumab was FDA-approved for use in combination with chlorambucil to treat previously untreated CLL in November 2013. The drug (which is known as Gazyvaro in Europe) was approved by the European Commission for the same indication in July 2014.
Obinutuzumab was discovered by Roche Glycart AG, an independent research unit of Roche. In the US, the drug is part of a collaboration between Genentech and Biogen Idec.
Credit: Bill Branson
The US Food and Drug Administration (FDA) has approved a supplemental biologics license application for obinutuzumab (Gazyva) in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL).
The approval adds to the drug’s label data from stage 2 of the CLL11 study, which showed that obinutuzumab plus chlorambucil offers significant clinical improvements when compared head-to-head with rituximab plus chlorambucil.
This includes progression-free survival (PFS), complete response (CR), and minimal residual disease (MRD) data from stage 2 of the study. In addition, overall survival data was added from stage 1, in which researchers compared obinutuzumab plus chlorambucil to chlorambucil alone.
The label now reflects that obinutuzumab plus chlorambucil improved PFS compared to rituximab plus chlorambucil. The median PFS was 26.7 months and 14.9 months, respectively (hazard ratio=0.42, P<0.0001).
Additionally, obinutuzumab plus chlorambucil nearly tripled the CR rate when compared to rituximab plus chlorambucil. The CR rates were 26.1% and 8.8%, respectively.
Of the patients who achieved a CR with or without complete recovery from abnormal blood cell counts, 19% (18/94) of patients in the obinutuzumab arm and 6% (2/34) in the rituximab arm were MRD negative in the bone marrow.
Forty-one percent (39/94) of patients in the obinutuzumab arm and 12% (4/34) in the rituximab arm were MRD-negative in the peripheral blood.
At nearly 2 years, the rate of death was 9% (22/238) for patients who received obinutuzumab plus chlorambucil and 20% (24/118) for those who received chlorambucil alone (hazard ratio=0.41). The median overall survival has not yet been reached.
About obinutuzumab
Obinutuzumab is an engineered monoclonal antibody designed to attach to CD20 on B cells. The drug attacks targeted cells both directly and together with the body’s immune system.
The prescribing information for obinutuzumab includes warnings that the drug can cause serious or life-threatening side effects. These include hepatitis B reactivation, progressive multifocal leukoencephalopathy, infusion reactions, tumor lysis syndrome, infections, and neutropenia.
The most common side effects of the drug are infusion reactions, neutropenia, thrombocytopenia, anemia, fever, cough, nausea, and diarrhea.
Obinutuzumab was FDA-approved for use in combination with chlorambucil to treat previously untreated CLL in November 2013. The drug (which is known as Gazyvaro in Europe) was approved by the European Commission for the same indication in July 2014.
Obinutuzumab was discovered by Roche Glycart AG, an independent research unit of Roche. In the US, the drug is part of a collaboration between Genentech and Biogen Idec.
Approach can cure even high-risk FL, study suggests
SAN FRANCISCO—Follicular lymphoma (FL) patients who receive high-dose therapy with autologous stem cell transplant (HDT/ASCT) after they’ve responded to chemotherapy can achieve long-term cancer-free survival, new research suggests.
The study showed that many patients transplanted in complete remission (CR) did not relapse and could be considered cured.
Patients transplanted in their first CR fared the best, as median progression-free survival (PFS) and overall survival (OS) times were not reached.
But even patients transplanted in their second/third CR or in their first partial remission (PR) survived a median of 15 years or more, although their PFS times were shorter, at about 14 years and 3 years, respectively.
Carlos Grande García, MD, of Hospital Universitario 12 de Octubre in Madrid, Spain, presented these results at the 2014 ASH Annual Meeting (abstract 675.)*
“In follicular lymphoma patients, intensification with high-dose therapy and autologous stem cell support offers an advantage in terms of progression-free survival in comparison with conventional chemo,” he said. “But, so far, no randomized studies have yet shown any overall survival advantage.”
“Follicular lymphoma has a long natural course, and most patients have received different salvage therapies. Probably, this is why the available phase 3 studies have had insufficient time to confirm the impact on OS.”
To investigate the impact of HDT/ASCT on OS, Dr Grande García and his colleagues conducted a retrospective study of 655 FL patients who received HDT/ASCT from 1989 to 2007. Patients with histological transformation, those undergoing a second transplant, and those with a follow-up of less than 7 years were excluded.
Patient characteristics
The median follow-up was 12 years from HDT/ASCT and 14.4 years from diagnosis. At diagnosis, the median patient age was 47, 49.6% of patients were male, and 90% had stage III/IV disease.
According to FLIPI, 33% of patients were good risk, 36% were intermediate risk, and 31% were poor risk. According to FLIPI-2, the percentages were 22%, 38%, and 40%, respectively. Thirty percent of patients had received rituximab prior to HDT/ASCT.
Thirty-one percent of patients (n=203) were in their first CR at the time of transplant, 43% of whom required more than one line of therapy to reach first CR.
Thirty-one percent of patients (n=202) were in second or third CR, 21.5% (n=149) were in first PR, 12.5% (n=81) were in sensitive relapse (defined as a response other than CR or first PR), and 5% (n=29) had overt disease (which included untreated relapsed disease, first refractory disease, and second refractory disease).
Patients received a variety of conditioning regimens, including total-body irradiation plus cyclophosphamide, BEAM (carmustine, etoposide, cytarabine, and melphalan), BEAC (carmustine, etoposide, cytarabine, and cyclophosphamide), and other regimens. They received stem cells from peripheral blood (81%), bone marrow (14%), or both sources (5%).
There were 4 graft failures and 17 early toxic deaths. Thirty-one percent of patients experienced grade 3/4 hematologic toxicities.
PFS and OS
In all patients, the median PFS was 9.25 years, and the median OS was 19.5 years.
When the researchers looked at outcomes according to patients’ status at transplant, they found the median OS and PFS were not reached among patients in first CR. At a median follow-up of 12.75 years, the OS rate was 72%, and the PFS rate was 68%.
“Beginning at 10 years from transplantation, only 6 patients have died,” Dr Grande García noted, “one from disease progression, 3 from second malignancy, [and] 2 from unrelated causes.”
For patients in second or third CR, the median OS was not reached, and the median PFS was 13.9 years. For those in first PR, the median OS was 15 years, and the median PFS was 2.6 years.
For patients with sensitive disease, the median OS was 5.1 years, and the median PFS was 2 years. For those with overt disease, the median OS was 4.4 years, and the median PFS was 0.5 years.
In multivariate analysis, the following characteristics were significant predictors of OS: being older than 47 years of age (hazard ratio [HR]=1.74, P=0.0001), female sex (HR=0.58, P=0.00004), status at HDT/ASCT (HR=2.06, P<10-5), and receipt of rituximab prior to HDT/ASCT (HR=0.61, P=0.004).
Significant predictors of PFS included age (HR=1.34, P=0.01), sex (HR=0.64, P<10-5), status at HDT/ASCT (HR=2.15, P<10-5), and rituximab use (HR=0.67, P=0.003).
For patients transplanted in first CR, only sex was a significant predictor of PFS (HR=0.48, P=0.008) and OS (HR=0.43, P=0.007).
Secondary malignancies
Overall, 13% of patients developed secondary malignancies, of which 46% were solid neoplasias, 44% were myelodysplastic syndromes/acute myeloid leukemias, and 10% were other malignancies.
The incidence of secondary malignancies at 10 years was 3.5%, and the median time from HDT/ASCT to diagnosis was 16 years. There were no significant differences in the rate of secondary malignancy according to a patient’s status at HDT/ASCT or according to the use of rituximab.
“The incidence of second malignancies is not higher than that reported in other series without transplantation,” Dr Grande García noted.
“[HDT/ASCT] is highly effective, even for patients with poor initial features. A significant number of patients transplanted in CR never relapse and may be considered cured.” 
*Information in the abstract differs from that presented at the meeting.
SAN FRANCISCO—Follicular lymphoma (FL) patients who receive high-dose therapy with autologous stem cell transplant (HDT/ASCT) after they’ve responded to chemotherapy can achieve long-term cancer-free survival, new research suggests.
The study showed that many patients transplanted in complete remission (CR) did not relapse and could be considered cured.
Patients transplanted in their first CR fared the best, as median progression-free survival (PFS) and overall survival (OS) times were not reached.
But even patients transplanted in their second/third CR or in their first partial remission (PR) survived a median of 15 years or more, although their PFS times were shorter, at about 14 years and 3 years, respectively.
Carlos Grande García, MD, of Hospital Universitario 12 de Octubre in Madrid, Spain, presented these results at the 2014 ASH Annual Meeting (abstract 675.)*
“In follicular lymphoma patients, intensification with high-dose therapy and autologous stem cell support offers an advantage in terms of progression-free survival in comparison with conventional chemo,” he said. “But, so far, no randomized studies have yet shown any overall survival advantage.”
“Follicular lymphoma has a long natural course, and most patients have received different salvage therapies. Probably, this is why the available phase 3 studies have had insufficient time to confirm the impact on OS.”
To investigate the impact of HDT/ASCT on OS, Dr Grande García and his colleagues conducted a retrospective study of 655 FL patients who received HDT/ASCT from 1989 to 2007. Patients with histological transformation, those undergoing a second transplant, and those with a follow-up of less than 7 years were excluded.
Patient characteristics
The median follow-up was 12 years from HDT/ASCT and 14.4 years from diagnosis. At diagnosis, the median patient age was 47, 49.6% of patients were male, and 90% had stage III/IV disease.
According to FLIPI, 33% of patients were good risk, 36% were intermediate risk, and 31% were poor risk. According to FLIPI-2, the percentages were 22%, 38%, and 40%, respectively. Thirty percent of patients had received rituximab prior to HDT/ASCT.
Thirty-one percent of patients (n=203) were in their first CR at the time of transplant, 43% of whom required more than one line of therapy to reach first CR.
Thirty-one percent of patients (n=202) were in second or third CR, 21.5% (n=149) were in first PR, 12.5% (n=81) were in sensitive relapse (defined as a response other than CR or first PR), and 5% (n=29) had overt disease (which included untreated relapsed disease, first refractory disease, and second refractory disease).
Patients received a variety of conditioning regimens, including total-body irradiation plus cyclophosphamide, BEAM (carmustine, etoposide, cytarabine, and melphalan), BEAC (carmustine, etoposide, cytarabine, and cyclophosphamide), and other regimens. They received stem cells from peripheral blood (81%), bone marrow (14%), or both sources (5%).
There were 4 graft failures and 17 early toxic deaths. Thirty-one percent of patients experienced grade 3/4 hematologic toxicities.
PFS and OS
In all patients, the median PFS was 9.25 years, and the median OS was 19.5 years.
When the researchers looked at outcomes according to patients’ status at transplant, they found the median OS and PFS were not reached among patients in first CR. At a median follow-up of 12.75 years, the OS rate was 72%, and the PFS rate was 68%.
“Beginning at 10 years from transplantation, only 6 patients have died,” Dr Grande García noted, “one from disease progression, 3 from second malignancy, [and] 2 from unrelated causes.”
For patients in second or third CR, the median OS was not reached, and the median PFS was 13.9 years. For those in first PR, the median OS was 15 years, and the median PFS was 2.6 years.
For patients with sensitive disease, the median OS was 5.1 years, and the median PFS was 2 years. For those with overt disease, the median OS was 4.4 years, and the median PFS was 0.5 years.
In multivariate analysis, the following characteristics were significant predictors of OS: being older than 47 years of age (hazard ratio [HR]=1.74, P=0.0001), female sex (HR=0.58, P=0.00004), status at HDT/ASCT (HR=2.06, P<10-5), and receipt of rituximab prior to HDT/ASCT (HR=0.61, P=0.004).
Significant predictors of PFS included age (HR=1.34, P=0.01), sex (HR=0.64, P<10-5), status at HDT/ASCT (HR=2.15, P<10-5), and rituximab use (HR=0.67, P=0.003).
For patients transplanted in first CR, only sex was a significant predictor of PFS (HR=0.48, P=0.008) and OS (HR=0.43, P=0.007).
Secondary malignancies
Overall, 13% of patients developed secondary malignancies, of which 46% were solid neoplasias, 44% were myelodysplastic syndromes/acute myeloid leukemias, and 10% were other malignancies.
The incidence of secondary malignancies at 10 years was 3.5%, and the median time from HDT/ASCT to diagnosis was 16 years. There were no significant differences in the rate of secondary malignancy according to a patient’s status at HDT/ASCT or according to the use of rituximab.
“The incidence of second malignancies is not higher than that reported in other series without transplantation,” Dr Grande García noted.
“[HDT/ASCT] is highly effective, even for patients with poor initial features. A significant number of patients transplanted in CR never relapse and may be considered cured.”
*Information in the abstract differs from that presented at the meeting.
SAN FRANCISCO—Follicular lymphoma (FL) patients who receive high-dose therapy with autologous stem cell transplant (HDT/ASCT) after they’ve responded to chemotherapy can achieve long-term cancer-free survival, new research suggests.
The study showed that many patients transplanted in complete remission (CR) did not relapse and could be considered cured.
Patients transplanted in their first CR fared the best, as median progression-free survival (PFS) and overall survival (OS) times were not reached.
But even patients transplanted in their second/third CR or in their first partial remission (PR) survived a median of 15 years or more, although their PFS times were shorter, at about 14 years and 3 years, respectively.
Carlos Grande García, MD, of Hospital Universitario 12 de Octubre in Madrid, Spain, presented these results at the 2014 ASH Annual Meeting (abstract 675.)*
“In follicular lymphoma patients, intensification with high-dose therapy and autologous stem cell support offers an advantage in terms of progression-free survival in comparison with conventional chemo,” he said. “But, so far, no randomized studies have yet shown any overall survival advantage.”
“Follicular lymphoma has a long natural course, and most patients have received different salvage therapies. Probably, this is why the available phase 3 studies have had insufficient time to confirm the impact on OS.”
To investigate the impact of HDT/ASCT on OS, Dr Grande García and his colleagues conducted a retrospective study of 655 FL patients who received HDT/ASCT from 1989 to 2007. Patients with histological transformation, those undergoing a second transplant, and those with a follow-up of less than 7 years were excluded.
Patient characteristics
The median follow-up was 12 years from HDT/ASCT and 14.4 years from diagnosis. At diagnosis, the median patient age was 47, 49.6% of patients were male, and 90% had stage III/IV disease.
According to FLIPI, 33% of patients were good risk, 36% were intermediate risk, and 31% were poor risk. According to FLIPI-2, the percentages were 22%, 38%, and 40%, respectively. Thirty percent of patients had received rituximab prior to HDT/ASCT.
Thirty-one percent of patients (n=203) were in their first CR at the time of transplant, 43% of whom required more than one line of therapy to reach first CR.
Thirty-one percent of patients (n=202) were in second or third CR, 21.5% (n=149) were in first PR, 12.5% (n=81) were in sensitive relapse (defined as a response other than CR or first PR), and 5% (n=29) had overt disease (which included untreated relapsed disease, first refractory disease, and second refractory disease).
Patients received a variety of conditioning regimens, including total-body irradiation plus cyclophosphamide, BEAM (carmustine, etoposide, cytarabine, and melphalan), BEAC (carmustine, etoposide, cytarabine, and cyclophosphamide), and other regimens. They received stem cells from peripheral blood (81%), bone marrow (14%), or both sources (5%).
There were 4 graft failures and 17 early toxic deaths. Thirty-one percent of patients experienced grade 3/4 hematologic toxicities.
PFS and OS
In all patients, the median PFS was 9.25 years, and the median OS was 19.5 years.
When the researchers looked at outcomes according to patients’ status at transplant, they found the median OS and PFS were not reached among patients in first CR. At a median follow-up of 12.75 years, the OS rate was 72%, and the PFS rate was 68%.
“Beginning at 10 years from transplantation, only 6 patients have died,” Dr Grande García noted, “one from disease progression, 3 from second malignancy, [and] 2 from unrelated causes.”
For patients in second or third CR, the median OS was not reached, and the median PFS was 13.9 years. For those in first PR, the median OS was 15 years, and the median PFS was 2.6 years.
For patients with sensitive disease, the median OS was 5.1 years, and the median PFS was 2 years. For those with overt disease, the median OS was 4.4 years, and the median PFS was 0.5 years.
In multivariate analysis, the following characteristics were significant predictors of OS: being older than 47 years of age (hazard ratio [HR]=1.74, P=0.0001), female sex (HR=0.58, P=0.00004), status at HDT/ASCT (HR=2.06, P<10-5), and receipt of rituximab prior to HDT/ASCT (HR=0.61, P=0.004).
Significant predictors of PFS included age (HR=1.34, P=0.01), sex (HR=0.64, P<10-5), status at HDT/ASCT (HR=2.15, P<10-5), and rituximab use (HR=0.67, P=0.003).
For patients transplanted in first CR, only sex was a significant predictor of PFS (HR=0.48, P=0.008) and OS (HR=0.43, P=0.007).
Secondary malignancies
Overall, 13% of patients developed secondary malignancies, of which 46% were solid neoplasias, 44% were myelodysplastic syndromes/acute myeloid leukemias, and 10% were other malignancies.
The incidence of secondary malignancies at 10 years was 3.5%, and the median time from HDT/ASCT to diagnosis was 16 years. There were no significant differences in the rate of secondary malignancy according to a patient’s status at HDT/ASCT or according to the use of rituximab.
“The incidence of second malignancies is not higher than that reported in other series without transplantation,” Dr Grande García noted.
“[HDT/ASCT] is highly effective, even for patients with poor initial features. A significant number of patients transplanted in CR never relapse and may be considered cured.”
*Information in the abstract differs from that presented at the meeting.
Antibody shows activity in relapsed/refractory NHL
SAN FRANCISCO—The anti-CD19 antibody M0R208 has demonstrated encouraging single-agent activity in patients with relapsed or refractory non-Hodgkin lymphoma (NHL), according to a presenter at the 2014 ASH Annual Meeting.
“It is encouraging to see results in an NHL study that selects a different target than CD20,” said Kristie Blum, MD, of The Ohio State University in Columbus.
“In particular, it is good to see activity in elderly large-cell lymphoma patients.”
MOR208 is an Fc-engineered humanized monoclonal antibody that targets the CD19 antigen.
“It possesses significantly enhanced antibody-dependent cell-mediated cytotoxicity, a key mechanism for tumor cell killing,” Dr Blum explained. “We have seen previous responses in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL).”
In fact, MOR208 recently received fast-track designation from the US Food and Drug Administration to treat DLBCL.
At ASH, Dr Blum reported on a non-randomized, phase 2a study designed to assess the efficacy and safety of single-agent MOR208 in adults with relapsed or refractory NHL (abstract 3089). The trial was sponsored by MorphoSys AG, the company developing MOR208.
The study included 89 patients—35 with DLBCL, 31 with FL, 12 with mantle cell lymphoma (MCL), and 11 with other indolent NHLs (iNHLs). The patients had a median age of 67 years, were previously treated with rituximab, and were not candidates for high-dose therapy with stem cell support.
The patients were treated over 56 days. MOR208 was given intravenously at 12 mg/kg as 8 weekly doses on days 1, 8, 15, and 22 of each cycle. Patients with at least stable disease continued treatment for another cycle.
After completing 12 weekly doses of treatment, responding patients received maintenance MOR208 every 2 or 4 weeks, depending on the investigator’s decision, until progression.
The results showed overall response rates of 26% for DLBCL patients, 23% for FL patients, and 36% in iNHL patients. No MCL patients responded.
There were 2 complete responses in the DLBCL cohort and 1 complete response each in the FL and iNHL cohorts. Response duration reached 13.8 months.
The drug was well-tolerated with an acceptable toxicity profile, Dr Blum said. The most frequently reported treatment-emergent adverse events of any grade were thrombocytopenia, anemia, and neutropenia, all at 9%.
Infusion-related reactions were reported in 9% of patients and were typically grade 1 or 2. There have been no treatment-related deaths.
Protocols are being developed for trials that combine MOR208 with other anti-lymphoma therapies, with plans to open phase 1/2 trials by mid-2015.
“We plan to take the drug forward in combination with bendamustine or lenalidomide plus rituximab,” Dr Blum said. “By adding the drug into a bendamustine-rituximab combination, we will hit 2 different targets and may see synergistic cell killing.”
SAN FRANCISCO—The anti-CD19 antibody M0R208 has demonstrated encouraging single-agent activity in patients with relapsed or refractory non-Hodgkin lymphoma (NHL), according to a presenter at the 2014 ASH Annual Meeting.
“It is encouraging to see results in an NHL study that selects a different target than CD20,” said Kristie Blum, MD, of The Ohio State University in Columbus.
“In particular, it is good to see activity in elderly large-cell lymphoma patients.”
MOR208 is an Fc-engineered humanized monoclonal antibody that targets the CD19 antigen.
“It possesses significantly enhanced antibody-dependent cell-mediated cytotoxicity, a key mechanism for tumor cell killing,” Dr Blum explained. “We have seen previous responses in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL).”
In fact, MOR208 recently received fast-track designation from the US Food and Drug Administration to treat DLBCL.
At ASH, Dr Blum reported on a non-randomized, phase 2a study designed to assess the efficacy and safety of single-agent MOR208 in adults with relapsed or refractory NHL (abstract 3089). The trial was sponsored by MorphoSys AG, the company developing MOR208.
The study included 89 patients—35 with DLBCL, 31 with FL, 12 with mantle cell lymphoma (MCL), and 11 with other indolent NHLs (iNHLs). The patients had a median age of 67 years, were previously treated with rituximab, and were not candidates for high-dose therapy with stem cell support.
The patients were treated over 56 days. MOR208 was given intravenously at 12 mg/kg as 8 weekly doses on days 1, 8, 15, and 22 of each cycle. Patients with at least stable disease continued treatment for another cycle.
After completing 12 weekly doses of treatment, responding patients received maintenance MOR208 every 2 or 4 weeks, depending on the investigator’s decision, until progression.
The results showed overall response rates of 26% for DLBCL patients, 23% for FL patients, and 36% in iNHL patients. No MCL patients responded.
There were 2 complete responses in the DLBCL cohort and 1 complete response each in the FL and iNHL cohorts. Response duration reached 13.8 months.
The drug was well-tolerated with an acceptable toxicity profile, Dr Blum said. The most frequently reported treatment-emergent adverse events of any grade were thrombocytopenia, anemia, and neutropenia, all at 9%.
Infusion-related reactions were reported in 9% of patients and were typically grade 1 or 2. There have been no treatment-related deaths.
Protocols are being developed for trials that combine MOR208 with other anti-lymphoma therapies, with plans to open phase 1/2 trials by mid-2015.
“We plan to take the drug forward in combination with bendamustine or lenalidomide plus rituximab,” Dr Blum said. “By adding the drug into a bendamustine-rituximab combination, we will hit 2 different targets and may see synergistic cell killing.”
SAN FRANCISCO—The anti-CD19 antibody M0R208 has demonstrated encouraging single-agent activity in patients with relapsed or refractory non-Hodgkin lymphoma (NHL), according to a presenter at the 2014 ASH Annual Meeting.
“It is encouraging to see results in an NHL study that selects a different target than CD20,” said Kristie Blum, MD, of The Ohio State University in Columbus.
“In particular, it is good to see activity in elderly large-cell lymphoma patients.”
MOR208 is an Fc-engineered humanized monoclonal antibody that targets the CD19 antigen.
“It possesses significantly enhanced antibody-dependent cell-mediated cytotoxicity, a key mechanism for tumor cell killing,” Dr Blum explained. “We have seen previous responses in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL).”
In fact, MOR208 recently received fast-track designation from the US Food and Drug Administration to treat DLBCL.
At ASH, Dr Blum reported on a non-randomized, phase 2a study designed to assess the efficacy and safety of single-agent MOR208 in adults with relapsed or refractory NHL (abstract 3089). The trial was sponsored by MorphoSys AG, the company developing MOR208.
The study included 89 patients—35 with DLBCL, 31 with FL, 12 with mantle cell lymphoma (MCL), and 11 with other indolent NHLs (iNHLs). The patients had a median age of 67 years, were previously treated with rituximab, and were not candidates for high-dose therapy with stem cell support.
The patients were treated over 56 days. MOR208 was given intravenously at 12 mg/kg as 8 weekly doses on days 1, 8, 15, and 22 of each cycle. Patients with at least stable disease continued treatment for another cycle.
After completing 12 weekly doses of treatment, responding patients received maintenance MOR208 every 2 or 4 weeks, depending on the investigator’s decision, until progression.
The results showed overall response rates of 26% for DLBCL patients, 23% for FL patients, and 36% in iNHL patients. No MCL patients responded.
There were 2 complete responses in the DLBCL cohort and 1 complete response each in the FL and iNHL cohorts. Response duration reached 13.8 months.
The drug was well-tolerated with an acceptable toxicity profile, Dr Blum said. The most frequently reported treatment-emergent adverse events of any grade were thrombocytopenia, anemia, and neutropenia, all at 9%.
Infusion-related reactions were reported in 9% of patients and were typically grade 1 or 2. There have been no treatment-related deaths.
Protocols are being developed for trials that combine MOR208 with other anti-lymphoma therapies, with plans to open phase 1/2 trials by mid-2015.
“We plan to take the drug forward in combination with bendamustine or lenalidomide plus rituximab,” Dr Blum said. “By adding the drug into a bendamustine-rituximab combination, we will hit 2 different targets and may see synergistic cell killing.”
Drug gets orphan designation for MM & CLL/SLL
The European Medicines Agency (EMA) has granted orphan drug designation for selinexor (KPT-330) to treat multiple myeloma (MM) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), including Richter’s transformation.
Selinexor previously received orphan designation from both the EMA and the US Food and Drug Administration to treat patients with acute myeloid leukemia and those with diffuse large B-cell lymphoma.
Orphan designation is granted to promote the development of drugs that target rare, life-threatening or debilitating conditions and are expected to provide a significant therapeutic advantage over existing treatments.
Orphan designation qualifies a company—in this case, Karyopharm Therapeutics Inc.—for benefits that include targeted scientific advice from the EMA regarding drug development and 10 years of market exclusivity following the drug’s approval.
About selinexor
Selinexor (KPT-330) is a first-in-class, oral selective inhibitor of nuclear export (SINE) compound. Selinexor functions by inhibiting the nuclear export protein XPO1 (also called CRM1).
This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which subsequently reinitiates and amplifies their tumor suppressor function. This is thought to prompt apoptosis in cancer cells while largely sparing normal cells.
Selinexor has shown promise in an ongoing phase 1 study of patients with a range of hematologic malignancies. Results of this trial were presented at the 2014 ASCO Annual Meeting.
At that point, the study included 51 patients who had received selinexor across 8 dose levels, ranging from 3 mg/m2 to 60 mg/m2.
Among the 43 patients evaluable for response, the overall response rate was 28%, and the complete response rate was 5%.
Most adverse events were gastrointestinal in nature, and most of them were grade 1 or 2. The most common adverse events were nausea, anorexia, and fatigue.
There were 3 dose-limiting toxicities, including 1 MM patient with grade 4 thrombocytopenia, 1 follicular lymphoma patient with grade 4 thrombocytopenia, and 1 CLL patient with grade 2 fatigue.
The European Medicines Agency (EMA) has granted orphan drug designation for selinexor (KPT-330) to treat multiple myeloma (MM) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), including Richter’s transformation.
Selinexor previously received orphan designation from both the EMA and the US Food and Drug Administration to treat patients with acute myeloid leukemia and those with diffuse large B-cell lymphoma.
Orphan designation is granted to promote the development of drugs that target rare, life-threatening or debilitating conditions and are expected to provide a significant therapeutic advantage over existing treatments.
Orphan designation qualifies a company—in this case, Karyopharm Therapeutics Inc.—for benefits that include targeted scientific advice from the EMA regarding drug development and 10 years of market exclusivity following the drug’s approval.
About selinexor
Selinexor (KPT-330) is a first-in-class, oral selective inhibitor of nuclear export (SINE) compound. Selinexor functions by inhibiting the nuclear export protein XPO1 (also called CRM1).
This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which subsequently reinitiates and amplifies their tumor suppressor function. This is thought to prompt apoptosis in cancer cells while largely sparing normal cells.
Selinexor has shown promise in an ongoing phase 1 study of patients with a range of hematologic malignancies. Results of this trial were presented at the 2014 ASCO Annual Meeting.
At that point, the study included 51 patients who had received selinexor across 8 dose levels, ranging from 3 mg/m2 to 60 mg/m2.
Among the 43 patients evaluable for response, the overall response rate was 28%, and the complete response rate was 5%.
Most adverse events were gastrointestinal in nature, and most of them were grade 1 or 2. The most common adverse events were nausea, anorexia, and fatigue.
There were 3 dose-limiting toxicities, including 1 MM patient with grade 4 thrombocytopenia, 1 follicular lymphoma patient with grade 4 thrombocytopenia, and 1 CLL patient with grade 2 fatigue.
The European Medicines Agency (EMA) has granted orphan drug designation for selinexor (KPT-330) to treat multiple myeloma (MM) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), including Richter’s transformation.
Selinexor previously received orphan designation from both the EMA and the US Food and Drug Administration to treat patients with acute myeloid leukemia and those with diffuse large B-cell lymphoma.
Orphan designation is granted to promote the development of drugs that target rare, life-threatening or debilitating conditions and are expected to provide a significant therapeutic advantage over existing treatments.
Orphan designation qualifies a company—in this case, Karyopharm Therapeutics Inc.—for benefits that include targeted scientific advice from the EMA regarding drug development and 10 years of market exclusivity following the drug’s approval.
About selinexor
Selinexor (KPT-330) is a first-in-class, oral selective inhibitor of nuclear export (SINE) compound. Selinexor functions by inhibiting the nuclear export protein XPO1 (also called CRM1).
This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which subsequently reinitiates and amplifies their tumor suppressor function. This is thought to prompt apoptosis in cancer cells while largely sparing normal cells.
Selinexor has shown promise in an ongoing phase 1 study of patients with a range of hematologic malignancies. Results of this trial were presented at the 2014 ASCO Annual Meeting.
At that point, the study included 51 patients who had received selinexor across 8 dose levels, ranging from 3 mg/m2 to 60 mg/m2.
Among the 43 patients evaluable for response, the overall response rate was 28%, and the complete response rate was 5%.
Most adverse events were gastrointestinal in nature, and most of them were grade 1 or 2. The most common adverse events were nausea, anorexia, and fatigue.
There were 3 dose-limiting toxicities, including 1 MM patient with grade 4 thrombocytopenia, 1 follicular lymphoma patient with grade 4 thrombocytopenia, and 1 CLL patient with grade 2 fatigue.
EZH2 inhibitor is active in NHL with wild-type EZH2
BARCELONA—A small molecule inhibitor of EZH2 has shown “encouraging” activity in patients with advanced non-Hodgkin lymphoma (NHL), according to researchers.
In a phase 1 study, 4 of 10 heavily pretreated NHL patients responded to the drug, E7438 (also known as EPZ6438), with 1 patient achieving a complete response.
And E7438’s activity was not dependent upon the presence of an EZH2 mutation, as all 4 patients had wild-type EZH2.
The drug also demonstrated activity in a patient with a malignant rhabdoid tumor in the brain.
“In this study, responses were seen in patients with lymphoma who were refractory to, or relapsed after, prior standard treatments, as well as in a patient with a malignant disease for which there is no available standard medical treatment [rhabdoid tumor in the brain],” said study investigator Vincent Ribrag, MD, of Institut Gustave Roussy in Villejuif, France.
Dr Ribrag and his colleagues also found E7438 to be well-tolerated. There were no grade 3 adverse events and only 1 grade 4 event at the maximum dose level.
The researchers presented these data at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics as abstract LBA6. Investigators from Esai and Epizyme, the companies developing E7438, were involved in this trial.
The study included 24 patients who ranged in age from 24 to 84. Twelve patients had solid tumor malignancies, and 12 had NHL. Six patients had diffuse large B-cell lymphoma (DLBCL), 5 had follicular lymphoma (FL), and 1 had marginal zone lymphoma.
All of the patients were heavily pretreated. Fourteen had received between 2 and 4 prior therapies, and 9 had received more than 4 prior treatments.
E7438 was given in 5 dosing cohorts: 100 mg BID (n=6), 200 mg BID (n=3), 400 mg BID (n=3), 800 mg BID (n=6), and 1600 mg BID (n=6).
‘Encouraging activity’
Twenty patients were evaluable for efficacy as of October 20. Among the 10 patients with solid tumor malignancies, 1 responded. The patient with an INI1-deficient malignant rhabdoid tumor achieved a partial response and remains on study.
Four of the 10 evaluable NHL patients achieved a partial response or better, including 1 complete response. Responses were seen across a range of doses, up to the 800 mg BID dose.
Among the 5 evaluable DLBCL patients, 3 achieved a partial response or better. One patient with a partial response subsequently evolved to a complete response upon continued treatment and remains on study at 41 weeks of treatment. One of the 2 patients who achieved a partial response remains on study.
Among the 4 evaluable patients with FL, 1 achieved a partial response and remains on study. Three FL patients achieved stable disease, and 2 of these patients remain on study.
The patient with marginal zone lymphoma achieved stable disease and remains on study.
Confirmatory sequencing in a central lab showed that all 10 NHL patients who were evaluable for efficacy had wild-type EZH2, and responses were observed in both germinal center and non-germinal center lymphoma.
“These results provide encouraging evidence of antitumor activity with [E7438] . . . , including the potential for responses to improve with continued treatment,” said Peter Ho, MD, PhD, chief development officer at Epizyme.
“Given the clinical activity we saw in both wild-type EZH2 and non-germinal center lymphoma patients, our plan for the first phase 2 NHL study is to evaluate EPZ-6438 in DLBCL and FL patients with and without EZH2 mutations.”
‘Little toxicity’
All 24 patients were evaluable for safety and tolerability. The majority of adverse events were grade 1 or 2. Events occurring in more than 10% of patients included asthenia, decreased appetite, and nausea.
The only grade 3/4 treatment-related adverse event was grade 4 thrombocytopenia in 1 patient who received the drug at 1600 mg, which met the criteria for a dose-limiting toxicity.
There were no adverse events that required treatment withdrawal or dose reduction. However, 3 events resulted in dose interruption.
“The maximum tolerated dose was not reached because there was little toxicity observed,” Dr Ribrag said. “Since we saw that the drug was active at doses lower than the maximum dose of 1600 mg twice a day, the dose used for the phase 2 trials planned for 2015 may be lower.”
E7438 was rapidly absorbed and eliminated, with a terminal half-life of 3 to 6 hours. In addition, H3K27Me3 inhibition in the skin, a marker of biologic activity, correlated to treatment exposure, with near maximal inhibition predicted by pharmacokinetic exposure at 800 mg.
Currently, a phase 2 dose of 800 mg BID is under consideration. A final recommendation for the phase 2 dose will be approved by a data monitoring committee based on efficacy, safety, and pharmacokinetic/pharmacodynamic parameters.
BARCELONA—A small molecule inhibitor of EZH2 has shown “encouraging” activity in patients with advanced non-Hodgkin lymphoma (NHL), according to researchers.
In a phase 1 study, 4 of 10 heavily pretreated NHL patients responded to the drug, E7438 (also known as EPZ6438), with 1 patient achieving a complete response.
And E7438’s activity was not dependent upon the presence of an EZH2 mutation, as all 4 patients had wild-type EZH2.
The drug also demonstrated activity in a patient with a malignant rhabdoid tumor in the brain.
“In this study, responses were seen in patients with lymphoma who were refractory to, or relapsed after, prior standard treatments, as well as in a patient with a malignant disease for which there is no available standard medical treatment [rhabdoid tumor in the brain],” said study investigator Vincent Ribrag, MD, of Institut Gustave Roussy in Villejuif, France.
Dr Ribrag and his colleagues also found E7438 to be well-tolerated. There were no grade 3 adverse events and only 1 grade 4 event at the maximum dose level.
The researchers presented these data at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics as abstract LBA6. Investigators from Esai and Epizyme, the companies developing E7438, were involved in this trial.
The study included 24 patients who ranged in age from 24 to 84. Twelve patients had solid tumor malignancies, and 12 had NHL. Six patients had diffuse large B-cell lymphoma (DLBCL), 5 had follicular lymphoma (FL), and 1 had marginal zone lymphoma.
All of the patients were heavily pretreated. Fourteen had received between 2 and 4 prior therapies, and 9 had received more than 4 prior treatments.
E7438 was given in 5 dosing cohorts: 100 mg BID (n=6), 200 mg BID (n=3), 400 mg BID (n=3), 800 mg BID (n=6), and 1600 mg BID (n=6).
‘Encouraging activity’
Twenty patients were evaluable for efficacy as of October 20. Among the 10 patients with solid tumor malignancies, 1 responded. The patient with an INI1-deficient malignant rhabdoid tumor achieved a partial response and remains on study.
Four of the 10 evaluable NHL patients achieved a partial response or better, including 1 complete response. Responses were seen across a range of doses, up to the 800 mg BID dose.
Among the 5 evaluable DLBCL patients, 3 achieved a partial response or better. One patient with a partial response subsequently evolved to a complete response upon continued treatment and remains on study at 41 weeks of treatment. One of the 2 patients who achieved a partial response remains on study.
Among the 4 evaluable patients with FL, 1 achieved a partial response and remains on study. Three FL patients achieved stable disease, and 2 of these patients remain on study.
The patient with marginal zone lymphoma achieved stable disease and remains on study.
Confirmatory sequencing in a central lab showed that all 10 NHL patients who were evaluable for efficacy had wild-type EZH2, and responses were observed in both germinal center and non-germinal center lymphoma.
“These results provide encouraging evidence of antitumor activity with [E7438] . . . , including the potential for responses to improve with continued treatment,” said Peter Ho, MD, PhD, chief development officer at Epizyme.
“Given the clinical activity we saw in both wild-type EZH2 and non-germinal center lymphoma patients, our plan for the first phase 2 NHL study is to evaluate EPZ-6438 in DLBCL and FL patients with and without EZH2 mutations.”
‘Little toxicity’
All 24 patients were evaluable for safety and tolerability. The majority of adverse events were grade 1 or 2. Events occurring in more than 10% of patients included asthenia, decreased appetite, and nausea.
The only grade 3/4 treatment-related adverse event was grade 4 thrombocytopenia in 1 patient who received the drug at 1600 mg, which met the criteria for a dose-limiting toxicity.
There were no adverse events that required treatment withdrawal or dose reduction. However, 3 events resulted in dose interruption.
“The maximum tolerated dose was not reached because there was little toxicity observed,” Dr Ribrag said. “Since we saw that the drug was active at doses lower than the maximum dose of 1600 mg twice a day, the dose used for the phase 2 trials planned for 2015 may be lower.”
E7438 was rapidly absorbed and eliminated, with a terminal half-life of 3 to 6 hours. In addition, H3K27Me3 inhibition in the skin, a marker of biologic activity, correlated to treatment exposure, with near maximal inhibition predicted by pharmacokinetic exposure at 800 mg.
Currently, a phase 2 dose of 800 mg BID is under consideration. A final recommendation for the phase 2 dose will be approved by a data monitoring committee based on efficacy, safety, and pharmacokinetic/pharmacodynamic parameters.
BARCELONA—A small molecule inhibitor of EZH2 has shown “encouraging” activity in patients with advanced non-Hodgkin lymphoma (NHL), according to researchers.
In a phase 1 study, 4 of 10 heavily pretreated NHL patients responded to the drug, E7438 (also known as EPZ6438), with 1 patient achieving a complete response.
And E7438’s activity was not dependent upon the presence of an EZH2 mutation, as all 4 patients had wild-type EZH2.
The drug also demonstrated activity in a patient with a malignant rhabdoid tumor in the brain.
“In this study, responses were seen in patients with lymphoma who were refractory to, or relapsed after, prior standard treatments, as well as in a patient with a malignant disease for which there is no available standard medical treatment [rhabdoid tumor in the brain],” said study investigator Vincent Ribrag, MD, of Institut Gustave Roussy in Villejuif, France.
Dr Ribrag and his colleagues also found E7438 to be well-tolerated. There were no grade 3 adverse events and only 1 grade 4 event at the maximum dose level.
The researchers presented these data at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics as abstract LBA6. Investigators from Esai and Epizyme, the companies developing E7438, were involved in this trial.
The study included 24 patients who ranged in age from 24 to 84. Twelve patients had solid tumor malignancies, and 12 had NHL. Six patients had diffuse large B-cell lymphoma (DLBCL), 5 had follicular lymphoma (FL), and 1 had marginal zone lymphoma.
All of the patients were heavily pretreated. Fourteen had received between 2 and 4 prior therapies, and 9 had received more than 4 prior treatments.
E7438 was given in 5 dosing cohorts: 100 mg BID (n=6), 200 mg BID (n=3), 400 mg BID (n=3), 800 mg BID (n=6), and 1600 mg BID (n=6).
‘Encouraging activity’
Twenty patients were evaluable for efficacy as of October 20. Among the 10 patients with solid tumor malignancies, 1 responded. The patient with an INI1-deficient malignant rhabdoid tumor achieved a partial response and remains on study.
Four of the 10 evaluable NHL patients achieved a partial response or better, including 1 complete response. Responses were seen across a range of doses, up to the 800 mg BID dose.
Among the 5 evaluable DLBCL patients, 3 achieved a partial response or better. One patient with a partial response subsequently evolved to a complete response upon continued treatment and remains on study at 41 weeks of treatment. One of the 2 patients who achieved a partial response remains on study.
Among the 4 evaluable patients with FL, 1 achieved a partial response and remains on study. Three FL patients achieved stable disease, and 2 of these patients remain on study.
The patient with marginal zone lymphoma achieved stable disease and remains on study.
Confirmatory sequencing in a central lab showed that all 10 NHL patients who were evaluable for efficacy had wild-type EZH2, and responses were observed in both germinal center and non-germinal center lymphoma.
“These results provide encouraging evidence of antitumor activity with [E7438] . . . , including the potential for responses to improve with continued treatment,” said Peter Ho, MD, PhD, chief development officer at Epizyme.
“Given the clinical activity we saw in both wild-type EZH2 and non-germinal center lymphoma patients, our plan for the first phase 2 NHL study is to evaluate EPZ-6438 in DLBCL and FL patients with and without EZH2 mutations.”
‘Little toxicity’
All 24 patients were evaluable for safety and tolerability. The majority of adverse events were grade 1 or 2. Events occurring in more than 10% of patients included asthenia, decreased appetite, and nausea.
The only grade 3/4 treatment-related adverse event was grade 4 thrombocytopenia in 1 patient who received the drug at 1600 mg, which met the criteria for a dose-limiting toxicity.
There were no adverse events that required treatment withdrawal or dose reduction. However, 3 events resulted in dose interruption.
“The maximum tolerated dose was not reached because there was little toxicity observed,” Dr Ribrag said. “Since we saw that the drug was active at doses lower than the maximum dose of 1600 mg twice a day, the dose used for the phase 2 trials planned for 2015 may be lower.”
E7438 was rapidly absorbed and eliminated, with a terminal half-life of 3 to 6 hours. In addition, H3K27Me3 inhibition in the skin, a marker of biologic activity, correlated to treatment exposure, with near maximal inhibition predicted by pharmacokinetic exposure at 800 mg.
Currently, a phase 2 dose of 800 mg BID is under consideration. A final recommendation for the phase 2 dose will be approved by a data monitoring committee based on efficacy, safety, and pharmacokinetic/pharmacodynamic parameters.
Chemo and CAR T cells prompt responses in NHL
An infusion of chimeric antigen receptor (CAR) T-cell therapy following chemotherapy can elicit responses in patients with non-Hodgkin lymphoma, a small study suggests.
However, patients also experienced significant acute toxicities, including fever, low blood pressure, focal neurological deficits, and delirium.
James N. Kochenderfer, MD, of the National Institutes of Health in Bethesda, Maryland, and his colleagues reported these results in the Journal of Clinical Oncology.
The trial was sponsored by the National Cancer Institute, but the CAR T-cell therapy being tested uses the same CAR construct as KTE-C19, which is being developed by Kite Pharma, Inc.
The study included 15 patients with advanced B-cell malignancies. The patients first received conditioning with cyclophosphamide and fludarabine.
A day later, they received a single infusion of the CAR T-cell therapy, which consists of T cells taken from each patient’s peripheral blood and modified to target CD19.
The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.
Response rates
Thirteen patients were evaluable for response. One patient was lost to follow-up because of noncompliance, and 1 died soon after treatment. The researchers said the cause of death was likely cardiac arrhythmia.
The overall response rate was 92%. Eight patients achieved a complete response (CR), and 4 had a partial response (PR).
Of the 7 patients with chemotherapy-refractory diffuse large B-cell lymphoma, 4 achieved a CR, 2 achieved a PR, and 1 had stable disease. Three of the CRs are ongoing, with the duration ranging from 9 months to 22 months.
Of the 4 patients with chronic lymphocytic leukemia, 3 had a CR, and 1 had a PR. All 3 CRs are ongoing, with the duration ranging from 14 months to 23 months.
Among the 2 patients with indolent lymphomas, 1 achieved a CR, and 1 had a PR. The duration of the ongoing CR is 11 months.
Toxicity
As seen in other studies, the CAR T-cell therapy was associated with fever, low blood pressure, focal neurological deficits, and delirium. Toxicities largely occurred in the first 2 weeks after infusion.
All but 2 patients experienced grade 3/4 adverse events. Four patients had grade 3/4 hypotension.
All patients had elevations in serum interferon gamma and/or IL-6 around the time of peak toxicity, but most did not develop elevations in serum tumor necrosis factor.
Neurologic toxicities included confusion and obtundation, which have been reported in previous studies. However, 3 patients developed unexpected neurologic abnormalities.
One of these patients developed aphasia on day 5 after CAR T-cell infusion. It occurred intermittently for 7 days before resolving. The patient also experienced right-sided facial paresis that lasted approximately 20 minutes on day 8 after infusion.
Another patient developed aphasia 5 days after CAR T-cell infusion, but this was followed by confusion and severe generalized myoclonus. All symptoms resolved by 11 days after the infusion, except for a mild tremor that resolved over the next month.
A third patient developed aphasia 5 days after CAR T-cell infusion. This was followed by confusion, hemifacial spasms, apraxia, and gait disturbances. These effects varied in severity but dramatically improved 20 days after the infusion, according to the researchers.
An infusion of chimeric antigen receptor (CAR) T-cell therapy following chemotherapy can elicit responses in patients with non-Hodgkin lymphoma, a small study suggests.
However, patients also experienced significant acute toxicities, including fever, low blood pressure, focal neurological deficits, and delirium.
James N. Kochenderfer, MD, of the National Institutes of Health in Bethesda, Maryland, and his colleagues reported these results in the Journal of Clinical Oncology.
The trial was sponsored by the National Cancer Institute, but the CAR T-cell therapy being tested uses the same CAR construct as KTE-C19, which is being developed by Kite Pharma, Inc.
The study included 15 patients with advanced B-cell malignancies. The patients first received conditioning with cyclophosphamide and fludarabine.
A day later, they received a single infusion of the CAR T-cell therapy, which consists of T cells taken from each patient’s peripheral blood and modified to target CD19.
The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.
Response rates
Thirteen patients were evaluable for response. One patient was lost to follow-up because of noncompliance, and 1 died soon after treatment. The researchers said the cause of death was likely cardiac arrhythmia.
The overall response rate was 92%. Eight patients achieved a complete response (CR), and 4 had a partial response (PR).
Of the 7 patients with chemotherapy-refractory diffuse large B-cell lymphoma, 4 achieved a CR, 2 achieved a PR, and 1 had stable disease. Three of the CRs are ongoing, with the duration ranging from 9 months to 22 months.
Of the 4 patients with chronic lymphocytic leukemia, 3 had a CR, and 1 had a PR. All 3 CRs are ongoing, with the duration ranging from 14 months to 23 months.
Among the 2 patients with indolent lymphomas, 1 achieved a CR, and 1 had a PR. The duration of the ongoing CR is 11 months.
Toxicity
As seen in other studies, the CAR T-cell therapy was associated with fever, low blood pressure, focal neurological deficits, and delirium. Toxicities largely occurred in the first 2 weeks after infusion.
All but 2 patients experienced grade 3/4 adverse events. Four patients had grade 3/4 hypotension.
All patients had elevations in serum interferon gamma and/or IL-6 around the time of peak toxicity, but most did not develop elevations in serum tumor necrosis factor.
Neurologic toxicities included confusion and obtundation, which have been reported in previous studies. However, 3 patients developed unexpected neurologic abnormalities.
One of these patients developed aphasia on day 5 after CAR T-cell infusion. It occurred intermittently for 7 days before resolving. The patient also experienced right-sided facial paresis that lasted approximately 20 minutes on day 8 after infusion.
Another patient developed aphasia 5 days after CAR T-cell infusion, but this was followed by confusion and severe generalized myoclonus. All symptoms resolved by 11 days after the infusion, except for a mild tremor that resolved over the next month.
A third patient developed aphasia 5 days after CAR T-cell infusion. This was followed by confusion, hemifacial spasms, apraxia, and gait disturbances. These effects varied in severity but dramatically improved 20 days after the infusion, according to the researchers.
An infusion of chimeric antigen receptor (CAR) T-cell therapy following chemotherapy can elicit responses in patients with non-Hodgkin lymphoma, a small study suggests.
However, patients also experienced significant acute toxicities, including fever, low blood pressure, focal neurological deficits, and delirium.
James N. Kochenderfer, MD, of the National Institutes of Health in Bethesda, Maryland, and his colleagues reported these results in the Journal of Clinical Oncology.
The trial was sponsored by the National Cancer Institute, but the CAR T-cell therapy being tested uses the same CAR construct as KTE-C19, which is being developed by Kite Pharma, Inc.
The study included 15 patients with advanced B-cell malignancies. The patients first received conditioning with cyclophosphamide and fludarabine.
A day later, they received a single infusion of the CAR T-cell therapy, which consists of T cells taken from each patient’s peripheral blood and modified to target CD19.
The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.
Response rates
Thirteen patients were evaluable for response. One patient was lost to follow-up because of noncompliance, and 1 died soon after treatment. The researchers said the cause of death was likely cardiac arrhythmia.
The overall response rate was 92%. Eight patients achieved a complete response (CR), and 4 had a partial response (PR).
Of the 7 patients with chemotherapy-refractory diffuse large B-cell lymphoma, 4 achieved a CR, 2 achieved a PR, and 1 had stable disease. Three of the CRs are ongoing, with the duration ranging from 9 months to 22 months.
Of the 4 patients with chronic lymphocytic leukemia, 3 had a CR, and 1 had a PR. All 3 CRs are ongoing, with the duration ranging from 14 months to 23 months.
Among the 2 patients with indolent lymphomas, 1 achieved a CR, and 1 had a PR. The duration of the ongoing CR is 11 months.
Toxicity
As seen in other studies, the CAR T-cell therapy was associated with fever, low blood pressure, focal neurological deficits, and delirium. Toxicities largely occurred in the first 2 weeks after infusion.
All but 2 patients experienced grade 3/4 adverse events. Four patients had grade 3/4 hypotension.
All patients had elevations in serum interferon gamma and/or IL-6 around the time of peak toxicity, but most did not develop elevations in serum tumor necrosis factor.
Neurologic toxicities included confusion and obtundation, which have been reported in previous studies. However, 3 patients developed unexpected neurologic abnormalities.
One of these patients developed aphasia on day 5 after CAR T-cell infusion. It occurred intermittently for 7 days before resolving. The patient also experienced right-sided facial paresis that lasted approximately 20 minutes on day 8 after infusion.
Another patient developed aphasia 5 days after CAR T-cell infusion, but this was followed by confusion and severe generalized myoclonus. All symptoms resolved by 11 days after the infusion, except for a mild tremor that resolved over the next month.
A third patient developed aphasia 5 days after CAR T-cell infusion. This was followed by confusion, hemifacial spasms, apraxia, and gait disturbances. These effects varied in severity but dramatically improved 20 days after the infusion, according to the researchers.
Combo appears safe and active in CLL, NHL
Credit: Linda Bartlett
KOHALA COAST, HAWAII—Early results of a small, phase 1 study suggest a novel combination treatment is active and generally well-tolerated in relapsed or refractory patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) or non-Hodgkin lymphomas (NHLs).
The treatment consists of ublituximab (TG-1101), a monoclonal antibody that targets a unique epitope on the CD20 antigen, and TGR-1202, a next-generation PI3K delta inhibitor.
The combination appeared to be well tolerated overall, although infusion-related reactions were common, and nearly a quarter of patients experienced grade 3/4 neutropenia.
Four of 5 CLL/SLL patients experienced a partial response (PR), and the remaining patient had stable disease (SD). Among the 10 NHL patients, 1 had progressive disease, 7 had SD, and 2 achieved a PR.
Matthew Lunning, DO, of the University of Nebraska Medical Center in Omaha, and his colleagues presented these results in a poster at the 2014 Pan Pacific Lymphoma Conference.
The study is sponsored by TG Therapeutics, the company developing both drugs.
The researchers presented results from 8 patients with CLL/SLL, 7 patients with diffuse large B-cell lymphoma (DLBCL), 5 with follicular lymphoma (FL), and 1 patient with Richter’s syndrome (RS).
Patients had a median age of 64 years (range, 35-82), and they had received a median of 3 prior therapies (range, 1-9). Fifty-seven percent of patients had received 3 or more prior therapies, and 38% were refractory to their prior therapy.
The patients received escalating doses of TGR-1202, with a fixed dose of ublituximab—900 mg for patients with NHL and 600 mg for patients with CLL.
As of the data cutoff, all 21 patients were evaluable for safety, but only 15 were evaluable for efficacy.
Adverse events
The most common adverse event was infusion-related reactions, which occurred in 48% of patients. All of these events were manageable without dose reductions, and all but 1 event was grade 1 or 2 in severity.
Neutropenia was also common, occurring in 38% of patients. Grade 3/4 neutropenia occurred in 24% of patients. One CLL patient required a dose delay for neutropenia in cycle 1, which met the criteria for a dose-limiting toxicity.
No additional dose-limiting toxicities have been observed to date. Likewise, none of the patients has required dose reductions for either drug, and there were no drug-related AST/ALT elevations.
On the other hand, 1 patient did come off the study due to grade 1 itching that was possibly related to TGR-1202.
Other common adverse events associated with treatment included diarrhea (29%), nausea (29%), hoarseness (10%), muscle aches (10%), and fatigue (10%).
Activity in CLL/SLL
Of the 8 CLL/SLL patients enrolled to date, 5 were evaluable for efficacy. Four patients achieved a PR at the first efficacy assessment. The remaining patient, a CLL patient with both 17p and 11q del, achieved SD with a 44% nodal reduction at the first assessment.
All 5 patients achieved a greater-than-50% reduction in ALC by the first efficacy assessment. One patient achieved complete normalization of ALC (less than 4000/uL), and the other 4 patients achieved at least an 80% reduction by the first efficacy assessment.
The lymphocytosis generally observed in CLL patients treated with TGR-1202, similar to other PI3K delta and BTK inhibitors, appears to be mitigated by the addition of ublituximab.
Activity in NHL
Of the 13 patients in this group, 10 were evaluable for efficacy, including 5 with DLBCL, 4 with FL, and 1 with RS. Results were not as favorable in this group as they were among CLL/SLL patients, but, as the researchers pointed out, these patients were heavily pretreated.
Among the DLBCL patients, 2 achieved PRs with TGR-1202 and ublituximab. Both of these responses occurred at the higher dose of TGR-1202.
Two DLBCL patients had SD, and 1 patient progressed. DLBCL patients had a median of 3 prior treatment lines, and 3 patients had GCB DLBCL, with 1 patient classified as triple-hit lymphoma (overexpression of BCL2, BCL6, and MYC rearrangements).
In the FL group, all 4 patients had SD after treatment and exhibited a reduction in tumor mass at the first assessment. These patients had advanced disease and a median of 6 prior lines of therapy.
The RS patient also had SD following TGR-1202 and ublituximab.
“We have been very impressed with the safety profile and the level of activity observed to date in all patient groups with TGR-1202 in combination with ublituximab, particularly given the advanced stage of disease . . . ,” said Susan O’Brien, MD, a professor at MD Anderson Cancer Center in Houston and study chair for the CLL patient group.
“Of particular interest is the absence of observed elevations in AST/ALT with TGR-1202, which is a known adverse event associated with other PI3K delta inhibitors. We look forward to continuing enrollment at all trial centers of this exciting combination and presenting data on more patients at upcoming medical meetings.”
Credit: Linda Bartlett
KOHALA COAST, HAWAII—Early results of a small, phase 1 study suggest a novel combination treatment is active and generally well-tolerated in relapsed or refractory patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) or non-Hodgkin lymphomas (NHLs).
The treatment consists of ublituximab (TG-1101), a monoclonal antibody that targets a unique epitope on the CD20 antigen, and TGR-1202, a next-generation PI3K delta inhibitor.
The combination appeared to be well tolerated overall, although infusion-related reactions were common, and nearly a quarter of patients experienced grade 3/4 neutropenia.
Four of 5 CLL/SLL patients experienced a partial response (PR), and the remaining patient had stable disease (SD). Among the 10 NHL patients, 1 had progressive disease, 7 had SD, and 2 achieved a PR.
Matthew Lunning, DO, of the University of Nebraska Medical Center in Omaha, and his colleagues presented these results in a poster at the 2014 Pan Pacific Lymphoma Conference.
The study is sponsored by TG Therapeutics, the company developing both drugs.
The researchers presented results from 8 patients with CLL/SLL, 7 patients with diffuse large B-cell lymphoma (DLBCL), 5 with follicular lymphoma (FL), and 1 patient with Richter’s syndrome (RS).
Patients had a median age of 64 years (range, 35-82), and they had received a median of 3 prior therapies (range, 1-9). Fifty-seven percent of patients had received 3 or more prior therapies, and 38% were refractory to their prior therapy.
The patients received escalating doses of TGR-1202, with a fixed dose of ublituximab—900 mg for patients with NHL and 600 mg for patients with CLL.
As of the data cutoff, all 21 patients were evaluable for safety, but only 15 were evaluable for efficacy.
Adverse events
The most common adverse event was infusion-related reactions, which occurred in 48% of patients. All of these events were manageable without dose reductions, and all but 1 event was grade 1 or 2 in severity.
Neutropenia was also common, occurring in 38% of patients. Grade 3/4 neutropenia occurred in 24% of patients. One CLL patient required a dose delay for neutropenia in cycle 1, which met the criteria for a dose-limiting toxicity.
No additional dose-limiting toxicities have been observed to date. Likewise, none of the patients has required dose reductions for either drug, and there were no drug-related AST/ALT elevations.
On the other hand, 1 patient did come off the study due to grade 1 itching that was possibly related to TGR-1202.
Other common adverse events associated with treatment included diarrhea (29%), nausea (29%), hoarseness (10%), muscle aches (10%), and fatigue (10%).
Activity in CLL/SLL
Of the 8 CLL/SLL patients enrolled to date, 5 were evaluable for efficacy. Four patients achieved a PR at the first efficacy assessment. The remaining patient, a CLL patient with both 17p and 11q del, achieved SD with a 44% nodal reduction at the first assessment.
All 5 patients achieved a greater-than-50% reduction in ALC by the first efficacy assessment. One patient achieved complete normalization of ALC (less than 4000/uL), and the other 4 patients achieved at least an 80% reduction by the first efficacy assessment.
The lymphocytosis generally observed in CLL patients treated with TGR-1202, similar to other PI3K delta and BTK inhibitors, appears to be mitigated by the addition of ublituximab.
Activity in NHL
Of the 13 patients in this group, 10 were evaluable for efficacy, including 5 with DLBCL, 4 with FL, and 1 with RS. Results were not as favorable in this group as they were among CLL/SLL patients, but, as the researchers pointed out, these patients were heavily pretreated.
Among the DLBCL patients, 2 achieved PRs with TGR-1202 and ublituximab. Both of these responses occurred at the higher dose of TGR-1202.
Two DLBCL patients had SD, and 1 patient progressed. DLBCL patients had a median of 3 prior treatment lines, and 3 patients had GCB DLBCL, with 1 patient classified as triple-hit lymphoma (overexpression of BCL2, BCL6, and MYC rearrangements).
In the FL group, all 4 patients had SD after treatment and exhibited a reduction in tumor mass at the first assessment. These patients had advanced disease and a median of 6 prior lines of therapy.
The RS patient also had SD following TGR-1202 and ublituximab.
“We have been very impressed with the safety profile and the level of activity observed to date in all patient groups with TGR-1202 in combination with ublituximab, particularly given the advanced stage of disease . . . ,” said Susan O’Brien, MD, a professor at MD Anderson Cancer Center in Houston and study chair for the CLL patient group.
“Of particular interest is the absence of observed elevations in AST/ALT with TGR-1202, which is a known adverse event associated with other PI3K delta inhibitors. We look forward to continuing enrollment at all trial centers of this exciting combination and presenting data on more patients at upcoming medical meetings.”
Credit: Linda Bartlett
KOHALA COAST, HAWAII—Early results of a small, phase 1 study suggest a novel combination treatment is active and generally well-tolerated in relapsed or refractory patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) or non-Hodgkin lymphomas (NHLs).
The treatment consists of ublituximab (TG-1101), a monoclonal antibody that targets a unique epitope on the CD20 antigen, and TGR-1202, a next-generation PI3K delta inhibitor.
The combination appeared to be well tolerated overall, although infusion-related reactions were common, and nearly a quarter of patients experienced grade 3/4 neutropenia.
Four of 5 CLL/SLL patients experienced a partial response (PR), and the remaining patient had stable disease (SD). Among the 10 NHL patients, 1 had progressive disease, 7 had SD, and 2 achieved a PR.
Matthew Lunning, DO, of the University of Nebraska Medical Center in Omaha, and his colleagues presented these results in a poster at the 2014 Pan Pacific Lymphoma Conference.
The study is sponsored by TG Therapeutics, the company developing both drugs.
The researchers presented results from 8 patients with CLL/SLL, 7 patients with diffuse large B-cell lymphoma (DLBCL), 5 with follicular lymphoma (FL), and 1 patient with Richter’s syndrome (RS).
Patients had a median age of 64 years (range, 35-82), and they had received a median of 3 prior therapies (range, 1-9). Fifty-seven percent of patients had received 3 or more prior therapies, and 38% were refractory to their prior therapy.
The patients received escalating doses of TGR-1202, with a fixed dose of ublituximab—900 mg for patients with NHL and 600 mg for patients with CLL.
As of the data cutoff, all 21 patients were evaluable for safety, but only 15 were evaluable for efficacy.
Adverse events
The most common adverse event was infusion-related reactions, which occurred in 48% of patients. All of these events were manageable without dose reductions, and all but 1 event was grade 1 or 2 in severity.
Neutropenia was also common, occurring in 38% of patients. Grade 3/4 neutropenia occurred in 24% of patients. One CLL patient required a dose delay for neutropenia in cycle 1, which met the criteria for a dose-limiting toxicity.
No additional dose-limiting toxicities have been observed to date. Likewise, none of the patients has required dose reductions for either drug, and there were no drug-related AST/ALT elevations.
On the other hand, 1 patient did come off the study due to grade 1 itching that was possibly related to TGR-1202.
Other common adverse events associated with treatment included diarrhea (29%), nausea (29%), hoarseness (10%), muscle aches (10%), and fatigue (10%).
Activity in CLL/SLL
Of the 8 CLL/SLL patients enrolled to date, 5 were evaluable for efficacy. Four patients achieved a PR at the first efficacy assessment. The remaining patient, a CLL patient with both 17p and 11q del, achieved SD with a 44% nodal reduction at the first assessment.
All 5 patients achieved a greater-than-50% reduction in ALC by the first efficacy assessment. One patient achieved complete normalization of ALC (less than 4000/uL), and the other 4 patients achieved at least an 80% reduction by the first efficacy assessment.
The lymphocytosis generally observed in CLL patients treated with TGR-1202, similar to other PI3K delta and BTK inhibitors, appears to be mitigated by the addition of ublituximab.
Activity in NHL
Of the 13 patients in this group, 10 were evaluable for efficacy, including 5 with DLBCL, 4 with FL, and 1 with RS. Results were not as favorable in this group as they were among CLL/SLL patients, but, as the researchers pointed out, these patients were heavily pretreated.
Among the DLBCL patients, 2 achieved PRs with TGR-1202 and ublituximab. Both of these responses occurred at the higher dose of TGR-1202.
Two DLBCL patients had SD, and 1 patient progressed. DLBCL patients had a median of 3 prior treatment lines, and 3 patients had GCB DLBCL, with 1 patient classified as triple-hit lymphoma (overexpression of BCL2, BCL6, and MYC rearrangements).
In the FL group, all 4 patients had SD after treatment and exhibited a reduction in tumor mass at the first assessment. These patients had advanced disease and a median of 6 prior lines of therapy.
The RS patient also had SD following TGR-1202 and ublituximab.
“We have been very impressed with the safety profile and the level of activity observed to date in all patient groups with TGR-1202 in combination with ublituximab, particularly given the advanced stage of disease . . . ,” said Susan O’Brien, MD, a professor at MD Anderson Cancer Center in Houston and study chair for the CLL patient group.
“Of particular interest is the absence of observed elevations in AST/ALT with TGR-1202, which is a known adverse event associated with other PI3K delta inhibitors. We look forward to continuing enrollment at all trial centers of this exciting combination and presenting data on more patients at upcoming medical meetings.”
Drug approved to treat NHL in Israel
The Israeli Ministry of Health has granted approval for the antineoplastic agent pixantrone (Pixuvri).
The drug is now approved as monotherapy for adults with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (NHL) who have received fewer than 4 previous courses of treatment.
The benefit of pixantrone has not been established when used as fifth-line or greater treatment in patients who were refractory to their last therapy.
Pixantrone will be distributed in Israel by the Neopharm Group.
“The approval of Pixuvri in Israel provides patients with aggressive B-cell NHL who have failed second- or third-line therapy a new approved option, where none existed before, that can effectively treat their disease with manageable side effects,” said Abraham Avigdor, MD, of Tel Aviv University.
“Patients who have relapsed after second-line therapy have a poor survival outcome. It is vital to have additional treatment options available, like Pixuvri, so we can provide these patients the best care possible and help them battle their disease.”
The main study of pixantrone, the phase 3 EXTEND PIX301 trial, compared the drug to other chemotherapeutic agents in patients with relapsed or refractory NHL. The response rate was 20% in the pixantrone arm and 6% in the comparator arm.
In addition, patients receiving pixantrone had longer progression-free survival than patients in the comparator group, with a median of 10.2 months and 7.6 months, respectively.
However, grade 3/4 adverse events—including neutropenia, leukopenia, and thrombocytopenia—were more common in the pixantrone arm.
Pixantrone is already marketed in the European Union. In 2012, the European Commission granted conditional marketing authorization for the drug as monotherapy for adults with relapsed or refractory aggressive B-cell NHL.
Under the provisions of the conditional marketing authorization, Cell Therapeutics, Inc., the company developing pixantrone, will be required to complete a post-marketing study aimed at confirming the drug’s clinical benefit.
The European Medicines Agency’s Committee for Medicinal Products for Human Use has accepted PIX306, a randomized, phase 3 trial comparing pixantrone plus rituximab to gemcitabine plus rituximab in patients who have relapsed after 1 to 3 prior regimens for aggressive B-cell NHL and who are not eligible for autologous stem cell transplant.
As a condition of approval, Cell Therapeutics has agreed to have the trial data available by June 2015.
Pixantrone is not approved for use in the US.
The Israeli Ministry of Health has granted approval for the antineoplastic agent pixantrone (Pixuvri).
The drug is now approved as monotherapy for adults with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (NHL) who have received fewer than 4 previous courses of treatment.
The benefit of pixantrone has not been established when used as fifth-line or greater treatment in patients who were refractory to their last therapy.
Pixantrone will be distributed in Israel by the Neopharm Group.
“The approval of Pixuvri in Israel provides patients with aggressive B-cell NHL who have failed second- or third-line therapy a new approved option, where none existed before, that can effectively treat their disease with manageable side effects,” said Abraham Avigdor, MD, of Tel Aviv University.
“Patients who have relapsed after second-line therapy have a poor survival outcome. It is vital to have additional treatment options available, like Pixuvri, so we can provide these patients the best care possible and help them battle their disease.”
The main study of pixantrone, the phase 3 EXTEND PIX301 trial, compared the drug to other chemotherapeutic agents in patients with relapsed or refractory NHL. The response rate was 20% in the pixantrone arm and 6% in the comparator arm.
In addition, patients receiving pixantrone had longer progression-free survival than patients in the comparator group, with a median of 10.2 months and 7.6 months, respectively.
However, grade 3/4 adverse events—including neutropenia, leukopenia, and thrombocytopenia—were more common in the pixantrone arm.
Pixantrone is already marketed in the European Union. In 2012, the European Commission granted conditional marketing authorization for the drug as monotherapy for adults with relapsed or refractory aggressive B-cell NHL.
Under the provisions of the conditional marketing authorization, Cell Therapeutics, Inc., the company developing pixantrone, will be required to complete a post-marketing study aimed at confirming the drug’s clinical benefit.
The European Medicines Agency’s Committee for Medicinal Products for Human Use has accepted PIX306, a randomized, phase 3 trial comparing pixantrone plus rituximab to gemcitabine plus rituximab in patients who have relapsed after 1 to 3 prior regimens for aggressive B-cell NHL and who are not eligible for autologous stem cell transplant.
As a condition of approval, Cell Therapeutics has agreed to have the trial data available by June 2015.
Pixantrone is not approved for use in the US.
The Israeli Ministry of Health has granted approval for the antineoplastic agent pixantrone (Pixuvri).
The drug is now approved as monotherapy for adults with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (NHL) who have received fewer than 4 previous courses of treatment.
The benefit of pixantrone has not been established when used as fifth-line or greater treatment in patients who were refractory to their last therapy.
Pixantrone will be distributed in Israel by the Neopharm Group.
“The approval of Pixuvri in Israel provides patients with aggressive B-cell NHL who have failed second- or third-line therapy a new approved option, where none existed before, that can effectively treat their disease with manageable side effects,” said Abraham Avigdor, MD, of Tel Aviv University.
“Patients who have relapsed after second-line therapy have a poor survival outcome. It is vital to have additional treatment options available, like Pixuvri, so we can provide these patients the best care possible and help them battle their disease.”
The main study of pixantrone, the phase 3 EXTEND PIX301 trial, compared the drug to other chemotherapeutic agents in patients with relapsed or refractory NHL. The response rate was 20% in the pixantrone arm and 6% in the comparator arm.
In addition, patients receiving pixantrone had longer progression-free survival than patients in the comparator group, with a median of 10.2 months and 7.6 months, respectively.
However, grade 3/4 adverse events—including neutropenia, leukopenia, and thrombocytopenia—were more common in the pixantrone arm.
Pixantrone is already marketed in the European Union. In 2012, the European Commission granted conditional marketing authorization for the drug as monotherapy for adults with relapsed or refractory aggressive B-cell NHL.
Under the provisions of the conditional marketing authorization, Cell Therapeutics, Inc., the company developing pixantrone, will be required to complete a post-marketing study aimed at confirming the drug’s clinical benefit.
The European Medicines Agency’s Committee for Medicinal Products for Human Use has accepted PIX306, a randomized, phase 3 trial comparing pixantrone plus rituximab to gemcitabine plus rituximab in patients who have relapsed after 1 to 3 prior regimens for aggressive B-cell NHL and who are not eligible for autologous stem cell transplant.
As a condition of approval, Cell Therapeutics has agreed to have the trial data available by June 2015.
Pixantrone is not approved for use in the US.