A Phase 1/2, Open-label, Multi-center Study to Assess the Safety and Tolerability of Durvalumab (Anti-PDL1 Antibody) as Monotherapy and in Combination Therapy in Subjects With Lymphoma or Chronic Lymphocitic Leukemia
Overview
- Phase
- Phase 1
- Intervention
- Durvalumab
- Conditions
- Lymphoma
- Sponsor
- Celgene
- Enrollment
- 106
- Locations
- 65
- Primary Endpoint
- Part 1: Number of Participants With Dose Limiting Toxicities (DLTs)
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
This study is designed to determine the recommended phase 2 dose (RP2D), and the safety, and efficacy of durvalumab as monotherapy and when given in combination with lenalidomide and rituximab; ibrutinib; or bendamustine and rituximab at the RP2D in adults with lymphoma or chronic lymphocytic leukemia (CLL).
Detailed Description
The study was to consist of 3 parts: dose-finding, dose-confirmation, and dose-expansion. In this study, 4 treatment arms were to be investigated: * Arm A: durvalumab and lenalidomide ± rituximab * Arm B: durvalumab and ibrutinib * Arm C: durvalumab and rituximab ± bendamustine * Arm D: durvalumab (monotherapy) The study was to start with 3 dose-finding cohorts (Arms A, B, and C) and 1 dose-confirmation cohort (Arm D) in parallel. All treatment arms were to be open for enrollment at study start except in the US, where Arm D was to enroll depending on the availability of treatment slots and following the completion of assessment of responses from the combination therapy arms. For Arms A and C, prior to enrolling participants to receive all 3 drugs, the doublet combinations were to be evaluated. Once the doublet combinations were deemed tolerable, the eventual triplet combinations were to be tested. On 05 September 2017, the US FDA issued a Partial Clinical Hold on the study Arm A. Following this Partial Clinical Hold no more participants were enrolled into study Arm A. Participants already enrolled and treated in Arm A who were receiving clinical benefit, based on the discretion of the investigator, could continue study treatment after being reconsented. Arm B and C completed dose confirmation. The dose expansion part of the study was not opened.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Subject who has histologically confirmed and documented B-cell lymphoma (eg, follicular, diffuse large B-cell, mantle cell, small lymphocytic, or Hodgkin lymphoma) and chronic lymphocytic leukemia.
- •Subject who has high-risk chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).
- •Subject who was previously treated with at least one prior systemic chemotherapy, immunotherapy, or chemoimmunotherapy.
- •Subject who has the Eastern Cooperative Oncology Group performance status of 0, 1, or
- •Subject who is willing and able to undergo biopsy.
- •Subject who has documented active relapsed or refractory disease requiring therapeutic intervention.
- •Subject with lymphoma who has measurable disease (≥ 2.0 cm in its longest dimension by computed tomography) or chronic lymphocytic leukemia in need of treatment.
- •Subject who fulfills the laboratory requirements as per protocol
- •Exclusion Criteria
- •Subject who has central nervous system (CNS) or meningeal involvement by lymphoma.
Exclusion Criteria
- Not provided
Arms & Interventions
Arm A: Durvalumab + Lenalidomide ± Rituximab
Participants assigned to Arm A will receive: * Durvalumab 1500 mg intravenous (IV) infusion on Day 1 of Cycles 1 through 13 (ie, 12 months) and * Lenalidomide orally at assigned dose levels (10 mg, 15 mg or 20 mg) once daily on Days 1 to 21 of: * Cycles 1 through 13 in indolent non-Hodgkin's lymphoma (NHL) or * All cycles of treatment period until disease progression, unacceptable toxicity, or discontinuation for any other reason in aggressive NHL * Rituximab 375 mg/m² IV infusion every week in Cycle 1 (Days 2, 8, 15, 22) and on Day 1 of Cycles 2 through 5. All treatment cycles were 28 days.
Intervention: Durvalumab
Arm A: Durvalumab + Lenalidomide ± Rituximab
Participants assigned to Arm A will receive: * Durvalumab 1500 mg intravenous (IV) infusion on Day 1 of Cycles 1 through 13 (ie, 12 months) and * Lenalidomide orally at assigned dose levels (10 mg, 15 mg or 20 mg) once daily on Days 1 to 21 of: * Cycles 1 through 13 in indolent non-Hodgkin's lymphoma (NHL) or * All cycles of treatment period until disease progression, unacceptable toxicity, or discontinuation for any other reason in aggressive NHL * Rituximab 375 mg/m² IV infusion every week in Cycle 1 (Days 2, 8, 15, 22) and on Day 1 of Cycles 2 through 5. All treatment cycles were 28 days.
Intervention: Lenalidomide
Arm A: Durvalumab + Lenalidomide ± Rituximab
Participants assigned to Arm A will receive: * Durvalumab 1500 mg intravenous (IV) infusion on Day 1 of Cycles 1 through 13 (ie, 12 months) and * Lenalidomide orally at assigned dose levels (10 mg, 15 mg or 20 mg) once daily on Days 1 to 21 of: * Cycles 1 through 13 in indolent non-Hodgkin's lymphoma (NHL) or * All cycles of treatment period until disease progression, unacceptable toxicity, or discontinuation for any other reason in aggressive NHL * Rituximab 375 mg/m² IV infusion every week in Cycle 1 (Days 2, 8, 15, 22) and on Day 1 of Cycles 2 through 5. All treatment cycles were 28 days.
Intervention: Rituximab
Arm B: Durvalumab + Ibrutinib
Participants assigned to Arm B will receive: * Durvalumab 1500 mg IV infusion on Day 1 of Cycles 1 through 13 * Ibrutinib orally at assigned dose levels (280 mg, 420 mg, or 560 mg) once daily until disease progression, unacceptable toxicity or discontinuation for any other reason. All treatment cycles were 28 days.
Intervention: Durvalumab
Arm B: Durvalumab + Ibrutinib
Participants assigned to Arm B will receive: * Durvalumab 1500 mg IV infusion on Day 1 of Cycles 1 through 13 * Ibrutinib orally at assigned dose levels (280 mg, 420 mg, or 560 mg) once daily until disease progression, unacceptable toxicity or discontinuation for any other reason. All treatment cycles were 28 days.
Intervention: Ibrutinib
Arm C: Durvalumab + Rituximab ± Bendamustine
Participants assigned to Arm C will receive: * Durvalumab 1500 mg IV infusion on Day 1 of Cycles 1 through 13 * Rituximab 375 mg/m² IV infusion on Day 2 of Cycles 1 through 6 (for CLL the rituximab dose will be 375 mg/m² Cycle 1 first dose and 500 mg/m² for each subsequent dose) * Bendamustine IV infusion at assigned dose levels (70 mg/m² or 90 mg/m²) on Days 1 and 2 of Cycles 1 through 6. All treatment cycles were 28 days.
Intervention: Durvalumab
Arm C: Durvalumab + Rituximab ± Bendamustine
Participants assigned to Arm C will receive: * Durvalumab 1500 mg IV infusion on Day 1 of Cycles 1 through 13 * Rituximab 375 mg/m² IV infusion on Day 2 of Cycles 1 through 6 (for CLL the rituximab dose will be 375 mg/m² Cycle 1 first dose and 500 mg/m² for each subsequent dose) * Bendamustine IV infusion at assigned dose levels (70 mg/m² or 90 mg/m²) on Days 1 and 2 of Cycles 1 through 6. All treatment cycles were 28 days.
Intervention: Rituximab
Arm C: Durvalumab + Rituximab ± Bendamustine
Participants assigned to Arm C will receive: * Durvalumab 1500 mg IV infusion on Day 1 of Cycles 1 through 13 * Rituximab 375 mg/m² IV infusion on Day 2 of Cycles 1 through 6 (for CLL the rituximab dose will be 375 mg/m² Cycle 1 first dose and 500 mg/m² for each subsequent dose) * Bendamustine IV infusion at assigned dose levels (70 mg/m² or 90 mg/m²) on Days 1 and 2 of Cycles 1 through 6. All treatment cycles were 28 days.
Intervention: Bendamustine
Arm D: Durvalumab Monotherapy
Participants assigned to Arm D will receive durvalumab 1500 mg IV infusion on Day 1 of Cycles 1 through 13. All treatment cycles were 28 days.
Intervention: Durvalumab
Outcomes
Primary Outcomes
Part 1: Number of Participants With Dose Limiting Toxicities (DLTs)
Time Frame: Cycle 1 (28 days)
Dose limiting toxicities were evaluated during the DLT evaluation period for participants in the dose finding cohorts. The severity grading was determined according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03. A DLT is defined as below: Hematologic DLT • Grade 4 neutropenia observed for greater than 5 days duration • Grade 3 neutropenia associated with fever (≥ 38.5 °C) of any duration • Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding, or any requirement for platelets transfusion • Grade 4 anemia, unexplained by underlying disease • Any other grade 4 hematologic toxicity that does not resolve to participant's pretreatment baseline level within 72 hours. Non-Hematologic DLT • Any non-hematological toxicity ≥ Grade 3 except for alopecia and nausea controlled by medical management • Any treatment interruption greater than 2 weeks due to adverse event.
Number of Participants With Treatment-emergent Adverse Events
Time Frame: From first dose of any study drug to 90 days after last dose of durvalumab or 28 days after last dose of other study drugs, up to the data cut-off date of 6 March 2019. Maximum time on treatment was 55.4 weeks for DUR and 130 weeks for other study drugs.
Treatment-emergent adverse events (TEAEs) are defined as adverse events (AEs) occurring or worsening on or after the first dose of any study treatment (durvalumab, lenalidomide, ibrutinib, bendamustine or rituximab) and within 90 days after last dose of durvalumab or 28 days after the last dose of other study drugs, whichever was later, as well as those serious adverse events made known to the investigator at any time thereafter that were suspected of being related to study treatment. The intensity of AEs was graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. For all other AEs not described in the CTCAE criteria, the intensity was assessed by the investigator as mild (Grade 1), moderate (Grade 2), severe (Grade 3), life-threatening (Grade 4), or death (Grade 5).
Secondary Outcomes
- Overall Response Rate During the Entire Study(From first dose of any study drug to the end of follow-up, up to the data cutoff date of March 6, 2019; median (minimum, maximum) time on study was 16.7 (0.9, 32.9) months.)
- Overall Response Rate (ORR) During Durvalumab Treatment(Up to 13 cycles (12 months))
- Time to First Response(From first dose of any study drug to the end of follow-up, up to the data cutoff date of March 6, 2019; median (minimum, maximum) time on study was 16.7 (0.9, 32.9) months.)
- Clearance (CL) of Durvalumab(Cycle 1, Day 1 (pre-dose and at end of infusion), and 4, 24, 48, 168 (Day 8), 336 (Day 15), and 508 (Day 22) hours after the end of infusion.)
- Kaplan-Meier Estimate of Duration of Response(From first dose of any study drug to the end of follow-up, up to the data cutoff date of March 6, 2019; median (minimum, maximum) time on study was 16.7 (0.9, 32.9) months.)
- Time to Maximum Plasma Concentration (Tmax) of Durvalumab(Cycle 1, Day 1 (pre-dose and at end of infusion), and 4, 24, 48, 168 (Day 8), 336 (Day 15), and 508 (Day 22) hours after the end of infusion.)
- Kaplan-Meier Estimate of Progression-free Survival (PFS)(From first dose of any study drug to the end of follow-up, up to the data cutoff date of March 6, 2019; median (minimum, maximum) time on study was 16.7 (0.9, 32.9) months.)
- Maximum Observed Plasma Concentration (Cmax) of Durvalumab(Cycle 1, Day 1 (pre-dose and at end of infusion), and 4, 24, 48, 168 (Day 8), 336 (Day 15), and 508 (Day 22) hours after the end of infusion.)
- Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUClast) of Durvalumab(Cycle 1, Day 1 (pre-dose and at end of infusion), and 4, 24, 48, 168 (Day 8), 336 (Day 15), and 508 (Day 22) hours after the end of infusion.)
- Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) of Durvalumab(Cycle 1, Day 1 (pre-dose and at end of infusion), and 4, 24, 48, 168 (Day 8), 336 (Day 15), and 508 (Day 22) hours after the end of infusion.)
- Maximum Observed Plasma Concentration (Cmax) of Lenalidomide(Cycle 1 Day 1 at predose and 1, 2, 4, and 24 hours post-dose, and Cycle 1 Day 15 at pre-dose, 1, 2, and 4 hours post-dose.)
- Terminal Elimination Phase Half-Life (t½) of Durvalumab(Cycle 1, Day 1 (pre-dose and at end of infusion), and 4, 24, 48, 168 (Day 8), 336 (Day 15), and 508 (Day 22) hours after the end of infusion.)
- Volume of Distribution (Vz) of Durvalumab(Cycle 1, Day 1 (pre-dose and at end of infusion), and 4, 24, 48, 168 (Day 8), 336 (Day 15), and 508 (Day 22) hours after the end of infusion.)
- Time to Maximum Observed Plasma Concentration (Tmax) of Lenalidomide(Cycle 1 Day 1 at predose and 1, 2, 4, and 24 hours post-dose, and Cycle 1 Day 15 at pre-dose, 1, 2, and 4 hours post-dose.)
- Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUClast) of Lenalidomide(Cycle 1 Day 1 at predose and 1, 2, 4, and 24 hours post-dose)
- Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUClast) of Ibrutinib(Cycle 1 Day 1 at predose and 1, 2, 4, and 24 hours post-dose)
- Change From Baseline in Soluble Programmed Cell Death Ligand-1 (sPD-L1) Concentration(Baseline (Cycle 1 Day 1 predose) and Day 1 of Cycles 2 to 13)
- Maximum Observed Plasma Concentration (Cmax) of Ibrutinib(Cycle 1 Day 1 at predose and 1, 2, 4, and 24 hours post-dose, and Cycle 1 Day 15 at pre-dose, 1, 2, and 4 hours post-dose.)
- Time to Maximum Observed Plasma Concentration (Tmax) of Ibrutinib(Cycle 1 Day 1 at predose and 1, 2, 4, and 24 hours post-dose, and Cycle 1 Day 15 at pre-dose, 1, 2, and 4 hours post-dose.)