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

NCT ID: NCT02733042

Last Updated: 2023-11-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 106 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-05-11
• Study Completion Date: 2022-08-21

Brief Summary

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

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.

Conditions

Lymphoma; Leukemia, Lymphocytic, Chronic, B-Cell

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm A: Durvalumab + Lenalidomide ± Rituximab

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.

Group Type: EXPERIMENTAL

Durvalumab

Intervention Type: DRUG

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

Lenalidomide

Intervention Type: DRUG

Administered orally

Rituximab

Intervention Type: DRUG

Administered by intravenous infusion

Arm B: Durvalumab + Ibrutinib

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.

Group Type: EXPERIMENTAL

Durvalumab

Intervention Type: DRUG

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

Ibrutinib

Intervention Type: DRUG

Administered orally

Arm C: Durvalumab + Rituximab ± Bendamustine

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.

Group Type: EXPERIMENTAL

Durvalumab

Intervention Type: DRUG

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

Rituximab

Intervention Type: DRUG

Administered by intravenous infusion

Bendamustine

Intervention Type: DRUG

Administered as a 30-minute intravenous infusion

Arm D: Durvalumab Monotherapy

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.

Group Type: EXPERIMENTAL

Durvalumab

Intervention Type: DRUG

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

Interventions

Durvalumab

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

Intervention Type: DRUG

Lenalidomide

Administered orally

Intervention Type: DRUG

Rituximab

Administered by intravenous infusion

Intervention Type: DRUG

Ibrutinib

Administered orally

Intervention Type: DRUG

Bendamustine

Administered as a 30-minute intravenous infusion

Intervention Type: DRUG

Other Intervention Names

MEDI4736; IMFINZI®; Revlimid®; Rituxan®; MabThera®; Imbruvica®; Treanda®; Bendeka®; Levact®

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Celgene

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Bristol-Myers Squibb

Role: STUDY_DIRECTOR

Bristol-Myers Squibb

Locations

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

Weill Cornell Medical College

New York, New York, United States

Local Institution - 005

Rochester, New York, United States

University of Rochester

Rochester, New York, United States

The Ohio State University

Columbus, Ohio, United States

University of Oklahoma Peggy and Charles Stephenson Cancer Center

Oklahoma City, Oklahoma, United States

Jefferson Medical Oncology Associates

Philadelphia, Pennsylvania, United States

MD Anderson Cancer Center

Houston, Texas, United States

Houston Methodist Cancer Center

Houston, Texas, United States

MD Anderson Cancer Center

Houston, Texas, United States

Centre Hospitalier Universitaire d'Avicennes

Bobigny, , France

Hopital Henri Mondor

Créteil, , France

Centre Hospitalier

Dijon, , France

Institut Paoli Calmettes

Marseille, , France

CHU Montpellier

Montpellier, , France

Local Institution - 102

Montpellier, , France

Centre Hospitalier Universitaire de Nantes

Nantes, , France

Local Institution - 105

Nantes, , France

Hopital Haut Leveque

Pessac, , France

Centre Hospitalier Lyon-Sud

Pierre-Bénite, , France

Local Institution - 103

Pierre-Bénite, , France

CHRU Rennes

Rennes, , France

Centre Henri Becquerel

Rouen, , France

Universitatsklinikum Essen

Essen, , Germany

UKG Universitatsklinikum Gottingen

Göttingen, , Germany

Universitatsklinikum des Saarlandes

Homburg-Saar, , Germany

Universitatsklinik Koln

Köln, , Germany

Medizinische Klinik III Klinikum der Universität München-Großhadern

München, , Germany

University of Bologna

Bologna, , Italy

Local Institution - 306

Brescia, , Italy

Spedali Civili Di Brescia

Brescia, , Italy

IEO- Istituto Europeo di Oncologia

Milan, , Italy

A.O. Ospedale Ca Granda - Niguarda

Milan, , Italy

Istituto Nazionale Per Lo Studio E La Cura Dei Tumori Fondazione Giovanni Pascale

Napoli, Campania, , Italy

Local Institution - 304

Napoli, Campania, , Italy

I.R.C.C.S. Policlinico San Matteo

Pavia, , Italy

IRCCS Humanitas Clinical Institute

Rozzano (milano), , Italy

Local Institution - 602

Chuo-ku, Tokyo, Japan

National Cancer Center Hospital

Chūōku, , Japan

Tokai University Hospital

Isehara City, Kanagawa, , Japan

Aichi Cancer Center

Nagoya, , Japan

VU Academic Medical Center, Amsterdam

Amsterdam, , Netherlands

UMC Groningen

Groningen, , Netherlands

Leids Universitair Medisch Centrum

Leiden, , Netherlands

Erasmus Medical Center

Rotterdam, , Netherlands

Local Institution - 501

Rotterdam, , Netherlands

Local Institution - 402

Plymouth, Devon, United Kingdom

Local Institution - 407

Nottingham, Nottinghamshire, United Kingdom

St James University Hospital

Leeds, , United Kingdom

UCL Cancer Institute

London, , United Kingdom

Christie Hospital NHS Trust

Manchester, , United Kingdom

Local Institution - 404

Manchester, , United Kingdom

Nottingham University Hospitals NHS Trust

Nottingham, , United Kingdom

Local Institution - 406

Oxford, , United Kingdom

Oxford University Hospitals NHS Trust- Churchill Hospital-Oxford Centre for Respiratory Medicine

Oxford, , United Kingdom

Derriford Hospital

Plymouth, , United Kingdom

Southampton University Hospitals NHS Trust

Southampton, , United Kingdom

Countries

United States; France; Germany; Italy; Japan; Netherlands; United Kingdom

References

Casulo C, Santoro A, Cartron G, Ando K, Munoz J, Le Gouill S, Izutsu K, Rule S, Lugtenburg P, Ruan J, Arcaini L, Casadebaig ML, Fox B, Kilavuz N, Rettby N, Dell'Aringa J, Taningco L, Delarue R, Czuczman M, Witzig T. Durvalumab as monotherapy and in combination therapy in patients with lymphoma or chronic lymphocytic leukemia: The FUSION NHL 001 trial. Cancer Rep (Hoboken). 2023 Jan;6(1):e1662. doi: 10.1002/cnr2.1662. Epub 2022 Jul 19.

Reference Type: DERIVED

PMID: 35852004 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan: MEDI4736-NHL-001_SAP_Redacted.14Dec2017

View Document

Document Type: Statistical Analysis Plan: MEDI4736-NHL-001_SAP_Amendment_1_Redacted.14Dec2017

View Document

Related Links

https://www.bms.com/researchers-and-partners/clinical-trials-and-research.html

BMS Clinical Trial Information

https://www.bmsstudyconnect.com/s/US/English/USenHome

BMS Clinical Trial Patient Recruiting

Other Identifiers

2015-003516-21

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

MEDI4736-NHL-001

Identifier Type: -

Identifier Source: org_study_id