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

NCT02733042 | Completed Phase 1 Results DMC

• 2 other identifiers: MEDI4736-NHL-0012015-003516-21
• Study Type: interventional
• Target: 106
• Locations: 7 countries
• Sites: 66

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).

Conditions

Lymphoma; Leukemia, Lymphocytic, Chronic, B-Cell

Keywords

Lymphoma; Chronic Lymphocytic Leukemia; Durvalumab; Anti-PD-L1 Antibody; MEDI4736; Immune Checkpoint; Lymphatic Disease; B-Cell Malignancies; Abscopal Effect; Lenalidomide; Bendamustine; Rituximab; Ibrutinib; Lymphoma, B-Cell; Lymphoma, Non Hodgkin,; Hodgkin Disease; Leukemia, Lymphocytic, Chronic, B-Cell,; Lymphoma, Follicular; Lymphoma, Diffuse Large B-Cell; Lymphoma, Mantle Cell; Lymphoma, Small Lymphocytic; Immune System Diseases; Immunoproliferative Disorders; Lymphoproliferative Disorders

Outcome Measures

Primary Outcomes (2)

• 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.

  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).

  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 (19)

• Overall Response Rate (ORR) During Durvalumab Treatment

  Up to 13 cycles (12 months)

• Overall Response Rate During the Entire Study

  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

  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

  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)

  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.

Study Arms (4)

Arm A: Durvalumab + Lenalidomide ± Rituximab

EXPERIMENTAL

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.

Drug: Durvalumab; Drug: Lenalidomide; Drug: Rituximab

Arm B: Durvalumab + Ibrutinib

EXPERIMENTAL

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.

Drug: Durvalumab; Drug: Ibrutinib

Arm C: Durvalumab + Rituximab ± Bendamustine

EXPERIMENTAL

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.

Drug: Durvalumab; Drug: Rituximab; Drug: Bendamustine

Arm D: Durvalumab Monotherapy

EXPERIMENTAL

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.

Drug: Durvalumab

Interventions

Durvalumab DRUG

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

Also known as: MEDI4736, IMFINZI®

Arm A: Durvalumab + Lenalidomide ± Rituximab; Arm B: Durvalumab + Ibrutinib; Arm C: Durvalumab + Rituximab ± Bendamustine; Arm D: Durvalumab Monotherapy

Lenalidomide DRUG

Administered orally

Also known as: Revlimid®

Arm A: Durvalumab + Lenalidomide ± Rituximab

Rituximab DRUG

Administered by intravenous infusion

Also known as: Rituxan®, MabThera®

Arm A: Durvalumab + Lenalidomide ± Rituximab; Arm C: Durvalumab + Rituximab ± Bendamustine

Ibrutinib DRUG

Administered orally

Also known as: Imbruvica®

Arm B: Durvalumab + Ibrutinib

Bendamustine DRUG

Administered as a 30-minute intravenous infusion

Also known as: Treanda®, Bendeka®, Levact®

Arm C: Durvalumab + Rituximab ± Bendamustine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Celgene: lead

Study Sites (66)

Banner MD Anderson Cancer Center

Gilbert, Arizona, 85234, United States

Location

Pinnacle Oncology Hematology

Scottsdale, Arizona, 85258, United States

Location

University of Colorado Cancer Center

Aurora, Colorado, 80045, United States

Location

Shands Cancer Center University of Florida

Gainesville, Florida, 32610, United States

Location

Moffitt Cancer Center

Tampa, Florida, 33612, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

Northwestern University Feinberg School of Medicine

Chicago, Illinois, 60611, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

John Theurer Cancer Center at Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

Weill Cornell Medical College

New York, New York, 10065, United States

Location

Local Institution - 005

Rochester, New York, 14642, United States

Location

University of Rochester

Rochester, New York, 14642, United States

Location

The Ohio State University

Columbus, Ohio, 43210, United States

Location

University of Oklahoma Peggy and Charles Stephenson Cancer Center

Oklahoma City, Oklahoma, 73104, United States

Location

Jefferson Medical Oncology Associates

Philadelphia, Pennsylvania, 19107, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030-4009, United States

Location

Houston Methodist Cancer Center

Houston, Texas, 77030, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Centre Hospitalier Universitaire d'Avicennes

Bobigny, 93009, France

Location

Hopital Henri Mondor

Créteil, 94010, France

Location

Centre Hospitalier

Dijon, 21079, France

Location

Institut Paoli Calmettes

Marseille, 13273, France

Location

CHU Montpellier

Montpellier, 34295, France

Location

Local Institution - 102

Montpellier, 34295, France

Location

Centre Hospitalier Universitaire de Nantes

Nantes, 44093, France

Location

Local Institution - 105

Nantes, 44093, France

Location

Hopital Haut Leveque

Pessac, 33604, France

Location

Centre Hospitalier Lyon-Sud

Pierre-Bénite, 69495, France

Location

Local Institution - 103

Pierre-Bénite, 69495, France

Location

CHRU Rennes

Rennes, 35033, France

Location

Centre Henri Becquerel

Rouen, 76038, France

Location

Universitatsklinikum Essen

Essen, 45122, Germany

Location

UKG Universitatsklinikum Gottingen

Göttingen, 37099, Germany

Location

Universitatsklinikum des Saarlandes

Homburg-Saar, 66421, Germany

Location

Universitatsklinik Koln

Köln, 50924, Germany

Location

Medizinische Klinik III Klinikum der Universität München-Großhadern

München, 81377, Germany

Location

University of Bologna

Bologna, 40138, Italy

Location

Local Institution - 306

Brescia, 25123, Italy

Location

Spedali Civili Di Brescia

Brescia, 25123, Italy

Location

IEO- Istituto Europeo di Oncologia

Milan, 20144, Italy

Location

A.O. Ospedale Ca Granda - Niguarda

Milan, 20162, Italy

Location

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

Napoli, Campania, 80131, Italy

Location

Local Institution - 304

Napoli, Campania, 80131, Italy

Location

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

Pavia, 27100, Italy

Location

IRCCS Humanitas Clinical Institute

Rozzano (milano), 20089, Italy

Location

Local Institution - 602

Chuo-ku, Tokyo, 104-0045, Japan

Location

National Cancer Center Hospital

Chūōku, 104-0045, Japan

Location

Tokai University Hospital

Isehara City, Kanagawa, 259-1193, Japan

Location

Aichi Cancer Center

Nagoya, 464-8681, Japan

Location

VU Academic Medical Center, Amsterdam

Amsterdam, 1081 HV, Netherlands

Location

UMC Groningen

Groningen, 9713 GZ, Netherlands

Location

Leids Universitair Medisch Centrum

Leiden, 2333 ZA, Netherlands

Location

Erasmus Medical Center

Rotterdam, 3015 CN, Netherlands

Location

Local Institution - 501

Rotterdam, 3015 CN, Netherlands

Location

Local Institution - 402

Plymouth, Devon, PL6 8DH, United Kingdom

Location

Local Institution - 407

Nottingham, Nottinghamshire, NG5 1PB, United Kingdom

Location

St James University Hospital

Leeds, LS9 7TF, United Kingdom

Location

UCL Cancer Institute

London, WC1E 6BT, United Kingdom

Location

Christie Hospital NHS Trust

Manchester, M20 4BX, United Kingdom

Location

Local Institution - 404

Manchester, M20 4BX, United Kingdom

Location

Nottingham University Hospitals NHS Trust

Nottingham, Ng5 1PB, United Kingdom

Location

Local Institution - 406

Oxford, 0X3 7LE, United Kingdom

Location

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

Oxford, 0X3 7LE, United Kingdom

Location

Derriford Hospital

Plymouth, PL6 8DH, United Kingdom

Location

Southampton University Hospitals NHS Trust

Southampton, SO16 6YD, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 35852004 DERIVED

Related Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting

MeSH Terms

Conditions

Lymphoma; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphatic Diseases; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Hodgkin Disease; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Immune System Diseases; Immunoproliferative Disorders; Lymphoproliferative Disorders

Interventions

durvalumab; Lenalidomide; Rituximab; ibrutinib; Bendamustine Hydrochloride

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Hemic and Lymphatic Diseases; Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Hematologic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Butyrates; Acids, Acyclic; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Benzimidazoles

Limitations and Caveats

The study was placed on full clinical hold by the United States (US) Food and Drug Administration (FDA) on 05 Sep 2017. As the result, the study was closed for further enrollment, and all participants were discontinued from all study treatments (durvalumab, lenalidomide and dexamethasone). All participants were followed for second primary malignancies (SPMs) for 5 years after the last participant has been enrolled as per protocol.

Results Point of Contact

• Title: Bristol-Myers Squibb Study Director
• Organization: Bristol-Myers Squibb

Clinical.Trials@bms.com

Please email

Study Officials

• Bristol-Myers Squibb

  Bristol-Myers Squibb

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Within Arms A, B, and C participants on the dose-finding part were enrolled sequentially according to a 3+3 design. 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.

Study Record Dates

• First Submitted: April 5, 2016
• First Posted: April 11, 2016
• Study Start: May 11, 2016
• Primary Completion: March 6, 2019
• Study Completion: August 21, 2022
• Last Updated: November 18, 2023
• Results First Posted: March 18, 2020

Record last verified: 2023-10

Locations

IT (9); JP (4); NL (5); FR (13); GB (11); US (19); DE (5)