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

Celgene106 enrolled

Overview

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).

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

106

Conditions

Lymphoma Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

DurvalumabDRUG

Administered as an IV infusion (250 mL) over approximately 1 hour in duration

LenalidomideDRUG

Administered orally

RituximabDRUG

Administered by intravenous infusion

Ibrutinib

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (66)

Outcomes

Primary Outcomes

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.

Time frame: 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).

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.

Secondary Outcomes

Overall Response Rate (ORR) During Durvalumab Treatment

Data from ClinicalTrials.gov

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BendamustineDRUG

Administered as a 30-minute intravenous infusion

Banner MD Anderson Cancer Center

Gilbert, Arizona, United States

Pinnacle Oncology Hematology

Scottsdale, Arizona, United States

University of Colorado Cancer Center

Aurora, Colorado, United States

Shands Cancer Center University of Florida

Gainesville, Florida, United States

Moffitt Cancer Center

Tampa, Florida, United States

Emory University

Atlanta, Georgia, United States

Northwestern University Feinberg School of Medicine

Chicago, Illinois, United States

Mayo Clinic

Rochester, Minnesota, United States

Washington University School of Medicine

St Louis, Missouri, United States

John Theurer Cancer Center at Hackensack University Medical Center

Hackensack, New Jersey, United States

...and 56 more locations

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).

Time frame: 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).

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.

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).

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.

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.

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.

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.

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.

Maximum Observed Plasma Concentration (Cmax) of Durvalumab