Description:
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).
Title
- Brief Title: A Study to Determine Dose, Safety, and Efficacy of Durvalumab as Monotherapy and in Combination Therapy in Subjects With Lymphoma or Chronic Lymphocytic Leukemia
- Official Title: 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
Clinical Trial IDs
- ORG STUDY ID:
MEDI4736-NHL-001
- SECONDARY ID:
2015-003516-21
- NCT ID:
NCT02733042
Conditions
- Lymphoma
- Leukemia, Lymphocytic, Chronic, B-Cell
Interventions
Drug | Synonyms | Arms |
---|
Durvalumab | MEDI4736, IMFINZI® | Arm A: Durvalumab + Lenalidomide ± Rituximab |
Lenalidomide | Revlimid® | Arm A: Durvalumab + Lenalidomide ± Rituximab |
Rituximab | Rituxan®, MabThera® | Arm A: Durvalumab + Lenalidomide ± Rituximab |
Ibrutinib | Imbruvica® | Arm B: Durvalumab + Ibrutinib |
Bendamustine | Treanda®, Bendeka®, Levact® | Arm C: Durvalumab + Rituximab ± Bendamustine |
Purpose
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.
Trial Arms
Name | Type | Description | Interventions |
---|
Arm A: Durvalumab + Lenalidomide ± Rituximab | Experimental | 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. | - Durvalumab
- Lenalidomide
- Rituximab
|
Arm B: Durvalumab + Ibrutinib | Experimental | 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. | |
Arm C: Durvalumab + Rituximab ± Bendamustine | Experimental | 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. | - Durvalumab
- Rituximab
- Bendamustine
|
Arm D: Durvalumab Monotherapy | Experimental | 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. | |
Eligibility Criteria
Inclusion Criteria:
1. 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.
2. Subject who has high-risk chronic lymphocytic leukemia (CLL)/small lymphocytic
lymphoma (SLL).
3. Subject who was previously treated with at least one prior systemic chemotherapy,
immunotherapy, or chemoimmunotherapy.
4. Subject who has the Eastern Cooperative Oncology Group performance status of 0, 1, or
2.
5. Subject who is willing and able to undergo biopsy.
6. Subject who has documented active relapsed or refractory disease requiring therapeutic
intervention.
7. 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.
8. Subject who fulfills the laboratory requirements as per protocol
Exclusion Criteria
1. Subject who has central nervous system (CNS) or meningeal involvement by lymphoma.
2. Subject who has any histopathologic finding consistent with myelodysplastic syndrome
on bone marrow studies.
3. Subject who received any prior monoclonal antibodies against programmed cell death-1
(PD-1) or programmed cell death ligand-1 (PD-L1) and/or any prior:
1. Arm A only: drugs with immunomodulatory and other properties (eg, lenalidomide,
thalidomide);
2. Arm B only: ibrutinib or other Bruton's tyrosine kinase (BTK) inhibitor;
3. Arms C only: bendamustine
4. Subject who has active auto-immune disease.
5. Subject who has history of organ transplant or allogeneic hematopoietic stem cell
transplantation.
6. Subject who is seropositive for or active viral infection with hepatitis B virus (HBV)
(hepatitis B surface antigen [HBsAg] positive and/or detectable viral DNA)
7. Subject who has known seropositivity for or active infection for human
immunodeficiency virus (HIV) or hepatitis C virus (HCV).
8. Subject who has history of primary immunodeficiency or tuberculosis.
9. Subject who other invasive malignancy within 2 years (5 years for Arm A) except for
noninvasive malignancies such as cervical carcinoma in situ, non-melanomatous
carcinoma of the skin, ductal carcinoma in situ of the breast, or incidental
histologic finding of prostate cancer (T1a or T1b using the TNM [tumor, nodes,
metastasis] clinical staging system) that has/have been surgically cured.
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Part 1: Number of Participants With Dose Limiting Toxicities (DLTs) |
Time Frame: | Cycle 1 (28 days) |
Safety Issue: | |
Description: | 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. |
Secondary Outcome Measures
Measure: | Overall Response Rate (ORR) During Durvalumab Treatment |
Time Frame: | Up to 13 cycles (12 months) |
Safety Issue: | |
Description: | For lymphoma participants, response evaluation was based on International Working Group (IWG) response criteria for malignant lymphoma (the Lugano Classification). Overall response rate is defined as the percent of participants with best response of complete response (CR) or partial response (PR).
For chronic lymphocytic leukemia participants, response evaluation was based on International Workshop on Chronic Lymphocytic Leukemia (IWCLL) guidelines for diagnosis and treatment of CLL. The ORR is defined as the percent of participants with best response of CR, complete response with incomplete marrow recovery (CRi), nodular partial response (nPR), PR, or partial response with lymphocytosis (PRL). |
Measure: | Overall Response Rate During the Entire Study |
Time Frame: | 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. |
Safety Issue: | |
Description: | For lymphoma participants, response evaluation was based on International Working Group (IWG) response criteria for malignant lymphoma (the Lugano Classification) (Cheson, 2014). Overall response rate is defined as the percent of participants with best response of complete response (CR) or partial response (PR).
For chronic lymphocytic leukemia participants, response evaluation was based on International Workshop on Chronic Lymphocytic Leukemia (IWCLL) guidelines for diagnosis and treatment of CLL. The ORR is defined as the percentage of participants with best response of CR, complete response with incomplete marrow recovery (CRi), nodular partial response (nPR), PR, or partial response with lymphocytosis (PRL). |
Measure: | Time to First Response |
Time Frame: | 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. |
Safety Issue: | |
Description: | Time to response was calculated as the time from first dose of study drug to the first response date (CR or PR for lymphoma participants and CR, CRi, nPR, PR, or PRL for CLL participants). |
Measure: | Kaplan-Meier Estimate of Duration of Response |
Time Frame: | 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. |
Safety Issue: | |
Description: | Duration of response is defined for responders only as the time from the first documented response (CR or PR for lymphoma participants or CR, CRi, nPR, PR, or PRL for CLL participants) to disease progression or death (from any cause). For participants with response but no progression, or death, duration of response was censored at the last date that the participant was known to be progression-free. |
Measure: | Kaplan-Meier Estimate of Progression-free Survival (PFS) |
Time Frame: | 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. |
Safety Issue: | |
Description: | Progression-free survival was calculated as the time from first dose of study drug to the first documented progression or death (from any cause) during the entire efficacy evaluation period. For participants with no progression or death, PFS was censored at the last assessment date the participant was known to be progression-free. |
Measure: | Maximum Observed Plasma Concentration (Cmax) of Durvalumab |
Time Frame: | 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. |
Safety Issue: | |
Description: | |
Measure: | Time to Maximum Plasma Concentration (Tmax) of Durvalumab |
Time Frame: | 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. |
Safety Issue: | |
Description: | |
Measure: | Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUClast) of Durvalumab |
Time Frame: | 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. |
Safety Issue: | |
Description: | |
Measure: | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) of Durvalumab |
Time Frame: | 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. |
Safety Issue: | |
Description: | |
Measure: | Terminal Elimination Phase Half-Life (t½) of Durvalumab |
Time Frame: | 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. |
Safety Issue: | |
Description: | |
Measure: | Clearance (CL) of Durvalumab |
Time Frame: | 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. |
Safety Issue: | |
Description: | |
Measure: | Volume of Distribution (Vz) of Durvalumab |
Time Frame: | 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. |
Safety Issue: | |
Description: | |
Measure: | Maximum Observed Plasma Concentration (Cmax) of Lenalidomide |
Time Frame: | 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. |
Safety Issue: | |
Description: | |
Measure: | Time to Maximum Observed Plasma Concentration (Tmax) of Lenalidomide |
Time Frame: | 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. |
Safety Issue: | |
Description: | |
Measure: | Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUClast) of Lenalidomide |
Time Frame: | Cycle 1 Day 1 at predose and 1, 2, 4, and 24 hours post-dose |
Safety Issue: | |
Description: | |
Measure: | Maximum Observed Plasma Concentration (Cmax) of Ibrutinib |
Time Frame: | 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. |
Safety Issue: | |
Description: | |
Measure: | Time to Maximum Observed Plasma Concentration (Tmax) of Ibrutinib |
Time Frame: | 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. |
Safety Issue: | |
Description: | |
Measure: | Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUClast) of Ibrutinib |
Time Frame: | Cycle 1 Day 1 at predose and 1, 2, 4, and 24 hours post-dose |
Safety Issue: | |
Description: | |
Measure: | Change From Baseline in Soluble Programmed Cell Death Ligand-1 (sPD-L1) Concentration |
Time Frame: | Baseline (Cycle 1 Day 1 predose) and Day 1 of Cycles 2 to 13 |
Safety Issue: | |
Description: | Change from baseline in sPD-L1 could not be calculated as all post-baseline samples were below the lower limit of quantification (<15.60 pg/mL). |
Details
Phase: | Phase 1/Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Active, not recruiting |
Lead Sponsor: | Celgene |
Trial Keywords
- Lymphoma
- Chronic Lymphocytic Leukemia
- Durvalumab
- Anti-PD-L1 Antibody
- MEDI4736
- Immune Checkpoint
- Lymphatic Disease
- B-Cell Malignancies
- Abscopal Effect
- Lenalidomide
- Bendamustine
- Rituximab
- Ibrutinib
- Lymphoma, B-Cell
- Lymphoma, Non Hodgkin,
- Hodgkin Disease
- Leukemia, Lymphocytic, Chronic, B-Cell,
- Lymphoma, Follicular
- Lymphoma, Diffuse Large B-Cell
- Lymphoma, Mantle Cell
- Lymphoma, Small Lymphocytic
- Immune System Diseases
- Immunoproliferative Disorders
- Lymphoproliferative Disorders
Last Updated
September 16, 2020