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

Phase 1

Completed

Conditions: Lymphoma
Leukemia, Lymphocytic, Chronic, B-Cell

Interventions: Drug: Durvalumab
Drug: Lenalidomide
Drug: Ibrutinib
Drug: Rituximab
Drug: Bendamustine

Registration Number: NCT02733042

Lead Sponsor: Celgene

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 106

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.

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Arm A: Durvalumab + Lenalidomide ± Rituximab	Lenalidomide	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.
Arm A: Durvalumab + Lenalidomide ± Rituximab	Durvalumab	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.
Arm A: Durvalumab + Lenalidomide ± Rituximab	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.
Arm B: Durvalumab + Ibrutinib	Durvalumab	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.
Arm B: Durvalumab + Ibrutinib	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.
Arm C: Durvalumab + Rituximab ± Bendamustine	Durvalumab	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.
Arm C: Durvalumab + Rituximab ± Bendamustine	Rituximab	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.
Arm C: Durvalumab + Rituximab ± Bendamustine	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.
Arm D: Durvalumab Monotherapy	Durvalumab	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.

Primary Outcome Measures

Name	Time	Method
Part 1: Number of Participants With Dose Limiting Toxicities (DLTs)	Cycle 1 (28 days)	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	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.	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

Name	Time	Method
Overall Response Rate (ORR) During Durvalumab Treatment	Up to 13 cycles (12 months)	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	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.	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	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 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).
Clearance (CL) of Durvalumab	Cycle 1, Day 1 (pre-dose and at end of infusion), and 4, 24, 48, 168 (Day 8), 336 (Day 15), and 508 (Day 22) hours after the end of infusion.
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.	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)	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.	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	Cycle 1, Day 1 (pre-dose and at end of infusion), and 4, 24, 48, 168 (Day 8), 336 (Day 15), and 508 (Day 22) hours after the end of infusion.
Time to Maximum Plasma Concentration (Tmax) of Durvalumab	Cycle 1, Day 1 (pre-dose and at end of infusion), and 4, 24, 48, 168 (Day 8), 336 (Day 15), and 508 (Day 22) hours after the end of infusion.
Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUClast) of Durvalumab	Cycle 1, Day 1 (pre-dose and at end of infusion), and 4, 24, 48, 168 (Day 8), 336 (Day 15), and 508 (Day 22) hours after the end of infusion.
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) of Durvalumab	Cycle 1, Day 1 (pre-dose and at end of infusion), and 4, 24, 48, 168 (Day 8), 336 (Day 15), and 508 (Day 22) hours after the end of infusion.
Maximum Observed Plasma Concentration (Cmax) of Lenalidomide	Cycle 1 Day 1 at predose and 1, 2, 4, and 24 hours post-dose, and Cycle 1 Day 15 at pre-dose, 1, 2, and 4 hours post-dose.
Maximum Observed Plasma Concentration (Cmax) of Ibrutinib	Cycle 1 Day 1 at predose and 1, 2, 4, and 24 hours post-dose, and Cycle 1 Day 15 at pre-dose, 1, 2, and 4 hours post-dose.
Terminal Elimination Phase Half-Life (t½) of Durvalumab	Cycle 1, Day 1 (pre-dose and at end of infusion), and 4, 24, 48, 168 (Day 8), 336 (Day 15), and 508 (Day 22) hours after the end of infusion.
Volume of Distribution (Vz) of Durvalumab	Cycle 1, Day 1 (pre-dose and at end of infusion), and 4, 24, 48, 168 (Day 8), 336 (Day 15), and 508 (Day 22) hours after the end of infusion.
Time to Maximum Observed Plasma Concentration (Tmax) of Lenalidomide	Cycle 1 Day 1 at predose and 1, 2, 4, and 24 hours post-dose, and Cycle 1 Day 15 at pre-dose, 1, 2, and 4 hours post-dose.
Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUClast) of Lenalidomide	Cycle 1 Day 1 at predose and 1, 2, 4, and 24 hours post-dose
Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUClast) of Ibrutinib	Cycle 1 Day 1 at predose and 1, 2, 4, and 24 hours post-dose
Change From Baseline in Soluble Programmed Cell Death Ligand-1 (sPD-L1) Concentration	Baseline (Cycle 1 Day 1 predose) and Day 1 of Cycles 2 to 13	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).
Time to Maximum Observed Plasma Concentration (Tmax) of Ibrutinib	Cycle 1 Day 1 at predose and 1, 2, 4, and 24 hours post-dose, and Cycle 1 Day 15 at pre-dose, 1, 2, and 4 hours post-dose.

Trial Locations

Locations (65): Northwestern University Feinberg School of Medicine
🇺🇸
Chicago, Illinois, United States
Jefferson Medical Oncology Associates
🇺🇸
Philadelphia, Pennsylvania, United States
Centre Hospitalier Universitaire d'Avicennes
🇫🇷
Bobigny Cedex, France
University of Colorado Cancer Center
🇺🇸
Aurora, Colorado, United States
Mayo Clinic
🇺🇸
Rochester, Minnesota, United States
Banner MD Anderson Cancer Center
🇺🇸
Gilbert, Arizona, United States
Hopital Henri Mondor
🇫🇷
Creteil, France
Pinnacle Oncology Hematology
🇺🇸
Scottsdale, Arizona, United States
Emory University
🇺🇸
Atlanta, Georgia, United States
Local Institution - 005
🇺🇸
Rochester, New York, United States
Houston Methodist Cancer Center
🇺🇸
Houston, Texas, United States
MD Anderson Cancer Center
🇺🇸
Houston, Texas, United States
University of Oklahoma Peggy and Charles Stephenson Cancer Center
🇺🇸
Oklahoma City, Oklahoma, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
The Ohio State University
🇺🇸
Columbus, Ohio, United States
University of Rochester
🇺🇸
Rochester, New York, United States
Centre Henri Becquerel
🇫🇷
Rouen Cedex, France
Universitatsklinikum Essen
🇩🇪
Essen, Germany
UKG Universitatsklinikum Gottingen
🇩🇪
GÃ¶ttingen, Germany
Universitatsklinikum des Saarlandes
🇩🇪
Homburg-Saar, Germany
Universitatsklinik Koln
🇩🇪
KÃ¶ln, Germany
Local Institution - 602
🇯🇵
Chuo-ku, Tokyo, Japan
Aichi Cancer Center
🇯🇵
Nagoya, Japan
Local Institution - 501
🇳🇱
Rotterdam, Netherlands
Local Institution - 407
🇬🇧
Nottingham, Nottinghamshire, United Kingdom
Local Institution - 406
🇬🇧
Oxford, United Kingdom
Nottingham University Hospitals NHS Trust
🇬🇧
Nottingham, United Kingdom
Derriford Hospital
🇬🇧
Plymouth, United Kingdom
Christie Hospital NHS Trust
🇬🇧
Manchester, United Kingdom
Oxford University Hospitals NHS Trust- Churchill Hospital-Oxford Centre for Respiratory Medicine
🇬🇧
Oxford, United Kingdom
Southampton University Hospitals NHS Trust
🇬🇧
Southampton, United Kingdom
Moffitt Cancer Center
🇺🇸
Tampa, Florida, United States
Shands Cancer Center University of Florida
🇺🇸
Gainesville, Florida, United States
Local Institution - 306
🇮🇹
Brescia, 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
Tokai University Hospital
🇯🇵
Isehara City, Kanagawa, Japan
National Cancer Center Hospital
🇯🇵
Chuo-ku, Japan
Leids Universitair Medisch Centrum
🇳🇱
Leiden, Netherlands
Local Institution - 402
🇬🇧
Plymouth, Devon, United Kingdom
St James University Hospital
🇬🇧
Leeds, United Kingdom
UCL Cancer Institute
🇬🇧
London, United Kingdom
Local Institution - 404
🇬🇧
Manchester, United Kingdom
Local Institution - 103
🇫🇷
Pierre-Benite CEDEX, France
CHRU Rennes
🇫🇷
Rennes, France
John Theurer Cancer Center at Hackensack University Medical Center
🇺🇸
Hackensack, New Jersey, United States
University of Bologna
🇮🇹
Bologna, Italy
Spedali Civili Di Brescia
🇮🇹
Brescia, Italy
IEO- Istituto Europeo di Oncologia
🇮🇹
Milano, Italy
A.O. Ospedale Ca Granda - Niguarda
🇮🇹
Milano, Italy
VU Academic Medical Center, Amsterdam
🇳🇱
Amsterdam, Netherlands
UMC Groningen
🇳🇱
Groningen, Netherlands
Erasmus Medical Center
🇳🇱
Rotterdam, Netherlands
Medizinische Klinik III Klinikum der UniversitÃ¤t MÃ¼nchen-GroÃŸhadern
🇩🇪
MÃ¼nchen, Germany
Weill Cornell Medical College
🇺🇸
New York, New York, United States
Centre Hospitalier Lyon-Sud
🇫🇷
Pierre-Benite CEDEX, France
Centre Hospitalier
🇫🇷
Dijon Cedex, France
Institut Paoli Calmettes
🇫🇷
Marseille Cedex 9, France
CHU Montpellier
🇫🇷
Montpellier Cedex 5, France
Local Institution - 102
🇫🇷
Montpellier Cedex 5, France
Centre Hospitalier Universitaire de Nantes
🇫🇷
Nantes, France
Local Institution - 105
🇫🇷
Nantes, France
Hopital Haut Leveque
🇫🇷
Pessac Cedex, France