A Phase 1b, Dose Escalation Study to Determine the Recommended Phase 2 Dose of TAK-659 in Combination With Bendamustine (±Rituximab), Gemcitabine, Lenalidomide, or Ibrutinib for the Treatment of Patients With Advanced Non-Hodgkin Lymphoma After At Least 1 Prior Line of Therapy
Overview
- Phase
- Phase 1
- Intervention
- TAK-659
- Conditions
- Lymphoma, Non-Hodgkin
- Sponsor
- Millennium Pharmaceuticals, Inc.
- Enrollment
- 43
- Locations
- 13
- Primary Endpoint
- Dose Escalation Phase: Maximum Tolerated Dose (MTD) of TAK-659
- Status
- Terminated
- Last Updated
- 4 years ago
Overview
Brief Summary
The purpose of this study is to determine the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of TAK-659 when administered in combination with bendamustine, bendamustine + rituximab, gemcitabine, lenalidomide, or ibrutinib.
Detailed Description
The drug being tested in this study is called TAK-659. TAK-659 is being tested to treat people who have advanced non-Hodgkin lymphoma. This study will determine the MTD or RP2D for TAK-659 in combination with bendamustine, bendamustine + rituximab, gemcitabine, lenalidomide, and ibrutinib. The study will enroll approximately 96 participants. Participants will be assigned to one of the 5 combination cohorts: * Dose Escalation Phase Cohort A: TAK-659 + Bendamustine * Dose Escalation Phase Cohort B: TAK-659 + Bendamustine + Rituximab * Dose Escalation Phase Cohort C: TAK-659 + Gemcitabine * Dose Escalation Phase Cohort D: TAK-659 + Lenalidomide * Dose Escalation Phase Cohort E: TAK-659 + Ibrutinib This study comprises 2 phases: a dose escalation phase and a safety expansion phase. Participants in all 5 cohorts (Cohorts A-E) will participate in the dose escalation phase of the study. Approximately 12 additional participants with advanced follicular lymphoma (FL) or marginal zone lymphoma (MZL) will be added to Cohort B, in the safety expansion phase. This multi-center trial will be conducted in North America and Europe. The overall time to participate in this study is approximately 30 months. Participants will make multiple visits to the clinic and will be followed up for safety for 28 days after the last dose of study drug.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Male or female participants aged 18 years or older.
- •In the dose escalation phase, histologically or cytologically confirmed diagnosis of advanced non-Hodgkin lymphoma (NHL) of any histology (with the exception of participants with Waldenström macroglobulinemia \[WM\] and chronic lymphocytic leukemia \[CLL\]). In the safety expansion phase for Cohort B, only participants with advanced FL or MZL will be included.
- •Radiographically or clinically measurable disease with at least 1 target lesion per International Working Group (IWG) criteria for malignant lymphoma.
- •In the dose escalation phase, participants who are refractory or relapsed after at least 1 prior line of therapy due to progression, intolerance, or physician/participant decision and for whom no effective standard therapy is available per the investigator's assessment. In the safety expansion phase for Cohort B in participants with FL or MZL, the prior line of therapy is limited to \<=
- •Either treatment naive to, relapsed/refractory to, or experienced treatment failure due to other reasons with ibrutinib, idelalisib, or any other investigational B-cell receptor (BCR) pathway inhibitors not directly targeting spleen tyrosine kinase (SYK).
- •Pre induction salvage chemotherapy and autologous stem cell transplant (ASCT) should be considered 1 therapy.
- •Any consolidation/maintenance therapy after a chemotherapy regimen (without intervening relapse) should be considered 1 line of therapy with the preceding combination therapy. Maintenance antibody therapy should not be considered a line of therapy.
- •For aggressive NHL (i.e., diffuse large B-cell lymphoma \[DLBCL\]), single-agent anti-CD20 monoclonal antibody therapy should not be considered a line of therapy. Antibody therapy in participants with indolent NHL (i.e., FL) given as a single agent after disease progression from a prior treatment should be considered a line of therapy.
- •For participants with DLBCL transformed from indolent lymphoma, any treatment received for the indolent disease before the transformation to DLBCL will, in general, not count toward the 2 to 3 prior lines of therapy required for DLBCL in this study.
- •Prior treatment with a regimen that includes the combination drug will not necessarily exclude a participant from that cohort if the investigator views treatment with that agent as appropriate. However, a participant who has a contraindication for a particular combination agent or who has been discontinued from prior therapy with a particular agent for toxicity will not be eligible for inclusion in that particular cohort.
Exclusion Criteria
- •Central nervous system (CNS) lymphoma; active brain or leptomeningeal metastases, as indicated by positive cytology from lumbar puncture or computed tomography (CT) scan/magnetic resonance imaging (MRI). Exceptions include those participants who have completed definitive therapy, are not on steroids, have a stable neurologic status for at least 2 weeks after completion of the definitive therapy and steroids, and do not have neurologic dysfunction that would confound the evaluation of neurologic and other adverse events (AEs).
- •Known human immunodeficiency virus (HIV)-related malignancy.
- •Known hypersensitivity (example, anaphylactic and anaphylactoid reactions) to any particular combination drug will result in a participant being ineligible for inclusion in that particular cohort.
- •For participant in the lenalidomide combination arm, demonstrated hypersensitivity (example, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide.
- •History of drug-induced pneumonitis requiring treatment with steroids; history of idiopathic pulmonary fibrosis, organizing pneumonia, or evidence of active pneumonitis on screening chest computerized tomography (CT) scan; history of radiation pneumonitis in the radiation field (fibrosis) is permitted.
- •Life-threatening illness unrelated to cancer that could, in the investigator's opinion, make the participant not appropriate for this study.
- •Female participants who are lactating and breast-feeding or a positive serum pregnancy test during the Screening period or a positive urine pregnancy test on Day 1 before the first dose of study drug.
- •Any serious medical or psychiatric illness, including drug or alcohol abuse, that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
- •Known human immunodeficiency virus (HIV) positive.
- •Known hepatitis B surface antigen positive, or known or suspected active hepatitis C infection.
Arms & Interventions
Dose Escalation Phase Cohort A: TAK-659 60 mg + Bendamustine 90 mg/m^2
TAK-659 60 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine 90 mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 in a 21-day treatment cycle, for up to 8 cycles. Participants continued to receive TAK-659 monotherapy until they experienced progressive disease (PD) or unacceptable toxicities or up to 39 cycles.
Intervention: TAK-659
Dose Escalation Phase Cohort A: TAK-659 60 mg + Bendamustine 90 mg/m^2
TAK-659 60 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine 90 mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 in a 21-day treatment cycle, for up to 8 cycles. Participants continued to receive TAK-659 monotherapy until they experienced progressive disease (PD) or unacceptable toxicities or up to 39 cycles.
Intervention: Bendamustine
Dose Escalation Phase Cohort A: TAK-659 80 mg + Bendamustine 90 mg/m^2
TAK-659 80 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine 90 mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 in a 21-day treatment cycle, for up to 8 cycles. The TAK-659 was escalated to 80 mg once daily after safety and tolerability of 60 mg dose was determined. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 39 cycles.
Intervention: TAK-659
Dose Escalation Phase Cohort A: TAK-659 80 mg + Bendamustine 90 mg/m^2
TAK-659 80 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine 90 mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 in a 21-day treatment cycle, for up to 8 cycles. The TAK-659 was escalated to 80 mg once daily after safety and tolerability of 60 mg dose was determined. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 39 cycles.
Intervention: Bendamustine
Dose Escalation Phase Cohort A: TAK-659 100 mg + Bendamustine 90 mg/m^2
TAK-659 100 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 in a 21-day treatment cycle, for up to 8 cycles. The TAK-659 was escalated to 100 mg once daily after safety and tolerability of 60 mg dose was determined. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 39 cycles.
Intervention: TAK-659
Dose Escalation Phase Cohort A: TAK-659 100 mg + Bendamustine 90 mg/m^2
TAK-659 100 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 in a 21-day treatment cycle, for up to 8 cycles. The TAK-659 was escalated to 100 mg once daily after safety and tolerability of 60 mg dose was determined. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 39 cycles.
Intervention: Bendamustine
Dose Escalation Phase Cohort B: TAK-659 60 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2
TAK-659 60 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine 90 mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 along with rituximab 375 mg/m\^2, infusion, intravenously, on Day 1 in a 21-day treatment cycle, for up to 8 cycles. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 12 cycles.
Intervention: TAK-659
Dose Escalation Phase Cohort B: TAK-659 60 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2
TAK-659 60 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine 90 mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 along with rituximab 375 mg/m\^2, infusion, intravenously, on Day 1 in a 21-day treatment cycle, for up to 8 cycles. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 12 cycles.
Intervention: Bendamustine
Dose Escalation Phase Cohort B: TAK-659 60 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2
TAK-659 60 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine 90 mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 along with rituximab 375 mg/m\^2, infusion, intravenously, on Day 1 in a 21-day treatment cycle, for up to 8 cycles. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 12 cycles.
Intervention: Rituximab
Dose Escalation Phase Cohort B: TAK-659 80 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2
TAK-659 80 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine 90 mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 along with rituximab 375 mg/m\^2, infusion, intravenously, on Day 1 in a 21-day treatment cycle, for up to 8 cycles. The TAK-659 was escalated to 80 mg once daily after safety and tolerability of 60 mg dose was determined. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 12 cycles.
Intervention: TAK-659
Dose Escalation Phase Cohort B: TAK-659 80 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2
TAK-659 80 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine 90 mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 along with rituximab 375 mg/m\^2, infusion, intravenously, on Day 1 in a 21-day treatment cycle, for up to 8 cycles. The TAK-659 was escalated to 80 mg once daily after safety and tolerability of 60 mg dose was determined. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 12 cycles.
Intervention: Bendamustine
Dose Escalation Phase Cohort B: TAK-659 80 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2
TAK-659 80 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine 90 mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 along with rituximab 375 mg/m\^2, infusion, intravenously, on Day 1 in a 21-day treatment cycle, for up to 8 cycles. The TAK-659 was escalated to 80 mg once daily after safety and tolerability of 60 mg dose was determined. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 12 cycles.
Intervention: Rituximab
Dose Escalation Phase Cohort B: TAK-659 100 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2
TAK-659 100 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine 90 mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 along with rituximab 375 mg/m\^2, infusion, intravenously, on Day 1 in a 21-day treatment cycle, for up to 8 cycles. The TAK-659 was escalated to 100 mg once daily after safety and tolerability of 60 mg dose was determined. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 12 cycles.
Intervention: TAK-659
Dose Escalation Phase Cohort B: TAK-659 100 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2
TAK-659 100 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine 90 mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 along with rituximab 375 mg/m\^2, infusion, intravenously, on Day 1 in a 21-day treatment cycle, for up to 8 cycles. The TAK-659 was escalated to 100 mg once daily after safety and tolerability of 60 mg dose was determined. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 12 cycles.
Intervention: Bendamustine
Dose Escalation Phase Cohort B: TAK-659 100 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2
TAK-659 100 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine 90 mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 along with rituximab 375 mg/m\^2, infusion, intravenously, on Day 1 in a 21-day treatment cycle, for up to 8 cycles. The TAK-659 was escalated to 100 mg once daily after safety and tolerability of 60 mg dose was determined. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 12 cycles.
Intervention: Rituximab
Dose Escalation Phase Cohort C: TAK-659 60 mg + Gemcitabine 1000 mg/m^2
TAK-659 60 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with gemcitabine 1000 mg/m\^2, infusion, intravenously, over 30 minutes on Days 1 and 8 in a 21-day treatment cycle. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 2 cycles.
Intervention: TAK-659
Dose Escalation Phase Cohort C: TAK-659 60 mg + Gemcitabine 1000 mg/m^2
TAK-659 60 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with gemcitabine 1000 mg/m\^2, infusion, intravenously, over 30 minutes on Days 1 and 8 in a 21-day treatment cycle. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 2 cycles.
Intervention: Gemcitabine
Dose Escalation Phase Cohort D: TAK-659 40 mg + Lenalidomide 25 mg
TAK-659 40 mg, immediate-release tablet, orally, once daily on Days 1 to 28 along with lenalidomide 25 mg, capsules orally, once daily on Days 1 to 21 in a 28-day treatment cycle. The TAK-659 60 mg dose was de-escalated to 40 mg in case of dose limiting toxicity or if the starting dose was determined to be not tolerable. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 26 cycles.
Intervention: TAK-659
Dose Escalation Phase Cohort D: TAK-659 40 mg + Lenalidomide 25 mg
TAK-659 40 mg, immediate-release tablet, orally, once daily on Days 1 to 28 along with lenalidomide 25 mg, capsules orally, once daily on Days 1 to 21 in a 28-day treatment cycle. The TAK-659 60 mg dose was de-escalated to 40 mg in case of dose limiting toxicity or if the starting dose was determined to be not tolerable. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 26 cycles.
Intervention: Lenalidomide
Dose Escalation Phase Cohort D: TAK-659 60 mg + Lenalidomide 25 mg
TAK-659 60 mg, immediate-release tablet, orally, once daily on Days 1 to 28 along with lenalidomide 25 mg, capsules orally, once daily on Days 1 to 21 in a 28-day treatment cycle. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 26 cycles.
Intervention: TAK-659
Dose Escalation Phase Cohort D: TAK-659 60 mg + Lenalidomide 25 mg
TAK-659 60 mg, immediate-release tablet, orally, once daily on Days 1 to 28 along with lenalidomide 25 mg, capsules orally, once daily on Days 1 to 21 in a 28-day treatment cycle. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 26 cycles.
Intervention: Lenalidomide
Dose Escalation Phase Cohort E: TAK-659 60 mg + Ibrutinib 560 mg
TAK-659 60 mg, immediate-release tablet, orally, once daily along with ibrutinib 560 mg capsules, orally, once daily on Days 1 to 28 in a 28-day treatment cycle. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 3 cycles.
Intervention: TAK-659
Dose Escalation Phase Cohort E: TAK-659 60 mg + Ibrutinib 560 mg
TAK-659 60 mg, immediate-release tablet, orally, once daily along with ibrutinib 560 mg capsules, orally, once daily on Days 1 to 28 in a 28-day treatment cycle. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 3 cycles.
Intervention: Ibrutinib
Safety Expansion Phase Cohort B: TAK-659 + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2
TAK-659 immediate-release tablet, at the MTD/maximally administered dose (MAD)/RP2D determined from Dose Escalation Phase, orally, once daily on Days 1 to 21 along with bendamustine 90 mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 along with rituximab 375 mg/m\^2, infusion, intravenously, on Day 1 in a 21-day treatment cycle, for up to 8 cycles in participants (who were to be entered in Phase 2) with advanced FL or MZL. Treatment could then be continued until they experienced PD or unacceptable toxicities or up to 12 cycles in participants who were to be enrolled in the Safety Expansion Phase Cohort.
Intervention: Bendamustine
Safety Expansion Phase Cohort B: TAK-659 + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2
TAK-659 immediate-release tablet, at the MTD/maximally administered dose (MAD)/RP2D determined from Dose Escalation Phase, orally, once daily on Days 1 to 21 along with bendamustine 90 mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 along with rituximab 375 mg/m\^2, infusion, intravenously, on Day 1 in a 21-day treatment cycle, for up to 8 cycles in participants (who were to be entered in Phase 2) with advanced FL or MZL. Treatment could then be continued until they experienced PD or unacceptable toxicities or up to 12 cycles in participants who were to be enrolled in the Safety Expansion Phase Cohort.
Intervention: TAK-659
Safety Expansion Phase Cohort B: TAK-659 + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2
TAK-659 immediate-release tablet, at the MTD/maximally administered dose (MAD)/RP2D determined from Dose Escalation Phase, orally, once daily on Days 1 to 21 along with bendamustine 90 mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 along with rituximab 375 mg/m\^2, infusion, intravenously, on Day 1 in a 21-day treatment cycle, for up to 8 cycles in participants (who were to be entered in Phase 2) with advanced FL or MZL. Treatment could then be continued until they experienced PD or unacceptable toxicities or up to 12 cycles in participants who were to be enrolled in the Safety Expansion Phase Cohort.
Intervention: Rituximab
Outcomes
Primary Outcomes
Dose Escalation Phase: Maximum Tolerated Dose (MTD) of TAK-659
Time Frame: Cycle 1 (Cohorts A, B and C - each cycle was of 21 days and Cohorts D and E - each cycle was of 28 days)
MTD was defined as the maximum dose that is determined to be safe and tolerable in different cohorts. Each cohort (A, B, C, D and E) received different escalating doses of TAK-659 in combination with other drugs. For each cohort the maximum tolerated dose of TAK-659 in combination with the other drug/s from the selected dose range is reported.
Dose Escalation Phase: Recommended Phase 2 Dose (RP2D) of TAK-659
Time Frame: Cycle 1 (Cohorts A, B and C - each cycle was of 21 days and Cohorts D and E each cycle was of 28 days)
The RP2D was the MTD or less. The dose recommended for use in phase 2 studies was analyzed on the basis of the safety, tolerability, and preliminary pharmacokinetic (PK) and efficacy data obtained in phase 1 studies. Each cohort (A, B, C, D and E) received different escalating doses of TAK-659 in combination with other drugs. For each cohort the recommended Phase 2 dose of TAK-659 in combination with the other drug/s from the selected dose range is reported.
Secondary Outcomes
- Cmax: Maximum Observed Plasma Concentration for TAK-659(Days 1 and 15: Pre-dose and at multiple time points (up to 24 hours) post-dose in Cycle 1 (Cohorts A, B and C - each cycle was of 21 days and Cohorts D and E - each cycle was of 28 days))
- Overall Response Rate (ORR)(Up to 123 weeks)
- Tmax: Time to Reach the Maximum Plasma Concentration for TAK-659(Days 1 and 15: Pre-dose and at multiple time points (up to 24 hours) post-dose in Cycle 1 (Cohorts A, B and C - each cycle was of 21 days and Cohorts D and E - each cycle was of 28 days))
- AUCtau: Area Under the Plasma Concentration-time Curve During Dosing Interval(Days 1 and 15: Pre-dose and at multiple time points (up to 24 hours) post-dose in Cycle 1 (Cohorts A, B and C - each cycle was of 21 days and Cohorts D and E - each cycle was of 28 days))
- Time to Progression (TTP)(Up to 123 weeks)
- Safety Expansion Phase: Progression-free Survival (PFS)(Up to study completion (Up to 123 weeks))
- Duration of Response (DOR)(Up to 123 weeks)