PRELIMINARY RESULTS OF A PHASE I/IB STUDY OF IBRUTINIB IN COMBINATION WITH TGR-1202 IN PATIENTS WITH RELAPSED/REFRACTORY CLL OR MCL
(Abstract release date: 05/19/16)
EHA Library. Davids M. 06/09/16; 132602; E1053
Dr. Matthew Davids
Contributions
Contributions
Abstract
Abstract: E1053
Type: Eposter Presentation
Background
The oral BTK inhibitor ibrutinib is effective and well-tolerated for patients (pts) with relapsed/refractory (R/R) CLL and MCL; however, the rate of complete remission (CR) is low, and response duration is limited in MCL and in CLL with del(17p) or complex cytogenetics. TGR-1202 is a 2nd generation oral PI3K-delta specific inhibitor with promising efficacy and tolerability. We hypothesized that dual BCR pathway blockade would be tolerable and efficacious.
Aims
The primary aim of this open-label, phase I/Ib investigator-initiated multicenter trial is to determine the RP2D (recommended phase 2 dose) and the safety/tolerability of TGR-1202 plus ibrutinib in pts with R/R CLL or MCL. Secondary aims are to assess efficacy including response rates, duration of response, and PFS/OS.
Methods
Pts received continuous simultaneous daily oral dosing of ibrutinib (420 mg CLL, 560 mg MCL) and TGR-1202, starting at 400 mg daily and escalating in a standard 3 + 3 design from 600 to 800 mg. The DLT observation period was the first 28 day cycle, with CLL and MCL pts evaluated in separate cohorts. Pts continue until progression or unacceptable toxicity. Eligibility criteria include: ≥1 prior therapy, requiring treatment by IW-CLL criteria, ECOG PS ≤2, and adequate hematologic and organ function. Prior BTK or PI3K inhibitors were allowed. CTCAE v4 and IW-CLL criteria were used to evaluate toxicity and efficacy, with response evaluations after 2 mo., every 3 mo. up to 1 year, and every 6 mo. thereafter.
Results
As of 25 Feb 2016, 20 pts were enrolled, 10 CLL, 10 MCL. The median age at enrollment was 66 yrs. (range 48-83). The median number of prior therapies was 2 for CLL (range 1-6, including 2 with prior ibrutinib and 2 with prior PI3Ki) and 3 for MCL (range 2-5, including 2 with prior ibrutinib). Two CLL pts had del(17p), 2 had del (11q), and 7/10 (70%) had unmutated IGHV. The phase I portion in both diseases is now complete. Hematologic toxicities in CLL: neutropenia (37.5%, all gr 3-4), thrombocytopenia (25%, all gr 1), and anemia (37.5%, all gr 1/2). All grade non-hematologic toxicities occurring in >25% of CLL pts: diarrhea and nausea (37.5% each, all gr 1). There were no DLTs, and SAEs included gr 3 atrial fibrillation, gr 3 lipase elevation, and gr 3 CNS infection. The RP2D of TGR-1202 was 800 mg. Hematologic toxicities in MCL: neutropenia (37.5%, 12.5% gr 4), thrombocytopenia (50%, 12.5% gr 3), and anemia (37.5%, 12.5% gr 3). All grade non-hematologic toxicities occurring in >25% of MCL pts: diarrhea (75% [62.5% gr 1, 12.5% gr 2]), fatigue (50%, all gr 1/2), and 37.5% each for nausea (all gr 1/2) and transaminitis, dizziness, hypocalcemia (all gr 1). There were no DLTs, and SAEs included gr 3 hypophosphatemia in 2 pts and 1 pt with gr 3 amylase / gr 4 lipase elevation. The RP2D of TGR-1202 was 800 mg. There were no gr 3/4 bleeding events in either cohort. 6/9 (68%) of CLL pts achieved response, including 1 CR and 5 PR or PR-L. 4/7 (57%) of MCL pts who have reached the first response evaluation achieved response (all PR).
Conclusion
We report to our knowledge the first clinical data on combined delta-PI3K and BTK inhibition in B cell malignancies. TGR-1202 plus ibrutinib is well-tolerated in pts with R/R CLL and MCL, with no DLTs observed to date. The RP2D of TGR-1202 for both CLL and MCL was 800 mg daily. Preliminary efficacy data suggest a high response rate in both diseases, and phase Ib expansion cohorts at 800 mg are now accruing in this ongoing study (NCT 02268851).
Session topic: E-poster
Keyword(s): Chronic lymphocytic leukemia, Clinical trial, Kinase inhibitor, Mantle cell lymphoma
Type: Eposter Presentation
Background
The oral BTK inhibitor ibrutinib is effective and well-tolerated for patients (pts) with relapsed/refractory (R/R) CLL and MCL; however, the rate of complete remission (CR) is low, and response duration is limited in MCL and in CLL with del(17p) or complex cytogenetics. TGR-1202 is a 2nd generation oral PI3K-delta specific inhibitor with promising efficacy and tolerability. We hypothesized that dual BCR pathway blockade would be tolerable and efficacious.
Aims
The primary aim of this open-label, phase I/Ib investigator-initiated multicenter trial is to determine the RP2D (recommended phase 2 dose) and the safety/tolerability of TGR-1202 plus ibrutinib in pts with R/R CLL or MCL. Secondary aims are to assess efficacy including response rates, duration of response, and PFS/OS.
Methods
Pts received continuous simultaneous daily oral dosing of ibrutinib (420 mg CLL, 560 mg MCL) and TGR-1202, starting at 400 mg daily and escalating in a standard 3 + 3 design from 600 to 800 mg. The DLT observation period was the first 28 day cycle, with CLL and MCL pts evaluated in separate cohorts. Pts continue until progression or unacceptable toxicity. Eligibility criteria include: ≥1 prior therapy, requiring treatment by IW-CLL criteria, ECOG PS ≤2, and adequate hematologic and organ function. Prior BTK or PI3K inhibitors were allowed. CTCAE v4 and IW-CLL criteria were used to evaluate toxicity and efficacy, with response evaluations after 2 mo., every 3 mo. up to 1 year, and every 6 mo. thereafter.
Results
As of 25 Feb 2016, 20 pts were enrolled, 10 CLL, 10 MCL. The median age at enrollment was 66 yrs. (range 48-83). The median number of prior therapies was 2 for CLL (range 1-6, including 2 with prior ibrutinib and 2 with prior PI3Ki) and 3 for MCL (range 2-5, including 2 with prior ibrutinib). Two CLL pts had del(17p), 2 had del (11q), and 7/10 (70%) had unmutated IGHV. The phase I portion in both diseases is now complete. Hematologic toxicities in CLL: neutropenia (37.5%, all gr 3-4), thrombocytopenia (25%, all gr 1), and anemia (37.5%, all gr 1/2). All grade non-hematologic toxicities occurring in >25% of CLL pts: diarrhea and nausea (37.5% each, all gr 1). There were no DLTs, and SAEs included gr 3 atrial fibrillation, gr 3 lipase elevation, and gr 3 CNS infection. The RP2D of TGR-1202 was 800 mg. Hematologic toxicities in MCL: neutropenia (37.5%, 12.5% gr 4), thrombocytopenia (50%, 12.5% gr 3), and anemia (37.5%, 12.5% gr 3). All grade non-hematologic toxicities occurring in >25% of MCL pts: diarrhea (75% [62.5% gr 1, 12.5% gr 2]), fatigue (50%, all gr 1/2), and 37.5% each for nausea (all gr 1/2) and transaminitis, dizziness, hypocalcemia (all gr 1). There were no DLTs, and SAEs included gr 3 hypophosphatemia in 2 pts and 1 pt with gr 3 amylase / gr 4 lipase elevation. The RP2D of TGR-1202 was 800 mg. There were no gr 3/4 bleeding events in either cohort. 6/9 (68%) of CLL pts achieved response, including 1 CR and 5 PR or PR-L. 4/7 (57%) of MCL pts who have reached the first response evaluation achieved response (all PR).
Conclusion
We report to our knowledge the first clinical data on combined delta-PI3K and BTK inhibition in B cell malignancies. TGR-1202 plus ibrutinib is well-tolerated in pts with R/R CLL and MCL, with no DLTs observed to date. The RP2D of TGR-1202 for both CLL and MCL was 800 mg daily. Preliminary efficacy data suggest a high response rate in both diseases, and phase Ib expansion cohorts at 800 mg are now accruing in this ongoing study (NCT 02268851).
Session topic: E-poster
Keyword(s): Chronic lymphocytic leukemia, Clinical trial, Kinase inhibitor, Mantle cell lymphoma
Abstract: E1053
Type: Eposter Presentation
Background
The oral BTK inhibitor ibrutinib is effective and well-tolerated for patients (pts) with relapsed/refractory (R/R) CLL and MCL; however, the rate of complete remission (CR) is low, and response duration is limited in MCL and in CLL with del(17p) or complex cytogenetics. TGR-1202 is a 2nd generation oral PI3K-delta specific inhibitor with promising efficacy and tolerability. We hypothesized that dual BCR pathway blockade would be tolerable and efficacious.
Aims
The primary aim of this open-label, phase I/Ib investigator-initiated multicenter trial is to determine the RP2D (recommended phase 2 dose) and the safety/tolerability of TGR-1202 plus ibrutinib in pts with R/R CLL or MCL. Secondary aims are to assess efficacy including response rates, duration of response, and PFS/OS.
Methods
Pts received continuous simultaneous daily oral dosing of ibrutinib (420 mg CLL, 560 mg MCL) and TGR-1202, starting at 400 mg daily and escalating in a standard 3 + 3 design from 600 to 800 mg. The DLT observation period was the first 28 day cycle, with CLL and MCL pts evaluated in separate cohorts. Pts continue until progression or unacceptable toxicity. Eligibility criteria include: ≥1 prior therapy, requiring treatment by IW-CLL criteria, ECOG PS ≤2, and adequate hematologic and organ function. Prior BTK or PI3K inhibitors were allowed. CTCAE v4 and IW-CLL criteria were used to evaluate toxicity and efficacy, with response evaluations after 2 mo., every 3 mo. up to 1 year, and every 6 mo. thereafter.
Results
As of 25 Feb 2016, 20 pts were enrolled, 10 CLL, 10 MCL. The median age at enrollment was 66 yrs. (range 48-83). The median number of prior therapies was 2 for CLL (range 1-6, including 2 with prior ibrutinib and 2 with prior PI3Ki) and 3 for MCL (range 2-5, including 2 with prior ibrutinib). Two CLL pts had del(17p), 2 had del (11q), and 7/10 (70%) had unmutated IGHV. The phase I portion in both diseases is now complete. Hematologic toxicities in CLL: neutropenia (37.5%, all gr 3-4), thrombocytopenia (25%, all gr 1), and anemia (37.5%, all gr 1/2). All grade non-hematologic toxicities occurring in >25% of CLL pts: diarrhea and nausea (37.5% each, all gr 1). There were no DLTs, and SAEs included gr 3 atrial fibrillation, gr 3 lipase elevation, and gr 3 CNS infection. The RP2D of TGR-1202 was 800 mg. Hematologic toxicities in MCL: neutropenia (37.5%, 12.5% gr 4), thrombocytopenia (50%, 12.5% gr 3), and anemia (37.5%, 12.5% gr 3). All grade non-hematologic toxicities occurring in >25% of MCL pts: diarrhea (75% [62.5% gr 1, 12.5% gr 2]), fatigue (50%, all gr 1/2), and 37.5% each for nausea (all gr 1/2) and transaminitis, dizziness, hypocalcemia (all gr 1). There were no DLTs, and SAEs included gr 3 hypophosphatemia in 2 pts and 1 pt with gr 3 amylase / gr 4 lipase elevation. The RP2D of TGR-1202 was 800 mg. There were no gr 3/4 bleeding events in either cohort. 6/9 (68%) of CLL pts achieved response, including 1 CR and 5 PR or PR-L. 4/7 (57%) of MCL pts who have reached the first response evaluation achieved response (all PR).
Conclusion
We report to our knowledge the first clinical data on combined delta-PI3K and BTK inhibition in B cell malignancies. TGR-1202 plus ibrutinib is well-tolerated in pts with R/R CLL and MCL, with no DLTs observed to date. The RP2D of TGR-1202 for both CLL and MCL was 800 mg daily. Preliminary efficacy data suggest a high response rate in both diseases, and phase Ib expansion cohorts at 800 mg are now accruing in this ongoing study (NCT 02268851).
Session topic: E-poster
Keyword(s): Chronic lymphocytic leukemia, Clinical trial, Kinase inhibitor, Mantle cell lymphoma
Type: Eposter Presentation
Background
The oral BTK inhibitor ibrutinib is effective and well-tolerated for patients (pts) with relapsed/refractory (R/R) CLL and MCL; however, the rate of complete remission (CR) is low, and response duration is limited in MCL and in CLL with del(17p) or complex cytogenetics. TGR-1202 is a 2nd generation oral PI3K-delta specific inhibitor with promising efficacy and tolerability. We hypothesized that dual BCR pathway blockade would be tolerable and efficacious.
Aims
The primary aim of this open-label, phase I/Ib investigator-initiated multicenter trial is to determine the RP2D (recommended phase 2 dose) and the safety/tolerability of TGR-1202 plus ibrutinib in pts with R/R CLL or MCL. Secondary aims are to assess efficacy including response rates, duration of response, and PFS/OS.
Methods
Pts received continuous simultaneous daily oral dosing of ibrutinib (420 mg CLL, 560 mg MCL) and TGR-1202, starting at 400 mg daily and escalating in a standard 3 + 3 design from 600 to 800 mg. The DLT observation period was the first 28 day cycle, with CLL and MCL pts evaluated in separate cohorts. Pts continue until progression or unacceptable toxicity. Eligibility criteria include: ≥1 prior therapy, requiring treatment by IW-CLL criteria, ECOG PS ≤2, and adequate hematologic and organ function. Prior BTK or PI3K inhibitors were allowed. CTCAE v4 and IW-CLL criteria were used to evaluate toxicity and efficacy, with response evaluations after 2 mo., every 3 mo. up to 1 year, and every 6 mo. thereafter.
Results
As of 25 Feb 2016, 20 pts were enrolled, 10 CLL, 10 MCL. The median age at enrollment was 66 yrs. (range 48-83). The median number of prior therapies was 2 for CLL (range 1-6, including 2 with prior ibrutinib and 2 with prior PI3Ki) and 3 for MCL (range 2-5, including 2 with prior ibrutinib). Two CLL pts had del(17p), 2 had del (11q), and 7/10 (70%) had unmutated IGHV. The phase I portion in both diseases is now complete. Hematologic toxicities in CLL: neutropenia (37.5%, all gr 3-4), thrombocytopenia (25%, all gr 1), and anemia (37.5%, all gr 1/2). All grade non-hematologic toxicities occurring in >25% of CLL pts: diarrhea and nausea (37.5% each, all gr 1). There were no DLTs, and SAEs included gr 3 atrial fibrillation, gr 3 lipase elevation, and gr 3 CNS infection. The RP2D of TGR-1202 was 800 mg. Hematologic toxicities in MCL: neutropenia (37.5%, 12.5% gr 4), thrombocytopenia (50%, 12.5% gr 3), and anemia (37.5%, 12.5% gr 3). All grade non-hematologic toxicities occurring in >25% of MCL pts: diarrhea (75% [62.5% gr 1, 12.5% gr 2]), fatigue (50%, all gr 1/2), and 37.5% each for nausea (all gr 1/2) and transaminitis, dizziness, hypocalcemia (all gr 1). There were no DLTs, and SAEs included gr 3 hypophosphatemia in 2 pts and 1 pt with gr 3 amylase / gr 4 lipase elevation. The RP2D of TGR-1202 was 800 mg. There were no gr 3/4 bleeding events in either cohort. 6/9 (68%) of CLL pts achieved response, including 1 CR and 5 PR or PR-L. 4/7 (57%) of MCL pts who have reached the first response evaluation achieved response (all PR).
Conclusion
We report to our knowledge the first clinical data on combined delta-PI3K and BTK inhibition in B cell malignancies. TGR-1202 plus ibrutinib is well-tolerated in pts with R/R CLL and MCL, with no DLTs observed to date. The RP2D of TGR-1202 for both CLL and MCL was 800 mg daily. Preliminary efficacy data suggest a high response rate in both diseases, and phase Ib expansion cohorts at 800 mg are now accruing in this ongoing study (NCT 02268851).
Session topic: E-poster
Keyword(s): Chronic lymphocytic leukemia, Clinical trial, Kinase inhibitor, Mantle cell lymphoma
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