Non-Hodgkin Lymphoma

Micrograph showing DLBCL

Interim results of a phase 1/2 trial suggest KTE-C19, a chimeric antigen receptor (CAR) T-cell therapy, can be effective against aggressive non-Hodgkin lymphoma (NHL).

KTE-C19, administered after conditioning chemotherapy, produced an overall response rate (ORR) of

79% and a complete response (CR) rate of 52%.

However, the therapy also caused severe adverse events (AEs), and there were 2 deaths resulting from KTE-C19-related AEs.

Kite Pharma, Inc., the company developing KTE-C19, released these results and said additional data from this trial, known as ZUMA-1, will be submitted for presentation at an upcoming scientific meeting.

ZUMA-1 has enrolled patients with chemo-refractory, aggressive NHL. The phase 1 portion of the trial included 7 patients with diffuse large B-cell lymphoma (DLBCL).

Thus far, the phase 2 portion includes 62 NHL patients—51 with DLBCL and 11 with transformed follicular lymphoma (TFL) or primary mediastinal B-cell lymphoma (PMBCL).

The patients received a conditioning chemotherapy regimen of fludarabine and cyclophosphamide, followed by a single infusion of KTE-C19 (at a target dose of 2 x 10⁶ CAR T cells/kg).

Responses

In the phase 1 portion of the trial (n=7), the initial ORR was 71%, and the CR rate was 57%. At 3 months of follow-up, the ORR and CR rate were both 43%. The response rates remained the same at 6 months and 9 months of follow-up.

In the phase 2 portion of the trial, for all 62 patients, the initial ORR was 79%, and the CR rate was 52%. At 3 months, the ORR was 44%, and the CR rate was 39%.

Among the 51 patients with DLBCL, the initial ORR was 76%, and the CR rate was 47%. At 3 months, the ORR was 39%, and the CR rate was 33%.

Among the 11 patients with TFL or PMBCL, the initial ORR was 91%, and the CR rate was 73%. At 3 months, the ORR and CR rates were 64%.

Longer follow-up data are not yet available for the phase 2 portion of the study.

Safety

For all 62 patients, the most common grade 3 or higher AEs were neutropenia (66%), anemia (40%), febrile neutropenia (29%), thrombocytopenia (29%), and encephalopathy (26%).

Grade 3 or higher cytokine release syndrome occurred in 18% of patients, and neurological toxicity occurred in 34%.

Two patients died from KTE-C19-related AEs—hemophagocytic lymphohistiocytosis and cardiac arrest in the setting of cytokine release syndrome.

Kite Pharma said the primary analysis from this study will include 101 patients with chemo-refractory NHL (DLBCL, TFL, and PMBCL), will have approximately 6 months of follow-up, and is expected in the first quarter of 2017.

ZUMA-1 is supported, in part, by funding from The Leukemia & Lymphoma Society Therapy Acceleration Program.

Micrograph showing DLBCL

Interim results of a phase 1/2 trial suggest KTE-C19, a chimeric antigen receptor (CAR) T-cell therapy, can be effective against aggressive non-Hodgkin lymphoma (NHL).

KTE-C19, administered after conditioning chemotherapy, produced an overall response rate (ORR) of

79% and a complete response (CR) rate of 52%.

However, the therapy also caused severe adverse events (AEs), and there were 2 deaths resulting from KTE-C19-related AEs.

Kite Pharma, Inc., the company developing KTE-C19, released these results and said additional data from this trial, known as ZUMA-1, will be submitted for presentation at an upcoming scientific meeting.

ZUMA-1 has enrolled patients with chemo-refractory, aggressive NHL. The phase 1 portion of the trial included 7 patients with diffuse large B-cell lymphoma (DLBCL).

Thus far, the phase 2 portion includes 62 NHL patients—51 with DLBCL and 11 with transformed follicular lymphoma (TFL) or primary mediastinal B-cell lymphoma (PMBCL).

The patients received a conditioning chemotherapy regimen of fludarabine and cyclophosphamide, followed by a single infusion of KTE-C19 (at a target dose of 2 x 10⁶ CAR T cells/kg).

Responses

In the phase 1 portion of the trial (n=7), the initial ORR was 71%, and the CR rate was 57%. At 3 months of follow-up, the ORR and CR rate were both 43%. The response rates remained the same at 6 months and 9 months of follow-up.

In the phase 2 portion of the trial, for all 62 patients, the initial ORR was 79%, and the CR rate was 52%. At 3 months, the ORR was 44%, and the CR rate was 39%.

Among the 51 patients with DLBCL, the initial ORR was 76%, and the CR rate was 47%. At 3 months, the ORR was 39%, and the CR rate was 33%.

Among the 11 patients with TFL or PMBCL, the initial ORR was 91%, and the CR rate was 73%. At 3 months, the ORR and CR rates were 64%.

Longer follow-up data are not yet available for the phase 2 portion of the study.

Safety

For all 62 patients, the most common grade 3 or higher AEs were neutropenia (66%), anemia (40%), febrile neutropenia (29%), thrombocytopenia (29%), and encephalopathy (26%).

Grade 3 or higher cytokine release syndrome occurred in 18% of patients, and neurological toxicity occurred in 34%.

Two patients died from KTE-C19-related AEs—hemophagocytic lymphohistiocytosis and cardiac arrest in the setting of cytokine release syndrome.

Kite Pharma said the primary analysis from this study will include 101 patients with chemo-refractory NHL (DLBCL, TFL, and PMBCL), will have approximately 6 months of follow-up, and is expected in the first quarter of 2017.

ZUMA-1 is supported, in part, by funding from The Leukemia & Lymphoma Society Therapy Acceleration Program.

Micrograph showing DLBCL

Interim results of a phase 1/2 trial suggest KTE-C19, a chimeric antigen receptor (CAR) T-cell therapy, can be effective against aggressive non-Hodgkin lymphoma (NHL).

KTE-C19, administered after conditioning chemotherapy, produced an overall response rate (ORR) of

79% and a complete response (CR) rate of 52%.

However, the therapy also caused severe adverse events (AEs), and there were 2 deaths resulting from KTE-C19-related AEs.

Kite Pharma, Inc., the company developing KTE-C19, released these results and said additional data from this trial, known as ZUMA-1, will be submitted for presentation at an upcoming scientific meeting.

ZUMA-1 has enrolled patients with chemo-refractory, aggressive NHL. The phase 1 portion of the trial included 7 patients with diffuse large B-cell lymphoma (DLBCL).

Thus far, the phase 2 portion includes 62 NHL patients—51 with DLBCL and 11 with transformed follicular lymphoma (TFL) or primary mediastinal B-cell lymphoma (PMBCL).

The patients received a conditioning chemotherapy regimen of fludarabine and cyclophosphamide, followed by a single infusion of KTE-C19 (at a target dose of 2 x 10⁶ CAR T cells/kg).

Responses

In the phase 1 portion of the trial (n=7), the initial ORR was 71%, and the CR rate was 57%. At 3 months of follow-up, the ORR and CR rate were both 43%. The response rates remained the same at 6 months and 9 months of follow-up.

In the phase 2 portion of the trial, for all 62 patients, the initial ORR was 79%, and the CR rate was 52%. At 3 months, the ORR was 44%, and the CR rate was 39%.

Among the 51 patients with DLBCL, the initial ORR was 76%, and the CR rate was 47%. At 3 months, the ORR was 39%, and the CR rate was 33%.

Among the 11 patients with TFL or PMBCL, the initial ORR was 91%, and the CR rate was 73%. At 3 months, the ORR and CR rates were 64%.

Longer follow-up data are not yet available for the phase 2 portion of the study.

Safety

For all 62 patients, the most common grade 3 or higher AEs were neutropenia (66%), anemia (40%), febrile neutropenia (29%), thrombocytopenia (29%), and encephalopathy (26%).

Grade 3 or higher cytokine release syndrome occurred in 18% of patients, and neurological toxicity occurred in 34%.

Two patients died from KTE-C19-related AEs—hemophagocytic lymphohistiocytosis and cardiac arrest in the setting of cytokine release syndrome.

Kite Pharma said the primary analysis from this study will include 101 patients with chemo-refractory NHL (DLBCL, TFL, and PMBCL), will have approximately 6 months of follow-up, and is expected in the first quarter of 2017.

ZUMA-1 is supported, in part, by funding from The Leukemia & Lymphoma Society Therapy Acceleration Program.

 

 

Cancer patient receives therapy

Photo by Rhoda Baer

 

A new report highlights recent advances made in the fight against cancer but suggests the burden of cancer in the US is still on the rise.

The AACR Cancer Progress Report 2016 states that the number of cancer survivors in the US rose by 1 million from 2014 to 2016, reaching an estimated 15.5 million.

Meanwhile, the US Food and Drug Administration (FDA) approved new treatments for a range of cancers.

Between August 1, 2015, and July 31, 2016, the FDA approved 13 new anticancer therapies and new uses for 11 previously approved anticancer therapies.

Six of these drugs were approved to treat hematologic malignancies:

• Venetoclax for chronic lymphocytic leukemia
• Daratumumab for multiple myeloma
• Elotuzumab for multiple myeloma
• Ixazomib for multiple myeloma
• Obinutuzumab for follicular lymphoma
• Nivolumab for classical Hodgkin lymphoma.

The report notes that the use of immunotherapy, in particular, is on the rise. For example, on August 1, 2015, checkpoint inhibitors were approved for just 2 cancers—melanoma and lung cancer.

As of September 1, 2016, checkpoint inhibitors have been approved for 6 cancers—Hodgkin lymphoma, bladder cancer, head and neck cancer, kidney cancer, lung cancer, and melanoma.

“The promise of immunotherapy for cancer therapy has never been greater, and the opportunity to make significant progress in this critical area is real,” said Nancy E. Davidson, MD, president of the AACR and director of the University of Pittsburgh Cancer Institute in Pennsylvania.

“However, continued progress is going to require a sustained federal commitment to the research agenda. And in fact, if the necessary funding is provided, we will accelerate the pace of progress and, in turn, markedly reduce morbidity and mortality from cancer.”

Growing burden of cancer

The report emphasizes that although advances are being made against cancers, these diseases continue to exert an immense personal and economic toll, and the burden of cancer is expected to grow in the coming decades.

According to the report:

• More than 595,000 people in the US are projected to die from cancer in 2016
• Cancer is the number one cause of disease-related death among US children
• The number of new cancer cases in the US is predicted to rise from 1.7 million in 2015 to 2.4 million in 2035
• It is estimated that the direct medical costs of cancer care in the US in 2010 were nearly $125 billion, and these costs will rise to $156 billion in 2020.

The report states that the increasing economic and personal burden of cancer underscores the need for more research to develop new approaches to cancer prevention and treatment.

The report also highlights the recommendations of the National Cancer Moonshot Initiative Blue Ribbon Panel for accelerating the pace of progress in cancer research.

“Research has made tremendous advances against cancer,” said Margaret Foti, PhD, MD, chief executive officer of the AACR.

“However, we need to accelerate the pace of progress because it is unacceptable that 1 American will die of cancer every minute of every day this year.”

 

 

Cancer patient receives therapy

Photo by Rhoda Baer

 

A new report highlights recent advances made in the fight against cancer but suggests the burden of cancer in the US is still on the rise.

The AACR Cancer Progress Report 2016 states that the number of cancer survivors in the US rose by 1 million from 2014 to 2016, reaching an estimated 15.5 million.

Meanwhile, the US Food and Drug Administration (FDA) approved new treatments for a range of cancers.

Between August 1, 2015, and July 31, 2016, the FDA approved 13 new anticancer therapies and new uses for 11 previously approved anticancer therapies.

Six of these drugs were approved to treat hematologic malignancies:

• Venetoclax for chronic lymphocytic leukemia
• Daratumumab for multiple myeloma
• Elotuzumab for multiple myeloma
• Ixazomib for multiple myeloma
• Obinutuzumab for follicular lymphoma
• Nivolumab for classical Hodgkin lymphoma.

The report notes that the use of immunotherapy, in particular, is on the rise. For example, on August 1, 2015, checkpoint inhibitors were approved for just 2 cancers—melanoma and lung cancer.

As of September 1, 2016, checkpoint inhibitors have been approved for 6 cancers—Hodgkin lymphoma, bladder cancer, head and neck cancer, kidney cancer, lung cancer, and melanoma.

“The promise of immunotherapy for cancer therapy has never been greater, and the opportunity to make significant progress in this critical area is real,” said Nancy E. Davidson, MD, president of the AACR and director of the University of Pittsburgh Cancer Institute in Pennsylvania.

“However, continued progress is going to require a sustained federal commitment to the research agenda. And in fact, if the necessary funding is provided, we will accelerate the pace of progress and, in turn, markedly reduce morbidity and mortality from cancer.”

Growing burden of cancer

The report emphasizes that although advances are being made against cancers, these diseases continue to exert an immense personal and economic toll, and the burden of cancer is expected to grow in the coming decades.

According to the report:

• More than 595,000 people in the US are projected to die from cancer in 2016
• Cancer is the number one cause of disease-related death among US children
• The number of new cancer cases in the US is predicted to rise from 1.7 million in 2015 to 2.4 million in 2035
• It is estimated that the direct medical costs of cancer care in the US in 2010 were nearly $125 billion, and these costs will rise to $156 billion in 2020.

The report states that the increasing economic and personal burden of cancer underscores the need for more research to develop new approaches to cancer prevention and treatment.

The report also highlights the recommendations of the National Cancer Moonshot Initiative Blue Ribbon Panel for accelerating the pace of progress in cancer research.

“Research has made tremendous advances against cancer,” said Margaret Foti, PhD, MD, chief executive officer of the AACR.

“However, we need to accelerate the pace of progress because it is unacceptable that 1 American will die of cancer every minute of every day this year.”

 

 

Cancer patient receives therapy

Photo by Rhoda Baer

 

A new report highlights recent advances made in the fight against cancer but suggests the burden of cancer in the US is still on the rise.

The AACR Cancer Progress Report 2016 states that the number of cancer survivors in the US rose by 1 million from 2014 to 2016, reaching an estimated 15.5 million.

Meanwhile, the US Food and Drug Administration (FDA) approved new treatments for a range of cancers.

Between August 1, 2015, and July 31, 2016, the FDA approved 13 new anticancer therapies and new uses for 11 previously approved anticancer therapies.

Six of these drugs were approved to treat hematologic malignancies:

• Venetoclax for chronic lymphocytic leukemia
• Daratumumab for multiple myeloma
• Elotuzumab for multiple myeloma
• Ixazomib for multiple myeloma
• Obinutuzumab for follicular lymphoma
• Nivolumab for classical Hodgkin lymphoma.

The report notes that the use of immunotherapy, in particular, is on the rise. For example, on August 1, 2015, checkpoint inhibitors were approved for just 2 cancers—melanoma and lung cancer.

As of September 1, 2016, checkpoint inhibitors have been approved for 6 cancers—Hodgkin lymphoma, bladder cancer, head and neck cancer, kidney cancer, lung cancer, and melanoma.

“The promise of immunotherapy for cancer therapy has never been greater, and the opportunity to make significant progress in this critical area is real,” said Nancy E. Davidson, MD, president of the AACR and director of the University of Pittsburgh Cancer Institute in Pennsylvania.

“However, continued progress is going to require a sustained federal commitment to the research agenda. And in fact, if the necessary funding is provided, we will accelerate the pace of progress and, in turn, markedly reduce morbidity and mortality from cancer.”

Growing burden of cancer

The report emphasizes that although advances are being made against cancers, these diseases continue to exert an immense personal and economic toll, and the burden of cancer is expected to grow in the coming decades.

According to the report:

• More than 595,000 people in the US are projected to die from cancer in 2016
• Cancer is the number one cause of disease-related death among US children
• The number of new cancer cases in the US is predicted to rise from 1.7 million in 2015 to 2.4 million in 2035
• It is estimated that the direct medical costs of cancer care in the US in 2010 were nearly $125 billion, and these costs will rise to $156 billion in 2020.

The report states that the increasing economic and personal burden of cancer underscores the need for more research to develop new approaches to cancer prevention and treatment.

The report also highlights the recommendations of the National Cancer Moonshot Initiative Blue Ribbon Panel for accelerating the pace of progress in cancer research.

“Research has made tremendous advances against cancer,” said Margaret Foti, PhD, MD, chief executive officer of the AACR.

“However, we need to accelerate the pace of progress because it is unacceptable that 1 American will die of cancer every minute of every day this year.”

Micrograph showing

mycosis fungoides

The US Food and Drug Administration (FDA) has granted fast track designation to Resimmune® (A-dmDT390-bisFv[UCHT1]) for the treatment of mycosis fungoides (MF).

Resimmune is an anti-CD3 immunotoxin that targets and transiently depletes a high percentage of malignant and normal T cells.

Researchers believe this high rate of T-cell depletion may “reset” a patient’s immune system, leading to immunomodulation. However, the safety and efficacy of Resimmune has not been established.

Resimmune is being developed by Angimmune LLC.

Resimmune research

The FDA’s fast track designation for Resimmune is based on results from a phase 1 trial, which were published in haematologica last year.

The trial included 25 patients with cutaneous T-cell lymphoma (CTCL)—17 with stage IB-IIB disease and 8 with stage III-IV disease. The patients received Resimmune at varying doses—between 2.5 µg/kg and 11.25 µg/kg.

Safety

Drug-related adverse events for the entire study cohort (n=30) included:

• Grade 2-3 AST/ALT elevations (n=6)
• Grade 2 chills (n=10)
• Grade 5 EBV infection (n=1)
• Grade 3 EBV/CMV infection (n=5)
• Grade 2 fever (n=6)
• Grade 5 heart failure (n=2)
• Grade 2-3 hypoalbuminemia (n=11)
• Grade 2 hypomagnesemia (n=1)
• Grade 3 hypophosphatemia (n=3)
• Grade 2-4 hypotension (n=3)
• Grade 4 hypoxia (n=1)
• Grade 4 liver failure (n=1)
• Grade 4 metabolic acidosis (n=1)
• Grade 3 supraventricular tachycardia (n=2)
• Grade 3-4 uremia (n=3)
• Grade 2-4 vascular leak syndrome (n=5).

Efficacy and phase 2

Nine of the CTCL patients (36%) responded to Resimmune, and 4 (16%) had complete responses (CRs). The duration of CR was more than 38 months for 1 patient, more than 60 months for another, and more than 72 months for 2 patients.

Of the 5 partial responses, 2 lasted 3 months, 1 lasted more than 3 months, 1 lasted more than 6 months, and the longest lasted 14 months.

The researchers said this trial revealed a subgroup of CTCL patients with a very high response rate.

When they excluded patients whose mSWAT scores never exceeded 50 and who never had lymph node involvement or stage III disease, the researchers were left with 9 patients. This subgroup had an overall response rate of 89% and a CR rate of 50% (at 6 months of follow-up).

“Results from our phase 1 trial demonstrated a particularly robust response among certain patients with early stage disease, and the randomized phase 2 trial is designed to further explore this potential therapeutic benefit,” said David Neville, MD, president and chief scientific officer of Angimmune.

The objective of this phase 2 trial is to document the incidence of CRs with Resimmune compared to oral vorinostat after a maximum of 12 months of treatment. The trial will enroll patients with stage IB/IIB MF with mSWAT < 50 who have never had lymphoid disease or a prior hematopoietic stem cell transplant.

About fast track designation

The FDA’s fast track program is designed to facilitate and expedite the development and review of new drugs intended to treat serious or life-threatening conditions and address unmet medical need.

Through the fast track program, a product may be eligible for priority review. In addition, the company developing the drug may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings with the FDA to discuss the drug’s development plan and ensure collection of the appropriate data needed to support drug approval. And the designation allows for more frequent written communication from the FDA about things such as the design of proposed clinical trials and the use of biomarkers.

Micrograph showing

mycosis fungoides

The US Food and Drug Administration (FDA) has granted fast track designation to Resimmune® (A-dmDT390-bisFv[UCHT1]) for the treatment of mycosis fungoides (MF).

Resimmune is an anti-CD3 immunotoxin that targets and transiently depletes a high percentage of malignant and normal T cells.

Researchers believe this high rate of T-cell depletion may “reset” a patient’s immune system, leading to immunomodulation. However, the safety and efficacy of Resimmune has not been established.

Resimmune is being developed by Angimmune LLC.

Resimmune research

The FDA’s fast track designation for Resimmune is based on results from a phase 1 trial, which were published in haematologica last year.

The trial included 25 patients with cutaneous T-cell lymphoma (CTCL)—17 with stage IB-IIB disease and 8 with stage III-IV disease. The patients received Resimmune at varying doses—between 2.5 µg/kg and 11.25 µg/kg.

Safety

Drug-related adverse events for the entire study cohort (n=30) included:

• Grade 2-3 AST/ALT elevations (n=6)
• Grade 2 chills (n=10)
• Grade 5 EBV infection (n=1)
• Grade 3 EBV/CMV infection (n=5)
• Grade 2 fever (n=6)
• Grade 5 heart failure (n=2)
• Grade 2-3 hypoalbuminemia (n=11)
• Grade 2 hypomagnesemia (n=1)
• Grade 3 hypophosphatemia (n=3)
• Grade 2-4 hypotension (n=3)
• Grade 4 hypoxia (n=1)
• Grade 4 liver failure (n=1)
• Grade 4 metabolic acidosis (n=1)
• Grade 3 supraventricular tachycardia (n=2)
• Grade 3-4 uremia (n=3)
• Grade 2-4 vascular leak syndrome (n=5).

Efficacy and phase 2

Nine of the CTCL patients (36%) responded to Resimmune, and 4 (16%) had complete responses (CRs). The duration of CR was more than 38 months for 1 patient, more than 60 months for another, and more than 72 months for 2 patients.

Of the 5 partial responses, 2 lasted 3 months, 1 lasted more than 3 months, 1 lasted more than 6 months, and the longest lasted 14 months.

The researchers said this trial revealed a subgroup of CTCL patients with a very high response rate.

When they excluded patients whose mSWAT scores never exceeded 50 and who never had lymph node involvement or stage III disease, the researchers were left with 9 patients. This subgroup had an overall response rate of 89% and a CR rate of 50% (at 6 months of follow-up).

“Results from our phase 1 trial demonstrated a particularly robust response among certain patients with early stage disease, and the randomized phase 2 trial is designed to further explore this potential therapeutic benefit,” said David Neville, MD, president and chief scientific officer of Angimmune.

The objective of this phase 2 trial is to document the incidence of CRs with Resimmune compared to oral vorinostat after a maximum of 12 months of treatment. The trial will enroll patients with stage IB/IIB MF with mSWAT < 50 who have never had lymphoid disease or a prior hematopoietic stem cell transplant.

About fast track designation

The FDA’s fast track program is designed to facilitate and expedite the development and review of new drugs intended to treat serious or life-threatening conditions and address unmet medical need.

Through the fast track program, a product may be eligible for priority review. In addition, the company developing the drug may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings with the FDA to discuss the drug’s development plan and ensure collection of the appropriate data needed to support drug approval. And the designation allows for more frequent written communication from the FDA about things such as the design of proposed clinical trials and the use of biomarkers.

Micrograph showing

mycosis fungoides

The US Food and Drug Administration (FDA) has granted fast track designation to Resimmune® (A-dmDT390-bisFv[UCHT1]) for the treatment of mycosis fungoides (MF).

Resimmune is an anti-CD3 immunotoxin that targets and transiently depletes a high percentage of malignant and normal T cells.

Researchers believe this high rate of T-cell depletion may “reset” a patient’s immune system, leading to immunomodulation. However, the safety and efficacy of Resimmune has not been established.

Resimmune is being developed by Angimmune LLC.

Resimmune research

The FDA’s fast track designation for Resimmune is based on results from a phase 1 trial, which were published in haematologica last year.

The trial included 25 patients with cutaneous T-cell lymphoma (CTCL)—17 with stage IB-IIB disease and 8 with stage III-IV disease. The patients received Resimmune at varying doses—between 2.5 µg/kg and 11.25 µg/kg.

Safety

Drug-related adverse events for the entire study cohort (n=30) included:

• Grade 2-3 AST/ALT elevations (n=6)
• Grade 2 chills (n=10)
• Grade 5 EBV infection (n=1)
• Grade 3 EBV/CMV infection (n=5)
• Grade 2 fever (n=6)
• Grade 5 heart failure (n=2)
• Grade 2-3 hypoalbuminemia (n=11)
• Grade 2 hypomagnesemia (n=1)
• Grade 3 hypophosphatemia (n=3)
• Grade 2-4 hypotension (n=3)
• Grade 4 hypoxia (n=1)
• Grade 4 liver failure (n=1)
• Grade 4 metabolic acidosis (n=1)
• Grade 3 supraventricular tachycardia (n=2)
• Grade 3-4 uremia (n=3)
• Grade 2-4 vascular leak syndrome (n=5).

Efficacy and phase 2

Nine of the CTCL patients (36%) responded to Resimmune, and 4 (16%) had complete responses (CRs). The duration of CR was more than 38 months for 1 patient, more than 60 months for another, and more than 72 months for 2 patients.

Of the 5 partial responses, 2 lasted 3 months, 1 lasted more than 3 months, 1 lasted more than 6 months, and the longest lasted 14 months.

The researchers said this trial revealed a subgroup of CTCL patients with a very high response rate.

When they excluded patients whose mSWAT scores never exceeded 50 and who never had lymph node involvement or stage III disease, the researchers were left with 9 patients. This subgroup had an overall response rate of 89% and a CR rate of 50% (at 6 months of follow-up).

“Results from our phase 1 trial demonstrated a particularly robust response among certain patients with early stage disease, and the randomized phase 2 trial is designed to further explore this potential therapeutic benefit,” said David Neville, MD, president and chief scientific officer of Angimmune.

The objective of this phase 2 trial is to document the incidence of CRs with Resimmune compared to oral vorinostat after a maximum of 12 months of treatment. The trial will enroll patients with stage IB/IIB MF with mSWAT < 50 who have never had lymphoid disease or a prior hematopoietic stem cell transplant.

About fast track designation

The FDA’s fast track program is designed to facilitate and expedite the development and review of new drugs intended to treat serious or life-threatening conditions and address unmet medical need.

Through the fast track program, a product may be eligible for priority review. In addition, the company developing the drug may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings with the FDA to discuss the drug’s development plan and ensure collection of the appropriate data needed to support drug approval. And the designation allows for more frequent written communication from the FDA about things such as the design of proposed clinical trials and the use of biomarkers.

Doctor and patient in hospital

Photo courtesy of CDC

A retrospective study has uncovered potential risk factors for early death in older patients with diffuse large B-cell lymphoma (DLBCL).

Researchers examined electronic health record data for roughly 5500 DLBCL patients over the age of 65 who received contemporary immunochemotherapy.

This revealed 7 factors that were significantly associated with the risk of death within 30 days of treatment initiation.

“The first month of treatment, when patients are compromised both by active lymphoma and toxicities of chemotherapy, is a period of particular concern, as nearly 1 in 4 patients were hospitalized during that time,” said study author Adam J. Olszewski, MD, of Rhode Island Hospital in Providence.

“While comprehensive geriatric assessment remains the gold standard for risk assessment, our study suggests that readily available data from electronic medical records can help identify the high-risk factors in practice.”

Dr Olszewski and his colleagues described their study in JNCCN.

The researchers looked at Medicare claims linked to Surveillance, Epidemiology and End Results registry data for 5530 DLBCL patients who had a median age of 76.

The patients were treated with rituximab, cyclophosphamide, and vincristine in combination with doxorubicin, mitoxantrone, or etoposide from 2003 to 2012.

The cumulative incidence of death at 30 days was 2.2%. The most common causes of death were lymphoma (72%), heart disease (9%), septicemia (3%), and cerebrovascular events (3%).

The researchers created a prediction model based on 7 factors that were significantly associated with early death in multivariate analysis. These include:

• B symptoms
• Chronic kidney disease
• Poor performance status
• Prior use of walking aids or wheelchairs
• Prior hospitalization within the past 12 months
• Upper endoscopy within the past 12 months
• Age 75 or older.

Patients with 0 to 1 of these risk factors were considered low-risk, with a 0.6% chance of early death. Fifty-six percent of the patients studied fit this definition.

Patients with 2 to 3 of the risk factors were intermediate-risk, with a 3.2% chance of early death. Thirty-eight percent of the patients studied fell into this category.

Only 6% of the patients studied were considered high-risk. These patients had 4 or more risk factors and an 8.3% chance of early death.

The researchers also found the administration of prophylactic granulocyte-colony stimulating factor (G-CSF) was associated with lower probability of early death in the high-risk group.

They noted that prophylactic G-CSF was given to 66% of patients in this study, which suggests an opportunity for preventing early deaths.

“It is equally important to realize that a majority of older patients without risk factors can safely receive curative immunochemotherapy,” Dr Olszewski said. “Enhanced supportive care and monitoring should be provided for high-risk groups.”

Doctor and patient in hospital

Photo courtesy of CDC

A retrospective study has uncovered potential risk factors for early death in older patients with diffuse large B-cell lymphoma (DLBCL).

Researchers examined electronic health record data for roughly 5500 DLBCL patients over the age of 65 who received contemporary immunochemotherapy.

This revealed 7 factors that were significantly associated with the risk of death within 30 days of treatment initiation.

“The first month of treatment, when patients are compromised both by active lymphoma and toxicities of chemotherapy, is a period of particular concern, as nearly 1 in 4 patients were hospitalized during that time,” said study author Adam J. Olszewski, MD, of Rhode Island Hospital in Providence.

“While comprehensive geriatric assessment remains the gold standard for risk assessment, our study suggests that readily available data from electronic medical records can help identify the high-risk factors in practice.”

Dr Olszewski and his colleagues described their study in JNCCN.

The researchers looked at Medicare claims linked to Surveillance, Epidemiology and End Results registry data for 5530 DLBCL patients who had a median age of 76.

The patients were treated with rituximab, cyclophosphamide, and vincristine in combination with doxorubicin, mitoxantrone, or etoposide from 2003 to 2012.

The cumulative incidence of death at 30 days was 2.2%. The most common causes of death were lymphoma (72%), heart disease (9%), septicemia (3%), and cerebrovascular events (3%).

The researchers created a prediction model based on 7 factors that were significantly associated with early death in multivariate analysis. These include:

• B symptoms
• Chronic kidney disease
• Poor performance status
• Prior use of walking aids or wheelchairs
• Prior hospitalization within the past 12 months
• Upper endoscopy within the past 12 months
• Age 75 or older.

Patients with 0 to 1 of these risk factors were considered low-risk, with a 0.6% chance of early death. Fifty-six percent of the patients studied fit this definition.

Patients with 2 to 3 of the risk factors were intermediate-risk, with a 3.2% chance of early death. Thirty-eight percent of the patients studied fell into this category.

Only 6% of the patients studied were considered high-risk. These patients had 4 or more risk factors and an 8.3% chance of early death.

The researchers also found the administration of prophylactic granulocyte-colony stimulating factor (G-CSF) was associated with lower probability of early death in the high-risk group.

They noted that prophylactic G-CSF was given to 66% of patients in this study, which suggests an opportunity for preventing early deaths.

“It is equally important to realize that a majority of older patients without risk factors can safely receive curative immunochemotherapy,” Dr Olszewski said. “Enhanced supportive care and monitoring should be provided for high-risk groups.”

Doctor and patient in hospital

Photo courtesy of CDC

A retrospective study has uncovered potential risk factors for early death in older patients with diffuse large B-cell lymphoma (DLBCL).

Researchers examined electronic health record data for roughly 5500 DLBCL patients over the age of 65 who received contemporary immunochemotherapy.

This revealed 7 factors that were significantly associated with the risk of death within 30 days of treatment initiation.

“The first month of treatment, when patients are compromised both by active lymphoma and toxicities of chemotherapy, is a period of particular concern, as nearly 1 in 4 patients were hospitalized during that time,” said study author Adam J. Olszewski, MD, of Rhode Island Hospital in Providence.

“While comprehensive geriatric assessment remains the gold standard for risk assessment, our study suggests that readily available data from electronic medical records can help identify the high-risk factors in practice.”

Dr Olszewski and his colleagues described their study in JNCCN.

The researchers looked at Medicare claims linked to Surveillance, Epidemiology and End Results registry data for 5530 DLBCL patients who had a median age of 76.

The patients were treated with rituximab, cyclophosphamide, and vincristine in combination with doxorubicin, mitoxantrone, or etoposide from 2003 to 2012.

The cumulative incidence of death at 30 days was 2.2%. The most common causes of death were lymphoma (72%), heart disease (9%), septicemia (3%), and cerebrovascular events (3%).

The researchers created a prediction model based on 7 factors that were significantly associated with early death in multivariate analysis. These include:

• B symptoms
• Chronic kidney disease
• Poor performance status
• Prior use of walking aids or wheelchairs
• Prior hospitalization within the past 12 months
• Upper endoscopy within the past 12 months
• Age 75 or older.

Patients with 0 to 1 of these risk factors were considered low-risk, with a 0.6% chance of early death. Fifty-six percent of the patients studied fit this definition.

Patients with 2 to 3 of the risk factors were intermediate-risk, with a 3.2% chance of early death. Thirty-eight percent of the patients studied fell into this category.

Only 6% of the patients studied were considered high-risk. These patients had 4 or more risk factors and an 8.3% chance of early death.

The researchers also found the administration of prophylactic granulocyte-colony stimulating factor (G-CSF) was associated with lower probability of early death in the high-risk group.

They noted that prophylactic G-CSF was given to 66% of patients in this study, which suggests an opportunity for preventing early deaths.

“It is equally important to realize that a majority of older patients without risk factors can safely receive curative immunochemotherapy,” Dr Olszewski said. “Enhanced supportive care and monitoring should be provided for high-risk groups.”

 

 

Stanley Riddell, MD

Photo from Fred Hutchinson

Cancer Research Center

 

Results from a phase 1 study have provided insights that may help researchers optimize treatment with JCAR014, a chimeric antigen receptor (CAR) T-cell therapy, in patients with advanced non-Hodgkin lymphoma (NHL).

Researchers said they identified a lymphodepleting regimen that improved the likelihood of complete response (CR) to JCAR014.

Although the regimen also increased the risk of severe cytokine release syndrome (CRS) and neurotoxicity, the researchers discovered biomarkers that might allow them to identify patients who have a high risk of these events and could potentially benefit from early interventions.

The researchers reported these findings in Science Translational Medicine. The trial (NCT01865617) was funded, in part, by Juno Therapeutics, the company developing JCAR014.

Previous results from this trial, in patients with acute lymphoblastic leukemia, were published in The Journal of Clinical Investigation.

About JCAR014

JCAR014 is a CD19-directed CAR T-cell therapy in which CD4+ and CD8+ cells are administered in equal proportions.

“The idea . . . is that by [controlling the ratio of T cells], we would get more reproducible data around the effects of the cells—both beneficial effects against the cancer and also any side effects they might cause the patient,” said study author Stanley Riddell, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.

“And then, by adjusting the dose, we could improve what we call the therapeutic index—the benefit against the tumor—without too much toxicity.”

Patients and treatment

Dr Riddell and his colleagues reported results with JCAR014, following lymphodepleting chemotherapy, in 32 patients with NHL who had a median age of 58 (range, 36-70).

The patients had de novo large B-cell lymphoma (n=11), transformed de novo large B-cell lymphoma (n=11), mantle cell lymphoma (n=4), and follicular lymphoma (n=6).

They had received a median of 5 prior treatment regimens (range, 2 to 11), including autologous

(n=14) and allogeneic (n=4) transplant. All patients had measurable disease (≥ 2 cm) in the lymph nodes or other extramedullary sites at baseline.

The patients received JCAR014 at 1 of 3 dose levels, given 36 to 96 hours after lymphodepleting chemotherapy.

Twelve patients received cyclophosphamide (Cy) alone or Cy and etoposide (E), and 20 received Cy plus fludarabine (Flu). Five patients received 2 × 10⁵ CAR T cells/kg, 18 received 2 × 10⁶ CAR T cells/kg, and 9 received 2 × 10⁷ CAR T cells/kg.

Efficacy

In the 30 evaluable patients, the overall response rate (ORR) was 63% (n=19), and the CR rate was 33% (n=10).

Among patients who received Cy or Cy/E, the ORR was 50% (n=6), and the CR rate was 8% (n=1). Among patients who received Cy/Flu, the ORR was 72% (n=13), and the CR rate was 50% (n=9).

The patients who received Cy/Flu had better CAR T-cell expansion and persistence than patients who received Cy or Cy/E, which was reflected in the higher response rates.

Higher response rates were also observed in patients who received 2 × 10⁶ CAR T cells/kg rather than the other 2 dose levels.

The researchers noted that, although follow-up is short, patients who received CAR T cells at ≤ 2 × 10⁶/kg after Cy/Flu had better progression-free survival (P=0.008) than patients who received CAR T cells at ≤ 2 × 10⁶/kg after Cy or Cy/E.

Of the 9 patients who achieved a CR after Cy/Flu and JCAR014, 1 has relapsed, with follow-up ranging from 2.3 months to 11.2 months. (Seven of these 9 patients had received 2 × 10⁶ CAR T cells/kg, and 1 patient each had received the other 2 doses.)

“The main message is that you can treat patients with non-Hodgkin’s lymphoma with CAR T cells and get very good response rates with optimization of the CAR T-cell dose and lymphodepletion,” said study author Cameron Turtle, MBBS, PhD, of the Fred Hutchinson Cancer Research Center.

“Strategies like modifying the lymphodepletion in conjunction with suitable CAR T-cell dosing can have a big impact on clinical outcome.”

Safety

Two patients who were treated with the highest CAR T-cell dose (2 × 10⁷ cells/kg) died—1 of pontine hemorrhage and 1 of gastrointestinal hemorrhage associated with a known gastrointestinal invasive lymphomatous mass.

This dose was also associated with an increased risk of severe CRS and neurotoxicity, as was the Cy/Flu regimen.

Twenty patients (62.5%) developed CRS, and 4 (12.5%) had severe CRS. All 4 of these patients had received Cy/Flu.

Nine patients (28%) developed severe neurotoxicity (grade 3 or higher), 7 of whom had received Cy/Flu.

Three of the 6 patients (50%) treated at 2 × 10⁷ CAR-T cells/kg after Cy/Flu developed severe CRS, and 4 of the 6 patients (67%) developed severe neurotoxicity.

The researchers looked for biomarkers of toxicity in serum collected 1 day after CAR T-cell infusion.

They found that high IL-6, IL-8, IL-10, IL-15, and IFN-γ concentrations were associated with subsequent severe CRS and neurotoxicity, and low TGF-Β concentration was associated with neurotoxicity.

The team said these findings provide an opportunity for studying the use of serum cytokine concentrations to identify patients at the highest risk of toxicity who might benefit from early interventions.

 

 

Stanley Riddell, MD

Photo from Fred Hutchinson

Cancer Research Center

 

Results from a phase 1 study have provided insights that may help researchers optimize treatment with JCAR014, a chimeric antigen receptor (CAR) T-cell therapy, in patients with advanced non-Hodgkin lymphoma (NHL).

Researchers said they identified a lymphodepleting regimen that improved the likelihood of complete response (CR) to JCAR014.

Although the regimen also increased the risk of severe cytokine release syndrome (CRS) and neurotoxicity, the researchers discovered biomarkers that might allow them to identify patients who have a high risk of these events and could potentially benefit from early interventions.

The researchers reported these findings in Science Translational Medicine. The trial (NCT01865617) was funded, in part, by Juno Therapeutics, the company developing JCAR014.

Previous results from this trial, in patients with acute lymphoblastic leukemia, were published in The Journal of Clinical Investigation.

About JCAR014

JCAR014 is a CD19-directed CAR T-cell therapy in which CD4+ and CD8+ cells are administered in equal proportions.

“The idea . . . is that by [controlling the ratio of T cells], we would get more reproducible data around the effects of the cells—both beneficial effects against the cancer and also any side effects they might cause the patient,” said study author Stanley Riddell, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.

“And then, by adjusting the dose, we could improve what we call the therapeutic index—the benefit against the tumor—without too much toxicity.”

Patients and treatment

Dr Riddell and his colleagues reported results with JCAR014, following lymphodepleting chemotherapy, in 32 patients with NHL who had a median age of 58 (range, 36-70).

The patients had de novo large B-cell lymphoma (n=11), transformed de novo large B-cell lymphoma (n=11), mantle cell lymphoma (n=4), and follicular lymphoma (n=6).

They had received a median of 5 prior treatment regimens (range, 2 to 11), including autologous

(n=14) and allogeneic (n=4) transplant. All patients had measurable disease (≥ 2 cm) in the lymph nodes or other extramedullary sites at baseline.

The patients received JCAR014 at 1 of 3 dose levels, given 36 to 96 hours after lymphodepleting chemotherapy.

Twelve patients received cyclophosphamide (Cy) alone or Cy and etoposide (E), and 20 received Cy plus fludarabine (Flu). Five patients received 2 × 10⁵ CAR T cells/kg, 18 received 2 × 10⁶ CAR T cells/kg, and 9 received 2 × 10⁷ CAR T cells/kg.

Efficacy

In the 30 evaluable patients, the overall response rate (ORR) was 63% (n=19), and the CR rate was 33% (n=10).

Among patients who received Cy or Cy/E, the ORR was 50% (n=6), and the CR rate was 8% (n=1). Among patients who received Cy/Flu, the ORR was 72% (n=13), and the CR rate was 50% (n=9).

The patients who received Cy/Flu had better CAR T-cell expansion and persistence than patients who received Cy or Cy/E, which was reflected in the higher response rates.

Higher response rates were also observed in patients who received 2 × 10⁶ CAR T cells/kg rather than the other 2 dose levels.

The researchers noted that, although follow-up is short, patients who received CAR T cells at ≤ 2 × 10⁶/kg after Cy/Flu had better progression-free survival (P=0.008) than patients who received CAR T cells at ≤ 2 × 10⁶/kg after Cy or Cy/E.

Of the 9 patients who achieved a CR after Cy/Flu and JCAR014, 1 has relapsed, with follow-up ranging from 2.3 months to 11.2 months. (Seven of these 9 patients had received 2 × 10⁶ CAR T cells/kg, and 1 patient each had received the other 2 doses.)

“The main message is that you can treat patients with non-Hodgkin’s lymphoma with CAR T cells and get very good response rates with optimization of the CAR T-cell dose and lymphodepletion,” said study author Cameron Turtle, MBBS, PhD, of the Fred Hutchinson Cancer Research Center.

“Strategies like modifying the lymphodepletion in conjunction with suitable CAR T-cell dosing can have a big impact on clinical outcome.”

Safety

Two patients who were treated with the highest CAR T-cell dose (2 × 10⁷ cells/kg) died—1 of pontine hemorrhage and 1 of gastrointestinal hemorrhage associated with a known gastrointestinal invasive lymphomatous mass.

This dose was also associated with an increased risk of severe CRS and neurotoxicity, as was the Cy/Flu regimen.

Twenty patients (62.5%) developed CRS, and 4 (12.5%) had severe CRS. All 4 of these patients had received Cy/Flu.

Nine patients (28%) developed severe neurotoxicity (grade 3 or higher), 7 of whom had received Cy/Flu.

Three of the 6 patients (50%) treated at 2 × 10⁷ CAR-T cells/kg after Cy/Flu developed severe CRS, and 4 of the 6 patients (67%) developed severe neurotoxicity.

The researchers looked for biomarkers of toxicity in serum collected 1 day after CAR T-cell infusion.

They found that high IL-6, IL-8, IL-10, IL-15, and IFN-γ concentrations were associated with subsequent severe CRS and neurotoxicity, and low TGF-Β concentration was associated with neurotoxicity.

The team said these findings provide an opportunity for studying the use of serum cytokine concentrations to identify patients at the highest risk of toxicity who might benefit from early interventions.

 

 

Stanley Riddell, MD

Photo from Fred Hutchinson

Cancer Research Center

 

Results from a phase 1 study have provided insights that may help researchers optimize treatment with JCAR014, a chimeric antigen receptor (CAR) T-cell therapy, in patients with advanced non-Hodgkin lymphoma (NHL).

Researchers said they identified a lymphodepleting regimen that improved the likelihood of complete response (CR) to JCAR014.

Although the regimen also increased the risk of severe cytokine release syndrome (CRS) and neurotoxicity, the researchers discovered biomarkers that might allow them to identify patients who have a high risk of these events and could potentially benefit from early interventions.

The researchers reported these findings in Science Translational Medicine. The trial (NCT01865617) was funded, in part, by Juno Therapeutics, the company developing JCAR014.

Previous results from this trial, in patients with acute lymphoblastic leukemia, were published in The Journal of Clinical Investigation.

About JCAR014

JCAR014 is a CD19-directed CAR T-cell therapy in which CD4+ and CD8+ cells are administered in equal proportions.

“The idea . . . is that by [controlling the ratio of T cells], we would get more reproducible data around the effects of the cells—both beneficial effects against the cancer and also any side effects they might cause the patient,” said study author Stanley Riddell, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.

“And then, by adjusting the dose, we could improve what we call the therapeutic index—the benefit against the tumor—without too much toxicity.”

Patients and treatment

Dr Riddell and his colleagues reported results with JCAR014, following lymphodepleting chemotherapy, in 32 patients with NHL who had a median age of 58 (range, 36-70).

The patients had de novo large B-cell lymphoma (n=11), transformed de novo large B-cell lymphoma (n=11), mantle cell lymphoma (n=4), and follicular lymphoma (n=6).

They had received a median of 5 prior treatment regimens (range, 2 to 11), including autologous

(n=14) and allogeneic (n=4) transplant. All patients had measurable disease (≥ 2 cm) in the lymph nodes or other extramedullary sites at baseline.

The patients received JCAR014 at 1 of 3 dose levels, given 36 to 96 hours after lymphodepleting chemotherapy.

Twelve patients received cyclophosphamide (Cy) alone or Cy and etoposide (E), and 20 received Cy plus fludarabine (Flu). Five patients received 2 × 10⁵ CAR T cells/kg, 18 received 2 × 10⁶ CAR T cells/kg, and 9 received 2 × 10⁷ CAR T cells/kg.

Efficacy

In the 30 evaluable patients, the overall response rate (ORR) was 63% (n=19), and the CR rate was 33% (n=10).

Among patients who received Cy or Cy/E, the ORR was 50% (n=6), and the CR rate was 8% (n=1). Among patients who received Cy/Flu, the ORR was 72% (n=13), and the CR rate was 50% (n=9).

The patients who received Cy/Flu had better CAR T-cell expansion and persistence than patients who received Cy or Cy/E, which was reflected in the higher response rates.

Higher response rates were also observed in patients who received 2 × 10⁶ CAR T cells/kg rather than the other 2 dose levels.

The researchers noted that, although follow-up is short, patients who received CAR T cells at ≤ 2 × 10⁶/kg after Cy/Flu had better progression-free survival (P=0.008) than patients who received CAR T cells at ≤ 2 × 10⁶/kg after Cy or Cy/E.

Of the 9 patients who achieved a CR after Cy/Flu and JCAR014, 1 has relapsed, with follow-up ranging from 2.3 months to 11.2 months. (Seven of these 9 patients had received 2 × 10⁶ CAR T cells/kg, and 1 patient each had received the other 2 doses.)

“The main message is that you can treat patients with non-Hodgkin’s lymphoma with CAR T cells and get very good response rates with optimization of the CAR T-cell dose and lymphodepletion,” said study author Cameron Turtle, MBBS, PhD, of the Fred Hutchinson Cancer Research Center.

“Strategies like modifying the lymphodepletion in conjunction with suitable CAR T-cell dosing can have a big impact on clinical outcome.”

Safety

Two patients who were treated with the highest CAR T-cell dose (2 × 10⁷ cells/kg) died—1 of pontine hemorrhage and 1 of gastrointestinal hemorrhage associated with a known gastrointestinal invasive lymphomatous mass.

This dose was also associated with an increased risk of severe CRS and neurotoxicity, as was the Cy/Flu regimen.

Twenty patients (62.5%) developed CRS, and 4 (12.5%) had severe CRS. All 4 of these patients had received Cy/Flu.

Nine patients (28%) developed severe neurotoxicity (grade 3 or higher), 7 of whom had received Cy/Flu.

Three of the 6 patients (50%) treated at 2 × 10⁷ CAR-T cells/kg after Cy/Flu developed severe CRS, and 4 of the 6 patients (67%) developed severe neurotoxicity.

The researchers looked for biomarkers of toxicity in serum collected 1 day after CAR T-cell infusion.

They found that high IL-6, IL-8, IL-10, IL-15, and IFN-γ concentrations were associated with subsequent severe CRS and neurotoxicity, and low TGF-Β concentration was associated with neurotoxicity.

The team said these findings provide an opportunity for studying the use of serum cytokine concentrations to identify patients at the highest risk of toxicity who might benefit from early interventions.

Ofatumumab (Arzerra)

Photo courtesy of GSK

The US Food and Drug Administration (FDA) has approved the use of ofatumumab (Arzerra®) in combination with fludarabine and cyclophosphamide to treat patients with relapsed chronic lymphocytic leukemia (CLL).

Ofatumumab was previously approved by the FDA for use in combination with chlorambucil to treat previously untreated CLL patients who cannot receive fludarabine-based therapy, as monotherapy for CLL that is refractory to fludarabine and alemtuzumab, and as maintenance therapy for patients who are in complete or partial response after receiving at least 2 lines of therapy for recurrent or progressive CLL.

Ofatumumab is a monoclonal antibody designed to target CD20.

The drug’s prescribing information includes a boxed warning noting that hepatitis B virus reactivation can occur in patients receiving CD20-directed cytolytic antibodies, including ofatumumab. In some cases, this results in fulminant hepatitis, hepatic failure, and death.

The boxed warning also states that progressive multifocal leukoencephalopathy, resulting in death, can occur in patients receiving CD20-directed cytolytic antibodies, including ofatumumab.

Ofatumumab is marketed under a collaboration agreement between Genmab and Novartis.

COMPLEMENT 2 trial

The FDA’s latest approval for ofatumumab is based on results of the phase 3 COMPLEMENT 2 trial. Novartis reported top-line results from this study in April.

The trial enrolled 365 patients with relapsed CLL. The patients were randomized 1:1 to receive up to 6 cycles of ofatumumab in combination with fludarabine and cyclophosphamide or up to 6 cycles of fludarabine and cyclophosphamide alone.

The primary endpoint was progression-free survival, as assessed by an independent review committee.

The median progression-free survival was 28.9 months for patients receiving ofatumumab plus fludarabine and cyclophosphamide, compared to 18.8 months for patients receiving fludarabine and cyclophosphamide alone (hazard ratio=0.67, P=0.0032).

Novartis said the safety profile observed in this study was consistent with other trials of ofatumumab, and no new safety signals were observed.

Ofatumumab (Arzerra)

Photo courtesy of GSK

The US Food and Drug Administration (FDA) has approved the use of ofatumumab (Arzerra®) in combination with fludarabine and cyclophosphamide to treat patients with relapsed chronic lymphocytic leukemia (CLL).

Ofatumumab was previously approved by the FDA for use in combination with chlorambucil to treat previously untreated CLL patients who cannot receive fludarabine-based therapy, as monotherapy for CLL that is refractory to fludarabine and alemtuzumab, and as maintenance therapy for patients who are in complete or partial response after receiving at least 2 lines of therapy for recurrent or progressive CLL.

Ofatumumab is a monoclonal antibody designed to target CD20.

The drug’s prescribing information includes a boxed warning noting that hepatitis B virus reactivation can occur in patients receiving CD20-directed cytolytic antibodies, including ofatumumab. In some cases, this results in fulminant hepatitis, hepatic failure, and death.

The boxed warning also states that progressive multifocal leukoencephalopathy, resulting in death, can occur in patients receiving CD20-directed cytolytic antibodies, including ofatumumab.

Ofatumumab is marketed under a collaboration agreement between Genmab and Novartis.

COMPLEMENT 2 trial

The FDA’s latest approval for ofatumumab is based on results of the phase 3 COMPLEMENT 2 trial. Novartis reported top-line results from this study in April.

The trial enrolled 365 patients with relapsed CLL. The patients were randomized 1:1 to receive up to 6 cycles of ofatumumab in combination with fludarabine and cyclophosphamide or up to 6 cycles of fludarabine and cyclophosphamide alone.

The primary endpoint was progression-free survival, as assessed by an independent review committee.

The median progression-free survival was 28.9 months for patients receiving ofatumumab plus fludarabine and cyclophosphamide, compared to 18.8 months for patients receiving fludarabine and cyclophosphamide alone (hazard ratio=0.67, P=0.0032).

Novartis said the safety profile observed in this study was consistent with other trials of ofatumumab, and no new safety signals were observed.

Ofatumumab (Arzerra)

Photo courtesy of GSK

The US Food and Drug Administration (FDA) has approved the use of ofatumumab (Arzerra®) in combination with fludarabine and cyclophosphamide to treat patients with relapsed chronic lymphocytic leukemia (CLL).

Ofatumumab was previously approved by the FDA for use in combination with chlorambucil to treat previously untreated CLL patients who cannot receive fludarabine-based therapy, as monotherapy for CLL that is refractory to fludarabine and alemtuzumab, and as maintenance therapy for patients who are in complete or partial response after receiving at least 2 lines of therapy for recurrent or progressive CLL.

Ofatumumab is a monoclonal antibody designed to target CD20.

The drug’s prescribing information includes a boxed warning noting that hepatitis B virus reactivation can occur in patients receiving CD20-directed cytolytic antibodies, including ofatumumab. In some cases, this results in fulminant hepatitis, hepatic failure, and death.

The boxed warning also states that progressive multifocal leukoencephalopathy, resulting in death, can occur in patients receiving CD20-directed cytolytic antibodies, including ofatumumab.

Ofatumumab is marketed under a collaboration agreement between Genmab and Novartis.

COMPLEMENT 2 trial

The FDA’s latest approval for ofatumumab is based on results of the phase 3 COMPLEMENT 2 trial. Novartis reported top-line results from this study in April.

The trial enrolled 365 patients with relapsed CLL. The patients were randomized 1:1 to receive up to 6 cycles of ofatumumab in combination with fludarabine and cyclophosphamide or up to 6 cycles of fludarabine and cyclophosphamide alone.

The primary endpoint was progression-free survival, as assessed by an independent review committee.

The median progression-free survival was 28.9 months for patients receiving ofatumumab plus fludarabine and cyclophosphamide, compared to 18.8 months for patients receiving fludarabine and cyclophosphamide alone (hazard ratio=0.67, P=0.0032).

Novartis said the safety profile observed in this study was consistent with other trials of ofatumumab, and no new safety signals were observed.

Micrograph showing CLL

The US Food and Drug Administration (FDA) has granted orphan drug designation to the PI3K delta inhibitor TGR-1202 for the treatment of chronic lymphocytic leukemia (CLL).

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases.

This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the drug is approved.

About TGR-1202

TG Therapeutics, Inc. is developing TGR-1202 as a treatment for hematologic malignancies.

The drug is currently being evaluated in the phase 3 UNITY-CLL trial (NCT02612311), which includes patients with previously treated and untreated CLL. Patients are receiving TGR-1202 plus ublituximab, obinutuzumab plus chlorambucil, ublituximab alone, or TGR-1202 alone.

At EHA 2016, researchers reported preliminary results of a phase 1/1b study (NCT02268851) of TGR-1202 in combination with ibrutinib in patients with relapsed/refractory CLL or mantle cell lymphoma.

At ASCO 2016, researchers reported long-term follow-up of 2 studies of TGR-1202.

The first (TGR-1202-101, NCT01767766) is a phase 1 study of TGR-1202 in patients with relapsed or refractory hematologic malignancies.

The second (UTX-TGR-103, NCT02006485) is a phase 1/1b trial evaluating the combination of ublituximab and TGR-1202 in patients with relapsed or refractory non-Hodgkin lymphoma or CLL.

At ASH 2015, researchers reported results of a phase 1 trial (TGR-GA-106, NCT02100852) of TGR-1202 in combination with obinutuzumab and chlorambucil in patients with CLL.

Micrograph showing CLL

The US Food and Drug Administration (FDA) has granted orphan drug designation to the PI3K delta inhibitor TGR-1202 for the treatment of chronic lymphocytic leukemia (CLL).

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases.

This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the drug is approved.

About TGR-1202

TG Therapeutics, Inc. is developing TGR-1202 as a treatment for hematologic malignancies.

The drug is currently being evaluated in the phase 3 UNITY-CLL trial (NCT02612311), which includes patients with previously treated and untreated CLL. Patients are receiving TGR-1202 plus ublituximab, obinutuzumab plus chlorambucil, ublituximab alone, or TGR-1202 alone.

At EHA 2016, researchers reported preliminary results of a phase 1/1b study (NCT02268851) of TGR-1202 in combination with ibrutinib in patients with relapsed/refractory CLL or mantle cell lymphoma.

At ASCO 2016, researchers reported long-term follow-up of 2 studies of TGR-1202.

The first (TGR-1202-101, NCT01767766) is a phase 1 study of TGR-1202 in patients with relapsed or refractory hematologic malignancies.

The second (UTX-TGR-103, NCT02006485) is a phase 1/1b trial evaluating the combination of ublituximab and TGR-1202 in patients with relapsed or refractory non-Hodgkin lymphoma or CLL.

At ASH 2015, researchers reported results of a phase 1 trial (TGR-GA-106, NCT02100852) of TGR-1202 in combination with obinutuzumab and chlorambucil in patients with CLL.

Micrograph showing CLL

The US Food and Drug Administration (FDA) has granted orphan drug designation to the PI3K delta inhibitor TGR-1202 for the treatment of chronic lymphocytic leukemia (CLL).

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases.

This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the drug is approved.

About TGR-1202

TG Therapeutics, Inc. is developing TGR-1202 as a treatment for hematologic malignancies.

The drug is currently being evaluated in the phase 3 UNITY-CLL trial (NCT02612311), which includes patients with previously treated and untreated CLL. Patients are receiving TGR-1202 plus ublituximab, obinutuzumab plus chlorambucil, ublituximab alone, or TGR-1202 alone.

At EHA 2016, researchers reported preliminary results of a phase 1/1b study (NCT02268851) of TGR-1202 in combination with ibrutinib in patients with relapsed/refractory CLL or mantle cell lymphoma.

At ASCO 2016, researchers reported long-term follow-up of 2 studies of TGR-1202.

The first (TGR-1202-101, NCT01767766) is a phase 1 study of TGR-1202 in patients with relapsed or refractory hematologic malignancies.

The second (UTX-TGR-103, NCT02006485) is a phase 1/1b trial evaluating the combination of ublituximab and TGR-1202 in patients with relapsed or refractory non-Hodgkin lymphoma or CLL.

At ASH 2015, researchers reported results of a phase 1 trial (TGR-GA-106, NCT02100852) of TGR-1202 in combination with obinutuzumab and chlorambucil in patients with CLL.

 

 

Follicular lymphoma

 

Results of the phase 3 GADOLIN trial have revealed a new treatment option for patients with relapsed/refractory non-Hodgkin lymphoma (NHL), according to researchers.

The trial showed that obinutuzumab plus bendamustine, followed by obinutuzumab maintenance, can ward off disease progression in NHL patients who have relapsed after rituximab-based

therapy or stopped responding to it.

The obinutuzumab regimen significantly improved progression-free survival (PFS) when compared to bendamustine alone (without maintenance).

However, there was no significant difference between the 2 treatment arms with regard to overall survival (OS).

Still, the trial was stopped before its protocol-specified final analysis because of the PFS benefit in the obinutuzumab arm.

Laurie Sehn, MD, of the BC Cancer Agency in Vancouver, British Columbia, Canada, and her colleagues reported the results of this trial in The Lancet. The research was funded by F. Hoffmann-La Roche Ltd.

Patients and treatment

GADOLIN enrolled patients with relapsed/refractory follicular lymphoma (FL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), and Waldenstrom’s macroglobulinemia (WM).

The patients were randomized to receive one of the following treatments:

• bendamustine alone (120 mg/m²/day on days 1 and 2 for up to six 28-day cycles)
• bendamustine (90 mg/m²/day on days 1 and 2 for up to six 28-day cycles) plus obinutuzumab (1000 mg on days 1, 8, and 15 for cycle 1, followed by 1 dose for up to six 28-day cycles), followed by obinutuzumab maintenance (1000 mg every 2 months for 2 years or until progression).

The investigators said baseline characteristics were well-balanced between the treatment arms. Patients in both arms had received a median of 2 prior treatments, and the median time from last treatment was about 4 months.

Of the 194 patients randomized to the obinutuzumab arm, 155 had FL, 27 had MZL, and 12 had SLL. Of the 202 patients randomized to the bendamustine (control) arm, 166 had FL, 19 had MZL, 16 had SLL, and 1 had WM.

Ultimately, 156 patients completed induction in the obinutuzumab arm, as did 129 patients in the control arm. Thirty-six patients completed maintenance with obinutuzumab, and 46 were still receiving maintenance at the time of analysis.

The median follow-up was 21.9 months in the obinutuzumab arm and 20.3 months in the control arm.

Safety

Nearly all patients in both arms experienced at least 1 adverse event (AE).

Grade 3-5 AEs occurred in 68% of patients in the obinutuzumab arm and 62% in the control arm. The most frequent of these were neutropenia (33% vs 26%), thrombocytopenia (11% vs 16%), anemia (8% vs 10%), and infusion-related reactions (11% vs 6%).

Serious AEs occurred in 38% of patients in the obinutuzumab arm and 33% in the control arm. The most common were febrile neutropenia (4% vs 3%), infusion-related reactions (4% vs 2%), and pneumonia (3% vs 5%).

Response

According to an independent review committee, the overall response rate at the end of induction was 69% in the obinutuzumab arm and 63% in the control arm. The complete response rates were 11% and 12%, respectively.

The median duration of response was not reached in the obinutuzumab arm and was 13.2 months in the control arm.

Survival

The median PFS was not reached in the obinutuzumab arm and was 14.9 months in the control arm (P=0.0001), according to the independent review committee.

According to investigators, the median PFS was 29.2 months and 14 months, respectively (P<0.0001).

At last follow-up, the median OS had not been reached in either arm (P=0.40).

There were 34 deaths in the obinutuzumab arm and 41 in the control arm (18% and 20%, respectively). Most patients died of disease progression (65% and 71%, respectively).

Twelve patients in each arm (6%) died of AEs. Three of these deaths were treatment-related in the obinutuzumab arm (acute myeloid leukemia, vascular pseudoaneurysm, and pseudomonal sepsis).

Five of the 12 AE deaths in the control arm were treatment-related (sepsis, 2 cases of leukemia, and 2 cases of Pneumocystis jirovecii pneumonia).

Taking these results together, the investigators said the obinutuzumab regimen had a manageable toxicity profile, and it produced a “clinically meaningful and significant” improvement in PFS when compared to bendamustine alone.

 

 

Follicular lymphoma

 

Results of the phase 3 GADOLIN trial have revealed a new treatment option for patients with relapsed/refractory non-Hodgkin lymphoma (NHL), according to researchers.

The trial showed that obinutuzumab plus bendamustine, followed by obinutuzumab maintenance, can ward off disease progression in NHL patients who have relapsed after rituximab-based

therapy or stopped responding to it.

The obinutuzumab regimen significantly improved progression-free survival (PFS) when compared to bendamustine alone (without maintenance).

However, there was no significant difference between the 2 treatment arms with regard to overall survival (OS).

Still, the trial was stopped before its protocol-specified final analysis because of the PFS benefit in the obinutuzumab arm.

Laurie Sehn, MD, of the BC Cancer Agency in Vancouver, British Columbia, Canada, and her colleagues reported the results of this trial in The Lancet. The research was funded by F. Hoffmann-La Roche Ltd.

Patients and treatment

GADOLIN enrolled patients with relapsed/refractory follicular lymphoma (FL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), and Waldenstrom’s macroglobulinemia (WM).

The patients were randomized to receive one of the following treatments:

• bendamustine alone (120 mg/m²/day on days 1 and 2 for up to six 28-day cycles)
• bendamustine (90 mg/m²/day on days 1 and 2 for up to six 28-day cycles) plus obinutuzumab (1000 mg on days 1, 8, and 15 for cycle 1, followed by 1 dose for up to six 28-day cycles), followed by obinutuzumab maintenance (1000 mg every 2 months for 2 years or until progression).

The investigators said baseline characteristics were well-balanced between the treatment arms. Patients in both arms had received a median of 2 prior treatments, and the median time from last treatment was about 4 months.

Of the 194 patients randomized to the obinutuzumab arm, 155 had FL, 27 had MZL, and 12 had SLL. Of the 202 patients randomized to the bendamustine (control) arm, 166 had FL, 19 had MZL, 16 had SLL, and 1 had WM.

Ultimately, 156 patients completed induction in the obinutuzumab arm, as did 129 patients in the control arm. Thirty-six patients completed maintenance with obinutuzumab, and 46 were still receiving maintenance at the time of analysis.

The median follow-up was 21.9 months in the obinutuzumab arm and 20.3 months in the control arm.

Safety

Nearly all patients in both arms experienced at least 1 adverse event (AE).

Grade 3-5 AEs occurred in 68% of patients in the obinutuzumab arm and 62% in the control arm. The most frequent of these were neutropenia (33% vs 26%), thrombocytopenia (11% vs 16%), anemia (8% vs 10%), and infusion-related reactions (11% vs 6%).

Serious AEs occurred in 38% of patients in the obinutuzumab arm and 33% in the control arm. The most common were febrile neutropenia (4% vs 3%), infusion-related reactions (4% vs 2%), and pneumonia (3% vs 5%).

Response

According to an independent review committee, the overall response rate at the end of induction was 69% in the obinutuzumab arm and 63% in the control arm. The complete response rates were 11% and 12%, respectively.

The median duration of response was not reached in the obinutuzumab arm and was 13.2 months in the control arm.

Survival

The median PFS was not reached in the obinutuzumab arm and was 14.9 months in the control arm (P=0.0001), according to the independent review committee.

According to investigators, the median PFS was 29.2 months and 14 months, respectively (P<0.0001).

At last follow-up, the median OS had not been reached in either arm (P=0.40).

There were 34 deaths in the obinutuzumab arm and 41 in the control arm (18% and 20%, respectively). Most patients died of disease progression (65% and 71%, respectively).

Twelve patients in each arm (6%) died of AEs. Three of these deaths were treatment-related in the obinutuzumab arm (acute myeloid leukemia, vascular pseudoaneurysm, and pseudomonal sepsis).

Five of the 12 AE deaths in the control arm were treatment-related (sepsis, 2 cases of leukemia, and 2 cases of Pneumocystis jirovecii pneumonia).

Taking these results together, the investigators said the obinutuzumab regimen had a manageable toxicity profile, and it produced a “clinically meaningful and significant” improvement in PFS when compared to bendamustine alone.

 

 

Follicular lymphoma

 

Results of the phase 3 GADOLIN trial have revealed a new treatment option for patients with relapsed/refractory non-Hodgkin lymphoma (NHL), according to researchers.

The trial showed that obinutuzumab plus bendamustine, followed by obinutuzumab maintenance, can ward off disease progression in NHL patients who have relapsed after rituximab-based

therapy or stopped responding to it.

The obinutuzumab regimen significantly improved progression-free survival (PFS) when compared to bendamustine alone (without maintenance).

However, there was no significant difference between the 2 treatment arms with regard to overall survival (OS).

Still, the trial was stopped before its protocol-specified final analysis because of the PFS benefit in the obinutuzumab arm.

Laurie Sehn, MD, of the BC Cancer Agency in Vancouver, British Columbia, Canada, and her colleagues reported the results of this trial in The Lancet. The research was funded by F. Hoffmann-La Roche Ltd.

Patients and treatment

GADOLIN enrolled patients with relapsed/refractory follicular lymphoma (FL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), and Waldenstrom’s macroglobulinemia (WM).

The patients were randomized to receive one of the following treatments:

• bendamustine alone (120 mg/m²/day on days 1 and 2 for up to six 28-day cycles)
• bendamustine (90 mg/m²/day on days 1 and 2 for up to six 28-day cycles) plus obinutuzumab (1000 mg on days 1, 8, and 15 for cycle 1, followed by 1 dose for up to six 28-day cycles), followed by obinutuzumab maintenance (1000 mg every 2 months for 2 years or until progression).

The investigators said baseline characteristics were well-balanced between the treatment arms. Patients in both arms had received a median of 2 prior treatments, and the median time from last treatment was about 4 months.

Of the 194 patients randomized to the obinutuzumab arm, 155 had FL, 27 had MZL, and 12 had SLL. Of the 202 patients randomized to the bendamustine (control) arm, 166 had FL, 19 had MZL, 16 had SLL, and 1 had WM.

Ultimately, 156 patients completed induction in the obinutuzumab arm, as did 129 patients in the control arm. Thirty-six patients completed maintenance with obinutuzumab, and 46 were still receiving maintenance at the time of analysis.

The median follow-up was 21.9 months in the obinutuzumab arm and 20.3 months in the control arm.

Safety

Nearly all patients in both arms experienced at least 1 adverse event (AE).

Grade 3-5 AEs occurred in 68% of patients in the obinutuzumab arm and 62% in the control arm. The most frequent of these were neutropenia (33% vs 26%), thrombocytopenia (11% vs 16%), anemia (8% vs 10%), and infusion-related reactions (11% vs 6%).

Serious AEs occurred in 38% of patients in the obinutuzumab arm and 33% in the control arm. The most common were febrile neutropenia (4% vs 3%), infusion-related reactions (4% vs 2%), and pneumonia (3% vs 5%).

Response

According to an independent review committee, the overall response rate at the end of induction was 69% in the obinutuzumab arm and 63% in the control arm. The complete response rates were 11% and 12%, respectively.

The median duration of response was not reached in the obinutuzumab arm and was 13.2 months in the control arm.

Survival

The median PFS was not reached in the obinutuzumab arm and was 14.9 months in the control arm (P=0.0001), according to the independent review committee.

According to investigators, the median PFS was 29.2 months and 14 months, respectively (P<0.0001).

At last follow-up, the median OS had not been reached in either arm (P=0.40).

There were 34 deaths in the obinutuzumab arm and 41 in the control arm (18% and 20%, respectively). Most patients died of disease progression (65% and 71%, respectively).

Twelve patients in each arm (6%) died of AEs. Three of these deaths were treatment-related in the obinutuzumab arm (acute myeloid leukemia, vascular pseudoaneurysm, and pseudomonal sepsis).

Five of the 12 AE deaths in the control arm were treatment-related (sepsis, 2 cases of leukemia, and 2 cases of Pneumocystis jirovecii pneumonia).

Taking these results together, the investigators said the obinutuzumab regimen had a manageable toxicity profile, and it produced a “clinically meaningful and significant” improvement in PFS when compared to bendamustine alone.

Diffuse large B-cell lymphoma

The histone deacetylase inhibitor panobinostat can produce durable responses in certain patients with relapsed diffuse large B-cell lymphoma (DLBCL), according to a phase 2 trial.

Though less than 30% of the patients in this trial responded to treatment, the median duration of response was 14.5 months, and the longest ongoing response has lasted more than 3.5 years.

In addition, researchers found the presence of mutations in MEF2B and levels of circulating tumor DNA (ctDNA) could be used to predict response.

Sarit Assouline, MD, of Jewish General Hospital in Montreal, Quebec, Canada, and her colleagues reported these findings in Blood.

“DLBCL is one of the more common forms of lymphoma and is highly aggressive,” Dr Assouline noted. “Following relapse, there are no effective standards of treatment, and life expectancy averages 6 months.”

“Our challenge is to identify new biomarkers and target specific mutations in order to improve the prognosis. While many clinical trials simply report on how patients respond to a therapy, we devised this study to reveal the mechanisms on which the therapy works in order to understand which patients would benefit.”

The trial enrolled 40 patients with relapsed or refractory de novo (n=27) or transformed (n=13) DLBCL. The patients’ median age was 59.8 (range, 28.9-78.6). They received a median of 3 prior therapies (range, 1-9), and 75% of patients (n=30) were refractory to their most recent therapy.

The patients received panobinostat at 30 mg three times a week, with rituximab (n=19) or without (n=21).

Adverse events

The most common grade 3 or higher adverse events (AEs) that were thought to be related to panobinostat (with and without rituximab, respectively) were thrombocytopenia (68% and 71%) and neutropenia (11% and 24%).

Twenty-three patients (58%) required dose reductions, and 22 (55%) required dose interruptions. All of these were due to AEs, and there was no difference between patients who received rituximab and those who did not.

All 19 serious AEs were a result of disease progression.

Response

Twenty-eight percent of the patients (11/40) responded to treatment, and receiving rituximab did not increase the likelihood of response. Six patients (29%) responded to panobinostat alone, and 5 (26%) responded to panobinostat and rituximab.

There were 7 complete responses—5 of them among patients who received panobinostat alone. And there were 4 partial responses—3 among the patients who received panobinostat plus rituximab.

The median duration of response was 14.5 months overall, 9.4 months among patients who received panobinostat plus rituximab, and it was not reached among patients who received panobinostat alone.

At the data cutoff, 6 of the 11 responders had not progressed. The longest response had lasted more than 43 months and was ongoing at the cutoff point.

Predicting response

The researchers performed genome and exome sequencing in relapsed tumor biopsies and quantified ctDNA in serial plasma samples.

They found that mutations in MEF2B were significantly associated with response to panobinostat. The likelihood ratio for response was 3.67 for patients with MEF2B mutations.

On the other hand, increased levels of ctDNA were strongly associated with treatment failure. A significant increase in ctDNA at day 15 after treatment initiation could predict a lack of response with a sensitivity of 71.4% and a specificity of 100%.

“This trial has generated considerable data regarding methodology for processing samples from a clinical study, the genetic mutations associated with DLBCL and how they evolve over time, on ctDNA, and mechanisms of resistance to histone deacetylase inhibitors,” Dr Assouline concluded.

Novartis provided panobinostat and financial support for this trial, and Hoffman-LaRoche supplied rituximab.

Diffuse large B-cell lymphoma

The histone deacetylase inhibitor panobinostat can produce durable responses in certain patients with relapsed diffuse large B-cell lymphoma (DLBCL), according to a phase 2 trial.

Though less than 30% of the patients in this trial responded to treatment, the median duration of response was 14.5 months, and the longest ongoing response has lasted more than 3.5 years.

In addition, researchers found the presence of mutations in MEF2B and levels of circulating tumor DNA (ctDNA) could be used to predict response.

Sarit Assouline, MD, of Jewish General Hospital in Montreal, Quebec, Canada, and her colleagues reported these findings in Blood.

“DLBCL is one of the more common forms of lymphoma and is highly aggressive,” Dr Assouline noted. “Following relapse, there are no effective standards of treatment, and life expectancy averages 6 months.”

“Our challenge is to identify new biomarkers and target specific mutations in order to improve the prognosis. While many clinical trials simply report on how patients respond to a therapy, we devised this study to reveal the mechanisms on which the therapy works in order to understand which patients would benefit.”

The trial enrolled 40 patients with relapsed or refractory de novo (n=27) or transformed (n=13) DLBCL. The patients’ median age was 59.8 (range, 28.9-78.6). They received a median of 3 prior therapies (range, 1-9), and 75% of patients (n=30) were refractory to their most recent therapy.

The patients received panobinostat at 30 mg three times a week, with rituximab (n=19) or without (n=21).

Adverse events

The most common grade 3 or higher adverse events (AEs) that were thought to be related to panobinostat (with and without rituximab, respectively) were thrombocytopenia (68% and 71%) and neutropenia (11% and 24%).

Twenty-three patients (58%) required dose reductions, and 22 (55%) required dose interruptions. All of these were due to AEs, and there was no difference between patients who received rituximab and those who did not.

All 19 serious AEs were a result of disease progression.

Response

Twenty-eight percent of the patients (11/40) responded to treatment, and receiving rituximab did not increase the likelihood of response. Six patients (29%) responded to panobinostat alone, and 5 (26%) responded to panobinostat and rituximab.

There were 7 complete responses—5 of them among patients who received panobinostat alone. And there were 4 partial responses—3 among the patients who received panobinostat plus rituximab.

The median duration of response was 14.5 months overall, 9.4 months among patients who received panobinostat plus rituximab, and it was not reached among patients who received panobinostat alone.

At the data cutoff, 6 of the 11 responders had not progressed. The longest response had lasted more than 43 months and was ongoing at the cutoff point.

Predicting response

The researchers performed genome and exome sequencing in relapsed tumor biopsies and quantified ctDNA in serial plasma samples.

They found that mutations in MEF2B were significantly associated with response to panobinostat. The likelihood ratio for response was 3.67 for patients with MEF2B mutations.

On the other hand, increased levels of ctDNA were strongly associated with treatment failure. A significant increase in ctDNA at day 15 after treatment initiation could predict a lack of response with a sensitivity of 71.4% and a specificity of 100%.

“This trial has generated considerable data regarding methodology for processing samples from a clinical study, the genetic mutations associated with DLBCL and how they evolve over time, on ctDNA, and mechanisms of resistance to histone deacetylase inhibitors,” Dr Assouline concluded.

Novartis provided panobinostat and financial support for this trial, and Hoffman-LaRoche supplied rituximab.

Diffuse large B-cell lymphoma

The histone deacetylase inhibitor panobinostat can produce durable responses in certain patients with relapsed diffuse large B-cell lymphoma (DLBCL), according to a phase 2 trial.

Though less than 30% of the patients in this trial responded to treatment, the median duration of response was 14.5 months, and the longest ongoing response has lasted more than 3.5 years.

In addition, researchers found the presence of mutations in MEF2B and levels of circulating tumor DNA (ctDNA) could be used to predict response.

Sarit Assouline, MD, of Jewish General Hospital in Montreal, Quebec, Canada, and her colleagues reported these findings in Blood.

“DLBCL is one of the more common forms of lymphoma and is highly aggressive,” Dr Assouline noted. “Following relapse, there are no effective standards of treatment, and life expectancy averages 6 months.”

“Our challenge is to identify new biomarkers and target specific mutations in order to improve the prognosis. While many clinical trials simply report on how patients respond to a therapy, we devised this study to reveal the mechanisms on which the therapy works in order to understand which patients would benefit.”

The trial enrolled 40 patients with relapsed or refractory de novo (n=27) or transformed (n=13) DLBCL. The patients’ median age was 59.8 (range, 28.9-78.6). They received a median of 3 prior therapies (range, 1-9), and 75% of patients (n=30) were refractory to their most recent therapy.

The patients received panobinostat at 30 mg three times a week, with rituximab (n=19) or without (n=21).

Adverse events

The most common grade 3 or higher adverse events (AEs) that were thought to be related to panobinostat (with and without rituximab, respectively) were thrombocytopenia (68% and 71%) and neutropenia (11% and 24%).

Twenty-three patients (58%) required dose reductions, and 22 (55%) required dose interruptions. All of these were due to AEs, and there was no difference between patients who received rituximab and those who did not.

All 19 serious AEs were a result of disease progression.

Response

Twenty-eight percent of the patients (11/40) responded to treatment, and receiving rituximab did not increase the likelihood of response. Six patients (29%) responded to panobinostat alone, and 5 (26%) responded to panobinostat and rituximab.

There were 7 complete responses—5 of them among patients who received panobinostat alone. And there were 4 partial responses—3 among the patients who received panobinostat plus rituximab.

The median duration of response was 14.5 months overall, 9.4 months among patients who received panobinostat plus rituximab, and it was not reached among patients who received panobinostat alone.

At the data cutoff, 6 of the 11 responders had not progressed. The longest response had lasted more than 43 months and was ongoing at the cutoff point.

Predicting response

The researchers performed genome and exome sequencing in relapsed tumor biopsies and quantified ctDNA in serial plasma samples.

They found that mutations in MEF2B were significantly associated with response to panobinostat. The likelihood ratio for response was 3.67 for patients with MEF2B mutations.

On the other hand, increased levels of ctDNA were strongly associated with treatment failure. A significant increase in ctDNA at day 15 after treatment initiation could predict a lack of response with a sensitivity of 71.4% and a specificity of 100%.

“This trial has generated considerable data regarding methodology for processing samples from a clinical study, the genetic mutations associated with DLBCL and how they evolve over time, on ctDNA, and mechanisms of resistance to histone deacetylase inhibitors,” Dr Assouline concluded.

Novartis provided panobinostat and financial support for this trial, and Hoffman-LaRoche supplied rituximab.

 

 

Micrograph showing DLBCL

 

ProNAi Therapeutics recently announced its decision to stop development of PNT2258, a drug designed to treat cancers characterized by overexpression of BCL2.

In June, the company suspended development of PNT2258, closing enrollment in a phase 2 trial of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and a phase 2 trial of patients with Richter’s transformation.

Now, ProNAi has said it does not plan to resume development of the drug.

“[N]o further investment in PNT2258 or the underlying DNAi platform by ProNAi is contemplated, and the company subsequently has closed its research facility based in Plymouth, Michigan, which supported these programs,” the company said in a statement.

About PNT2258

PNT2258 consists of a single-stranded, 24-base DNAi oligonucleotide known as PNT100 that is encapsulated in lipid nanoparticles.

The DNAi technology platform is based on a discovery that single-stranded DNA oligonucleotides can interact with genomic DNA to interfere with oncogenes. PNT100 DNAi is designed to target a genetic regulatory region associated with BCL2.

Last March, PNT2258 was granted orphan drug designation from the US Food and Drug Administration for the treatment of DLBCL.

ProNAi initially suspended the development of PNT2258 in June, following a review of interim data from the phase 2 Wolverine trial. The company said the drug produced “modest efficacy” in this trial, but it seemed the data were not “robust enough” to justify continued development of PNT2258.

“We have decided to suspend development of PNT2258 pending further review of these data in order to determine next steps for both this asset and the DNAi platform,” Nick Glover, president and CEO of ProNAi, said at the time.

The Wolverine trial was designed to evaluate the safety and efficacy of PNT2258 monotherapy in 61 patients with relapsed/refractory DLBCL.

ProNAi reported interim safety and efficacy data as of April 25, 2016, for the first 37 subjects enrolled. The response rate was 8.1% overall (n=37) and 15.8% in the response-evaluable subgroup (n=19).

Subjects were considered response-evaluable if they met the amended eligibility criteria—a performance status of 0 to 1, 1 to 3 prior systemic treatment regimens, and receipt of at least 8 doses of PNT2258 within 35 days of starting therapy.

PNT2258 was also being evaluated in patients with Richter’s transformation in the phase 2 Brighton study. In June, ProNAi said it had enrolled 5 subjects in this study, and 4 had discontinued. No responses were observed.

“On the basis of these interim assessments, we have decided to close the Wolverine and Brighton studies to further enrollment of new subjects,” Barbara Klencke, chief development officer of ProNAi, said at the time.

PNT2258 was evaluated in 2 prior studies as well. In a phase 1 study (NCT01191775), PNT2258 was given to 22 subjects with advanced solid tumors. The drug was considered well tolerated at doses ranging from 1 mg/m² through 150 mg/m².

A pilot study of PNT2258 (NCT01733238) enrolled 13 subjects with relapsed/refractory B-cell non-Hodgkin lymphoma. Responses were observed in subjects with DLBCL and those with follicular lymphoma.

Six subjects were progression-free at 12 months, and progression-free survival extended to 2 years and beyond in 4 subjects. The majority of the adverse events were grade 1 or 2.

 

 

Micrograph showing DLBCL

 

ProNAi Therapeutics recently announced its decision to stop development of PNT2258, a drug designed to treat cancers characterized by overexpression of BCL2.

In June, the company suspended development of PNT2258, closing enrollment in a phase 2 trial of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and a phase 2 trial of patients with Richter’s transformation.

Now, ProNAi has said it does not plan to resume development of the drug.

“[N]o further investment in PNT2258 or the underlying DNAi platform by ProNAi is contemplated, and the company subsequently has closed its research facility based in Plymouth, Michigan, which supported these programs,” the company said in a statement.

About PNT2258

PNT2258 consists of a single-stranded, 24-base DNAi oligonucleotide known as PNT100 that is encapsulated in lipid nanoparticles.

The DNAi technology platform is based on a discovery that single-stranded DNA oligonucleotides can interact with genomic DNA to interfere with oncogenes. PNT100 DNAi is designed to target a genetic regulatory region associated with BCL2.

Last March, PNT2258 was granted orphan drug designation from the US Food and Drug Administration for the treatment of DLBCL.

ProNAi initially suspended the development of PNT2258 in June, following a review of interim data from the phase 2 Wolverine trial. The company said the drug produced “modest efficacy” in this trial, but it seemed the data were not “robust enough” to justify continued development of PNT2258.

“We have decided to suspend development of PNT2258 pending further review of these data in order to determine next steps for both this asset and the DNAi platform,” Nick Glover, president and CEO of ProNAi, said at the time.

The Wolverine trial was designed to evaluate the safety and efficacy of PNT2258 monotherapy in 61 patients with relapsed/refractory DLBCL.

ProNAi reported interim safety and efficacy data as of April 25, 2016, for the first 37 subjects enrolled. The response rate was 8.1% overall (n=37) and 15.8% in the response-evaluable subgroup (n=19).

Subjects were considered response-evaluable if they met the amended eligibility criteria—a performance status of 0 to 1, 1 to 3 prior systemic treatment regimens, and receipt of at least 8 doses of PNT2258 within 35 days of starting therapy.

PNT2258 was also being evaluated in patients with Richter’s transformation in the phase 2 Brighton study. In June, ProNAi said it had enrolled 5 subjects in this study, and 4 had discontinued. No responses were observed.

“On the basis of these interim assessments, we have decided to close the Wolverine and Brighton studies to further enrollment of new subjects,” Barbara Klencke, chief development officer of ProNAi, said at the time.

PNT2258 was evaluated in 2 prior studies as well. In a phase 1 study (NCT01191775), PNT2258 was given to 22 subjects with advanced solid tumors. The drug was considered well tolerated at doses ranging from 1 mg/m² through 150 mg/m².

A pilot study of PNT2258 (NCT01733238) enrolled 13 subjects with relapsed/refractory B-cell non-Hodgkin lymphoma. Responses were observed in subjects with DLBCL and those with follicular lymphoma.

Six subjects were progression-free at 12 months, and progression-free survival extended to 2 years and beyond in 4 subjects. The majority of the adverse events were grade 1 or 2.

 

 

Micrograph showing DLBCL

 

ProNAi Therapeutics recently announced its decision to stop development of PNT2258, a drug designed to treat cancers characterized by overexpression of BCL2.

In June, the company suspended development of PNT2258, closing enrollment in a phase 2 trial of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and a phase 2 trial of patients with Richter’s transformation.

Now, ProNAi has said it does not plan to resume development of the drug.

“[N]o further investment in PNT2258 or the underlying DNAi platform by ProNAi is contemplated, and the company subsequently has closed its research facility based in Plymouth, Michigan, which supported these programs,” the company said in a statement.

About PNT2258

PNT2258 consists of a single-stranded, 24-base DNAi oligonucleotide known as PNT100 that is encapsulated in lipid nanoparticles.

The DNAi technology platform is based on a discovery that single-stranded DNA oligonucleotides can interact with genomic DNA to interfere with oncogenes. PNT100 DNAi is designed to target a genetic regulatory region associated with BCL2.

Last March, PNT2258 was granted orphan drug designation from the US Food and Drug Administration for the treatment of DLBCL.

ProNAi initially suspended the development of PNT2258 in June, following a review of interim data from the phase 2 Wolverine trial. The company said the drug produced “modest efficacy” in this trial, but it seemed the data were not “robust enough” to justify continued development of PNT2258.

“We have decided to suspend development of PNT2258 pending further review of these data in order to determine next steps for both this asset and the DNAi platform,” Nick Glover, president and CEO of ProNAi, said at the time.

The Wolverine trial was designed to evaluate the safety and efficacy of PNT2258 monotherapy in 61 patients with relapsed/refractory DLBCL.

ProNAi reported interim safety and efficacy data as of April 25, 2016, for the first 37 subjects enrolled. The response rate was 8.1% overall (n=37) and 15.8% in the response-evaluable subgroup (n=19).

Subjects were considered response-evaluable if they met the amended eligibility criteria—a performance status of 0 to 1, 1 to 3 prior systemic treatment regimens, and receipt of at least 8 doses of PNT2258 within 35 days of starting therapy.

PNT2258 was also being evaluated in patients with Richter’s transformation in the phase 2 Brighton study. In June, ProNAi said it had enrolled 5 subjects in this study, and 4 had discontinued. No responses were observed.

“On the basis of these interim assessments, we have decided to close the Wolverine and Brighton studies to further enrollment of new subjects,” Barbara Klencke, chief development officer of ProNAi, said at the time.

PNT2258 was evaluated in 2 prior studies as well. In a phase 1 study (NCT01191775), PNT2258 was given to 22 subjects with advanced solid tumors. The drug was considered well tolerated at doses ranging from 1 mg/m² through 150 mg/m².

A pilot study of PNT2258 (NCT01733238) enrolled 13 subjects with relapsed/refractory B-cell non-Hodgkin lymphoma. Responses were observed in subjects with DLBCL and those with follicular lymphoma.

Six subjects were progression-free at 12 months, and progression-free survival extended to 2 years and beyond in 4 subjects. The majority of the adverse events were grade 1 or 2.