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A novel Bruton’s tyrosine kinase inhibitor has proven life-changing for patients with chronic lymphocytic leukemia (CLL) who received the drug as part of a phase 1 trial, according to the study’s lead author.
The inhibitor, ONO/GS-4059, produced a response in 96% of evaluable CLL patients.
Most CLL patients are still on the study after 3 years, although a handful withdrew due to adverse events (AEs) or disease progression.
“These patients were confronted with a cruel reality: they had failed multiple chemotherapy lines, and there were no other treatment options available for them,” said lead study author Harriet Walter, MBChB, of the University of Leicester in the UK.
“This drug has changed their lives. From desperate and tired, they are now leading a normal and really active life. This is hugely rewarding and encouraging.”
Dr Walter and her colleagues reported these results in Blood. The trial was funded by ONO Pharmaceuticals, the company developing ONO/GS-4059.
This study opened in January 2012, and 90 patients were enrolled at centers in the UK and France. There were 28 patients with CLL and 62 with non-Hodgkin lymphoma (NHL), including 16 with mantle cell lymphoma (MCL) and 35 with diffuse large B-cell lymphoma (DLBCL).
The study also included patients with follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, and Waldenstrom’s macroglobulinemia, but patient numbers were small for these groups, so the results were not discussed in detail.
There were 9 dose-escalation cohorts in this study. ONO/GS-4059 was given once-daily at doses ranging from 20 mg to 600 mg. Or the drug was given twice daily at doses of 240 mg or 300 mg.
Results
The maximum tolerated dose was not reached in the CLL cohort, but it was 480 mg once-daily in the NHL cohort. Four NHL patients had a dose-limiting toxicity.
In the CLL cohort, 2 patients went off study due to progression and 5 due to AEs.
In the NHL cohort, 49 patients discontinued treatment, 32 due to progression and 5 due to dose-limiting toxicities or AEs. The other 12 NHL patients discontinued due to patient or investigator decision, proceeding to transplant (n=1), or death due to progressive disease.
The median duration of follow-up was 560 days for CLL patients, 309 days for MCL patients, and 60 days for DLBCL patients.
The overall estimated mean progression-free survival was 874 days for CLL patients, 341 days for MCL patients, and 54 days for DLBCL patients.
CLL patients
Of all 28 CLL patients, 16 had relapsed CLL, 11 had refractory disease, and 1 had unknown status. The median number of prior therapies was 3.5 (range, 2-7).
Twenty-five patients were evaluable. Of the 3 who were not evaluable, 1 had not reached cycle 3 disease assessment at the time of data analysis, 1 progressed during cycle 1, and 1 was withdrawn due to an AE (idiopathic thrombocytopenia).
Of the 25 evaluable patients, 24 (96%) responded to ONO/GS-4059. The researchers said they observed rapid resolution of bulky lymphadenopathy within the first 3 months of treatment, but improvement in lymphadenopathy continued for up to 18 months in most patients.
The median treatment duration for these patients is 80 weeks, and 21 patients are still on treatment. Two of the evaluable patients progressed during therapy, one at cycle 3 and one at cycle 12.
MCL patients
Of the 16 MCL patients enrolled, 7 were refractory to their last course of immuno-chemotherapy. The median number of prior therapies was 3 (range, 2-7).
Eleven of 12 (92%) evaluable patients with MCL responded to ONO/GS-4059. Six patients had a partial response, and 5 had a complete response (CR) or unconfirmed CR.
Three patients progressed after an initial response. Four patients were not evaluable because they progressed.
The median treatment duration for MCL patients is 40 weeks, and 8 patients remain on study.
DLBCL patients
All 35 DLBCL patients had relapsed or refractory disease. The median number of prior treatments was 3
(range, 2-10), and 30 patients were refractory to their last line of chemotherapy.
Eleven of 31 (35%) patients with non-germinal center B-cell (non-GCB) DLBCL responded to ONO/GS-4059. Two non-GCB DLBCL patients had a confirmed CR, 1 had an unconfirmed CR, and the rest had partial responses.
The median duration of response was 54 days. And, among responders, the median treatment duration was 12 weeks.
The majority of non-GCB DLBCL patients progressed. There were no responses among the 2 patients with GCB DLBCL, and there were no responses among patients with primary mediastinal B-cell lymphoma or plasmablastic DLBCL.
Toxicity
AEs in this study were mostly grade 1/2—75% in the CLL cohort and 50% in the NHL cohort. However, treatment-related grade 3/4 AEs occurred in 14.3% of CLL patients and 16.1% of NHL patients.
Grade 3/4 events were mainly hematologic in nature and included neutropenia (10%), anemia (13.3%), and thrombocytopenia (13.3%).
There was a grade 3 episode of drug-related hemorrhage in a CLL patient, which resulted in a psoas hematoma (with concomitant CLL progression) in the presence of a normal platelet count. This patient was among those taken off the study.
“The next step is now to see how best we can improve on these outstanding results,” said study author Martin Dyer, DPhil, of the University of Leicester.
“A further study using this drug in combination with additional targeted agents is shortly to open in Leicester with the aim of achieving cure. In parallel with the clinical development of the drug, our team of scientists at the Haematological Research Institute are studying how this drug is working and how to overcome potential resistance.” 
Photo courtesy of NIH
A novel Bruton’s tyrosine kinase inhibitor has proven life-changing for patients with chronic lymphocytic leukemia (CLL) who received the drug as part of a phase 1 trial, according to the study’s lead author.
The inhibitor, ONO/GS-4059, produced a response in 96% of evaluable CLL patients.
Most CLL patients are still on the study after 3 years, although a handful withdrew due to adverse events (AEs) or disease progression.
“These patients were confronted with a cruel reality: they had failed multiple chemotherapy lines, and there were no other treatment options available for them,” said lead study author Harriet Walter, MBChB, of the University of Leicester in the UK.
“This drug has changed their lives. From desperate and tired, they are now leading a normal and really active life. This is hugely rewarding and encouraging.”
Dr Walter and her colleagues reported these results in Blood. The trial was funded by ONO Pharmaceuticals, the company developing ONO/GS-4059.
This study opened in January 2012, and 90 patients were enrolled at centers in the UK and France. There were 28 patients with CLL and 62 with non-Hodgkin lymphoma (NHL), including 16 with mantle cell lymphoma (MCL) and 35 with diffuse large B-cell lymphoma (DLBCL).
The study also included patients with follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, and Waldenstrom’s macroglobulinemia, but patient numbers were small for these groups, so the results were not discussed in detail.
There were 9 dose-escalation cohorts in this study. ONO/GS-4059 was given once-daily at doses ranging from 20 mg to 600 mg. Or the drug was given twice daily at doses of 240 mg or 300 mg.
Results
The maximum tolerated dose was not reached in the CLL cohort, but it was 480 mg once-daily in the NHL cohort. Four NHL patients had a dose-limiting toxicity.
In the CLL cohort, 2 patients went off study due to progression and 5 due to AEs.
In the NHL cohort, 49 patients discontinued treatment, 32 due to progression and 5 due to dose-limiting toxicities or AEs. The other 12 NHL patients discontinued due to patient or investigator decision, proceeding to transplant (n=1), or death due to progressive disease.
The median duration of follow-up was 560 days for CLL patients, 309 days for MCL patients, and 60 days for DLBCL patients.
The overall estimated mean progression-free survival was 874 days for CLL patients, 341 days for MCL patients, and 54 days for DLBCL patients.
CLL patients
Of all 28 CLL patients, 16 had relapsed CLL, 11 had refractory disease, and 1 had unknown status. The median number of prior therapies was 3.5 (range, 2-7).
Twenty-five patients were evaluable. Of the 3 who were not evaluable, 1 had not reached cycle 3 disease assessment at the time of data analysis, 1 progressed during cycle 1, and 1 was withdrawn due to an AE (idiopathic thrombocytopenia).
Of the 25 evaluable patients, 24 (96%) responded to ONO/GS-4059. The researchers said they observed rapid resolution of bulky lymphadenopathy within the first 3 months of treatment, but improvement in lymphadenopathy continued for up to 18 months in most patients.
The median treatment duration for these patients is 80 weeks, and 21 patients are still on treatment. Two of the evaluable patients progressed during therapy, one at cycle 3 and one at cycle 12.
MCL patients
Of the 16 MCL patients enrolled, 7 were refractory to their last course of immuno-chemotherapy. The median number of prior therapies was 3 (range, 2-7).
Eleven of 12 (92%) evaluable patients with MCL responded to ONO/GS-4059. Six patients had a partial response, and 5 had a complete response (CR) or unconfirmed CR.
Three patients progressed after an initial response. Four patients were not evaluable because they progressed.
The median treatment duration for MCL patients is 40 weeks, and 8 patients remain on study.
DLBCL patients
All 35 DLBCL patients had relapsed or refractory disease. The median number of prior treatments was 3
(range, 2-10), and 30 patients were refractory to their last line of chemotherapy.
Eleven of 31 (35%) patients with non-germinal center B-cell (non-GCB) DLBCL responded to ONO/GS-4059. Two non-GCB DLBCL patients had a confirmed CR, 1 had an unconfirmed CR, and the rest had partial responses.
The median duration of response was 54 days. And, among responders, the median treatment duration was 12 weeks.
The majority of non-GCB DLBCL patients progressed. There were no responses among the 2 patients with GCB DLBCL, and there were no responses among patients with primary mediastinal B-cell lymphoma or plasmablastic DLBCL.
Toxicity
AEs in this study were mostly grade 1/2—75% in the CLL cohort and 50% in the NHL cohort. However, treatment-related grade 3/4 AEs occurred in 14.3% of CLL patients and 16.1% of NHL patients.
Grade 3/4 events were mainly hematologic in nature and included neutropenia (10%), anemia (13.3%), and thrombocytopenia (13.3%).
There was a grade 3 episode of drug-related hemorrhage in a CLL patient, which resulted in a psoas hematoma (with concomitant CLL progression) in the presence of a normal platelet count. This patient was among those taken off the study.
“The next step is now to see how best we can improve on these outstanding results,” said study author Martin Dyer, DPhil, of the University of Leicester.
“A further study using this drug in combination with additional targeted agents is shortly to open in Leicester with the aim of achieving cure. In parallel with the clinical development of the drug, our team of scientists at the Haematological Research Institute are studying how this drug is working and how to overcome potential resistance.”
Photo courtesy of NIH
A novel Bruton’s tyrosine kinase inhibitor has proven life-changing for patients with chronic lymphocytic leukemia (CLL) who received the drug as part of a phase 1 trial, according to the study’s lead author.
The inhibitor, ONO/GS-4059, produced a response in 96% of evaluable CLL patients.
Most CLL patients are still on the study after 3 years, although a handful withdrew due to adverse events (AEs) or disease progression.
“These patients were confronted with a cruel reality: they had failed multiple chemotherapy lines, and there were no other treatment options available for them,” said lead study author Harriet Walter, MBChB, of the University of Leicester in the UK.
“This drug has changed their lives. From desperate and tired, they are now leading a normal and really active life. This is hugely rewarding and encouraging.”
Dr Walter and her colleagues reported these results in Blood. The trial was funded by ONO Pharmaceuticals, the company developing ONO/GS-4059.
This study opened in January 2012, and 90 patients were enrolled at centers in the UK and France. There were 28 patients with CLL and 62 with non-Hodgkin lymphoma (NHL), including 16 with mantle cell lymphoma (MCL) and 35 with diffuse large B-cell lymphoma (DLBCL).
The study also included patients with follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, and Waldenstrom’s macroglobulinemia, but patient numbers were small for these groups, so the results were not discussed in detail.
There were 9 dose-escalation cohorts in this study. ONO/GS-4059 was given once-daily at doses ranging from 20 mg to 600 mg. Or the drug was given twice daily at doses of 240 mg or 300 mg.
Results
The maximum tolerated dose was not reached in the CLL cohort, but it was 480 mg once-daily in the NHL cohort. Four NHL patients had a dose-limiting toxicity.
In the CLL cohort, 2 patients went off study due to progression and 5 due to AEs.
In the NHL cohort, 49 patients discontinued treatment, 32 due to progression and 5 due to dose-limiting toxicities or AEs. The other 12 NHL patients discontinued due to patient or investigator decision, proceeding to transplant (n=1), or death due to progressive disease.
The median duration of follow-up was 560 days for CLL patients, 309 days for MCL patients, and 60 days for DLBCL patients.
The overall estimated mean progression-free survival was 874 days for CLL patients, 341 days for MCL patients, and 54 days for DLBCL patients.
CLL patients
Of all 28 CLL patients, 16 had relapsed CLL, 11 had refractory disease, and 1 had unknown status. The median number of prior therapies was 3.5 (range, 2-7).
Twenty-five patients were evaluable. Of the 3 who were not evaluable, 1 had not reached cycle 3 disease assessment at the time of data analysis, 1 progressed during cycle 1, and 1 was withdrawn due to an AE (idiopathic thrombocytopenia).
Of the 25 evaluable patients, 24 (96%) responded to ONO/GS-4059. The researchers said they observed rapid resolution of bulky lymphadenopathy within the first 3 months of treatment, but improvement in lymphadenopathy continued for up to 18 months in most patients.
The median treatment duration for these patients is 80 weeks, and 21 patients are still on treatment. Two of the evaluable patients progressed during therapy, one at cycle 3 and one at cycle 12.
MCL patients
Of the 16 MCL patients enrolled, 7 were refractory to their last course of immuno-chemotherapy. The median number of prior therapies was 3 (range, 2-7).
Eleven of 12 (92%) evaluable patients with MCL responded to ONO/GS-4059. Six patients had a partial response, and 5 had a complete response (CR) or unconfirmed CR.
Three patients progressed after an initial response. Four patients were not evaluable because they progressed.
The median treatment duration for MCL patients is 40 weeks, and 8 patients remain on study.
DLBCL patients
All 35 DLBCL patients had relapsed or refractory disease. The median number of prior treatments was 3
(range, 2-10), and 30 patients were refractory to their last line of chemotherapy.
Eleven of 31 (35%) patients with non-germinal center B-cell (non-GCB) DLBCL responded to ONO/GS-4059. Two non-GCB DLBCL patients had a confirmed CR, 1 had an unconfirmed CR, and the rest had partial responses.
The median duration of response was 54 days. And, among responders, the median treatment duration was 12 weeks.
The majority of non-GCB DLBCL patients progressed. There were no responses among the 2 patients with GCB DLBCL, and there were no responses among patients with primary mediastinal B-cell lymphoma or plasmablastic DLBCL.
Toxicity
AEs in this study were mostly grade 1/2—75% in the CLL cohort and 50% in the NHL cohort. However, treatment-related grade 3/4 AEs occurred in 14.3% of CLL patients and 16.1% of NHL patients.
Grade 3/4 events were mainly hematologic in nature and included neutropenia (10%), anemia (13.3%), and thrombocytopenia (13.3%).
There was a grade 3 episode of drug-related hemorrhage in a CLL patient, which resulted in a psoas hematoma (with concomitant CLL progression) in the presence of a normal platelet count. This patient was among those taken off the study.
“The next step is now to see how best we can improve on these outstanding results,” said study author Martin Dyer, DPhil, of the University of Leicester.
“A further study using this drug in combination with additional targeted agents is shortly to open in Leicester with the aim of achieving cure. In parallel with the clinical development of the drug, our team of scientists at the Haematological Research Institute are studying how this drug is working and how to overcome potential resistance.”