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A Study to Determine Dose, Safety, and Efficacy of Durvalumab as Monotherapy and in Combination Therapy in Subjects With Lymphoma or Chronic Lymphocytic Leukemia (FUSION NHL 001)

Primary Purpose

Lymphoma, Leukemia, Lymphocytic, Chronic, B-Cell

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

Durvalumab

Lenalidomide

Rituximab

Ibrutinib

Bendamustine

About this trial

This is an interventional treatment trial for Lymphoma focused on measuring 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

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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:
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
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.

Sites / Locations

Banner MD Anderson Cancer Center
Pinnacle Oncology Hematology
University of Colorado Cancer Center
Shands Cancer Center University of Florida
Moffitt Cancer Center
Emory University
Northwestern University Feinberg School of Medicine
Mayo Clinic
Washington University School of Medicine
John Theurer Cancer Center at Hackensack University Medical Center
Weill Cornell Medical College
Local Institution - 005
University of Rochester
The Ohio State University
University of Oklahoma Peggy and Charles Stephenson Cancer Center
Jefferson Medical Oncology Associates
MD Anderson Cancer Center
Houston Methodist Cancer Center
MD Anderson Cancer Center
Centre Hospitalier Universitaire d'Avicennes
Hopital Henri Mondor
Centre Hospitalier
Institut Paoli Calmettes
CHU Montpellier
Centre Hospitalier Universitaire de Nantes
Local Institution - 105
Hopital Haut Leveque
Centre Hospitalier Lyon-Sud
Local Institution - 103
CHRU Rennes
Centre Henri Becquerel
Universitatsklinikum Essen
UKG Universitatsklinikum Gottingen
Universitatsklinikum des Saarlandes
Universitatsklinik Koln
Medizinische Klinik III Klinikum der UniversitÃ¤t MÃ¼nchen-GroÃŸhadern
University of Bologna
Local Institution - 306
Spedali Civili Di Brescia
IEO- Istituto Europeo di Oncologia
A.O. Ospedale Ca Granda - Niguarda
Istituto Nazionale Per Lo Studio E La Cura Dei Tumori Fondazione Giovanni Pascale
Local Institution - 304
I.R.C.C.S. Policlinico San Matteo
IRCCS Humanitas Clinical Institute
Local Institution - 602
National Cancer Center Hospital
Tokai University Hospital
Aichi Cancer Center
VU Academic Medical Center, Amsterdam
UMC Groningen
Leids Universitair Medisch Centrum
Erasmus Medical Center
Local Institution - 501
Local Institution - 402
Local Institution - 407
St James University Hospital
UCL Cancer Institute
Christie Hospital NHS Trust
Local Institution - 404
Nottingham University Hospitals NHS Trust
Local Institution - 406
Oxford University Hospitals NHS Trust- Churchill Hospital-Oxford Centre for Respiratory Medicine
Derriford Hospital
Southampton University Hospitals NHS Trust

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

Arm A: Durvalumab + Lenalidomide ± Rituximab

Arm B: Durvalumab + Ibrutinib

Arm C: Durvalumab + Rituximab ± Bendamustine

Arm D: Durvalumab Monotherapy

Arm Description

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

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.

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).

Secondary Outcome Measures

Overall Response Rate (ORR) During Durvalumab Treatment

For lymphoma participants, response evaluation was based on International Working Group (IWG) response criteria for malignant lymphoma (the Lugano Classification). Overall response rate is defined as the percent of participants with best response of complete response (CR) or partial response (PR). For chronic lymphocytic leukemia participants, response evaluation was based on International Workshop on Chronic Lymphocytic Leukemia (IWCLL) guidelines for diagnosis and treatment of CLL. The ORR is defined as the percent of participants with best response of CR, complete response with incomplete marrow recovery (CRi), nodular partial response (nPR), PR, or partial response with lymphocytosis (PRL).

Overall Response Rate During the Entire Study

For lymphoma participants, response evaluation was based on International Working Group (IWG) response criteria for malignant lymphoma (the Lugano Classification) (Cheson, 2014). Overall response rate is defined as the percent of participants with best response of complete response (CR) or partial response (PR). For chronic lymphocytic leukemia participants, response evaluation was based on International Workshop on Chronic Lymphocytic Leukemia (IWCLL) guidelines for diagnosis and treatment of CLL. The ORR is defined as the percentage of participants with best response of CR, complete response with incomplete marrow recovery (CRi), nodular partial response (nPR), PR, or partial response with lymphocytosis (PRL).

Time to First Response

Time to response was calculated as the time from first dose of study drug to the first response date (CR or PR for lymphoma participants and CR, CRi, nPR, PR, or PRL for CLL participants).

Kaplan-Meier Estimate of Duration of Response

Duration of response is defined for responders only as the time from the first documented response (CR or PR for lymphoma participants or CR, CRi, nPR, PR, or PRL for CLL participants) to disease progression or death (from any cause). For participants with response but no progression, or death, duration of response was censored at the last date that the participant was known to be progression-free.

Kaplan-Meier Estimate of Progression-free Survival (PFS)

Progression-free survival was calculated as the time from first dose of study drug to the first documented progression or death (from any cause) during the entire efficacy evaluation period. For participants with no progression or death, PFS was censored at the last assessment date the participant was known to be progression-free.

Maximum Observed Plasma Concentration (Cmax) of Durvalumab

Time to Maximum Plasma Concentration (Tmax) of Durvalumab

Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUClast) of Durvalumab

Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) of Durvalumab

Terminal Elimination Phase Half-Life (t½) of Durvalumab

Clearance (CL) of Durvalumab

Volume of Distribution (Vz) of Durvalumab

Maximum Observed Plasma Concentration (Cmax) of Lenalidomide

Time to Maximum Observed Plasma Concentration (Tmax) of Lenalidomide

Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUClast) of Lenalidomide

Maximum Observed Plasma Concentration (Cmax) of Ibrutinib

Time to Maximum Observed Plasma Concentration (Tmax) of Ibrutinib

Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUClast) of Ibrutinib

Change From Baseline in Soluble Programmed Cell Death Ligand-1 (sPD-L1) Concentration

Change from baseline in sPD-L1 could not be calculated as all post-baseline samples were below the lower limit of quantification (<15.60 pg/mL).

Full Information

NCT ID

NCT02733042

First Posted

April 5, 2016

Last Updated

December 16, 2022

Sponsor

Celgene

1. Study Identification

Unique Protocol Identification Number

NCT02733042

Brief Title

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

Acronym

FUSION NHL 001

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

December 2022

Overall Recruitment Status

Completed

Study Start Date

May 11, 2016 (Actual)

Primary Completion Date

March 6, 2019 (Actual)

Study Completion Date

August 21, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Celgene

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Sequential Assignment

Model Description

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.

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

106 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm A: Durvalumab + Lenalidomide ± Rituximab

Arm Type

Experimental

Arm Description

Arm Title

Arm B: Durvalumab + Ibrutinib

Arm Type

Experimental

Arm Description

Arm Title

Arm C: Durvalumab + Rituximab ± Bendamustine

Arm Type

Experimental

Arm Description

Arm Title

Arm D: Durvalumab Monotherapy

Arm Type

Experimental

Arm Description

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.

Intervention Type

Drug

Intervention Name(s)

Durvalumab

Other Intervention Name(s)

MEDI4736, IMFINZI®

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Lenalidomide

Other Intervention Name(s)

Revlimid®

Intervention Description

Administered orally

Intervention Type

Drug

Intervention Name(s)

Rituximab

Other Intervention Name(s)

Rituxan®, MabThera®

Intervention Description

Administered by intravenous infusion

Intervention Type

Drug

Intervention Name(s)

Ibrutinib

Other Intervention Name(s)

Imbruvica®

Intervention Description

Administered orally

Intervention Type

Drug

Intervention Name(s)

Bendamustine

Other Intervention Name(s)

Treanda®, Bendeka®, Levact®

Intervention Description

Administered as a 30-minute intravenous infusion

Primary Outcome Measure Information:

Title

Part 1: Number of Participants With Dose Limiting Toxicities (DLTs)

Description

Time Frame

Cycle 1 (28 days)

Title

Number of Participants With Treatment-emergent Adverse Events

Description

Time Frame

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 Outcome Measure Information:

Title

Overall Response Rate (ORR) During Durvalumab Treatment

Description

Time Frame

Up to 13 cycles (12 months)

Title

Overall Response Rate During the Entire Study

Description

Time Frame

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.

Title

Time to First Response

Description

Time to response was calculated as the time from first dose of study drug to the first response date (CR or PR for lymphoma participants and CR, CRi, nPR, PR, or PRL for CLL participants).

Time Frame

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.

Title

Kaplan-Meier Estimate of Duration of Response

Description

Time Frame

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.

Title

Kaplan-Meier Estimate of Progression-free Survival (PFS)

Description

Time Frame

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.

Title

Maximum Observed Plasma Concentration (Cmax) of Durvalumab

Time Frame