Protocol Summary

Protocol No.: OCR15352

Sponsor Protocol No.: MEDI4736-NHL-001; Celgene

Study Title
A Phase 1/2, open label, multicentre study to assess the safety and tolerability of durvalumab (anti-PD-L1 antibody) as monotherapy and in combination therapy in subjects with lymphoma or chronic lymphocytic leukemia

Principal Investigator(s)
Dang, Nam

Objective
This open-label, multicenter, global study is designed to determine the recommended phase 2 dose, safety, efficacy, and pharmacokinetics/pharmacodynamics of durvalumab in subjects with certain lymphoma subtypes or CLL. Globally, 265 subjects may be enrolled into 4 treatment arms, including durvalumab monotherapy; durvalumab in combination with lenalidomide +/- rituximab; ibrutinib; or rituximab +/- bendamustine. The study will have 3 parts: dose finding, dose confirmation, and dose expansion. Subjects receiving monotherapy may receive combination therapy or involved-field radiation to a single nodal site at time of progressive disease.

Description
Subjects assigned to Arm A will receive:
- Durvalumab 1500 mg (IV) infusion on Day 1 of Cycles 1 through 13 (ie, 12 months) and
- Lenalidomide (oral) at assigned dose levels (10 mg, 15 mg or 20 mg) once daily on Days 1 to 21 (inclusive) of:
- Cycles 1 through 13 in indolent Non-Hodgkin lymphoma (NHL) (ie, FL or MZL) 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 Schedule 1 (dose levels 2 and -1B) on Days 2, 8, 15 and 22 of Cycle 1 and on Day 1 from Cycles 2 through 5.
Rituximab 375 mg/m2 (IV) infusion Schedule 2 (dose levels -2 and -3) on Day 2 of Cycle 1 and on Day 1 from Cycles 2 through 8.

Subjects assigned to Arm B will receive:
- Durvalumab (IV) infusion on Day 1 of Cycles 1 through 13
- Ibrutinib (oral) at assigned dose levels (280 mg, 420 mg, or 560 mg)continuous once daily until disease progression, unacceptable toxicity or discontinuation for any other reason

Subjects assigned to Arm C will receive:
- Durvalumab 1500 mg (IV) infusion on Day 1 of Cycles 1 through 13
- Bendamustine (IV) infusion at assigned dose levels (70 mg/m2 or 90 mg/m2) on Days 1 and 2 of Cycles 1 through 6
- Rituximab 375 mg/m2 (IV) infusion on Day 2 Cycles 1 through 6

Subjects assigned to Arm D will receive:
- Durvalumab (IV) infusion at a fixed dose of 1500 mg, on Day 1 of Cycles 1 through 13

One cycle is 28-day.

Phase: Phase I/II

Age Group: Adult

Scope: National

Treatment
Arm A: Durvalumab and Lenalidomide plus or minus Rituximab

Arm B: Durvalumab and Ibrutinib

Arm C: Durvalumab and Bendamustine plus or minus Rituximab

Arm D: Durvalumab Monotherapy

Detailed Eligibility
INCLUSION CRITERIA:
1. Ages 18 years old and older
2. 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.
3. Subject who has high-risk chronic lymphocytic leukemia/small lymphocytic lymphoma.
4. Subject who was previously treated with at least one prior systemic chemotherapy, immunotherapy, or chemoimmunotherapy.
5. Subject who has the Eastern Cooperative Oncology Group performance status of 0, 1, or 2.
6. Subject who is willing and able to undergo biopsy.
7. Subject who has documented active relapsed or refractory disease requiring therapeutic intervention.
8. 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.
9. 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 PD-1 or PD-L1 and/or any prior:
- Arm A only: ImiDs (eg, lenalidomide, thalidomide);
- Arm B only: ibrutinib or other Bruton's tyrosine kinase (BTK) inhibitor;
- 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.

Applicable Disease Sites
Leukemia
Lymphoma - Non-Hodgkin

Participating Institutions
UF Gainesville : Ashton Monismith

Contact
Ashton Monismith, RN
Phone: +1 352-265-0680 ext. 87657

Email: amonismith@ufl.edu