A Study to Determine Dose, Safety, and Efficacy of Durvalumab as Monotherapy and in Combination Therapy in Subjects With Lymphoma or Chronic Lymphocytic Leukemia

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Lymphoma, Leukemia, Lymphocytic, Chronic, B-Cell

Intervention / Treatment
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* Drug: Durvalumab
* Drug: Lenalidomide
* Drug: Rituximab
* Drug: Ibrutinib
* Drug: Bendamustine


Participation Criteria
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Eligibility Criteria
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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 2. 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. Subject who has any histopathologic finding consistent with myelodysplastic syndrome on bone marrow studies. 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: Arm A only: drugs with immunomodulatory and other properties (eg, lenalidomide, thalidomide); Arm B only: ibrutinib or other Bruton's tyrosine kinase (BTK) inhibitor; Arms C only: bendamustine Subject who has active auto-immune disease. Subject who has history of organ transplant or allogeneic hematopoietic stem cell transplantation. 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) Subject who has known seropositivity for or active infection for human immunodeficiency virus (HIV) or hepatitis C virus (HCV). Subject who has history of primary immunodeficiency or tuberculosis. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Within Arms A, B, and C participants on the dose-finding part were enrolled sequentially according to a 3+3 design. 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Durvalumab + Lenalidomide ± Rituximab<br>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. | Drug: Durvalumab<br>* Administered as an IV infusion (250 mL) over approximately 1 hour in duration<br>* Other names: IMFINZI®;Drug: Lenalidomide<br>* Administered orally<br>* Other names: Revlimid®;Drug: Rituximab<br>* Administered by intravenous infusion<br>* Other names: MabThera®;|
| Experimental: Arm B: Durvalumab + Ibrutinib<br>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. | Drug: Durvalumab<br>* Administered as an IV infusion (250 mL) over approximately 1 hour in duration<br>* Other names: IMFINZI®;Drug: Ibrutinib<br>* Administered orally<br>* Other names: Imbruvica®;|
| Experimental: Arm C: Durvalumab + Rituximab ± Bendamustine<br>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. | Drug: Durvalumab<br>* Administered as an IV infusion (250 mL) over approximately 1 hour in duration<br>* Other names: IMFINZI®;Drug: Rituximab<br>* Administered by intravenous infusion<br>* Other names: MabThera®;Drug: Bendamustine<br>* Administered as a 30-minute intravenous infusion<br>* Other names: Levact®;|
| Experimental: Arm D: Durvalumab Monotherapy<br>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. | Drug: Durvalumab<br>* Administered as an IV infusion (250 mL) over approximately 1 hour in duration<br>* Other names: IMFINZI®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of Participants With Dose Limiting Toxicities (DLTs) | 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. | Cycle 1 (28 days) | 
| Number of Participants With Treatment-emergent Adverse Events | 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). | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) During Durvalumab Treatment | 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). | Up to 13 cycles (12 months) | 
| Overall Response Rate During the Entire Study | 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). | 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 First Response | 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). | 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. | 
| Kaplan-Meier Estimate of Duration of Response | 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. | 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. | 
| Kaplan-Meier Estimate of Progression-free Survival (PFS) | 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. | 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. | 
| 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. | 
| 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. | 
| 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. | 
| 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. | 
| 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. | 
| 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. | 
| 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 | 
| 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. | 
| 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 | 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). | Baseline (Cycle 1 Day 1 predose) and Day 1 of Cycles 2 to 13 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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