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

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

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.

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.