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

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.

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.