Clinical trial NCT02733042: A Study to Determine Dose, Safety, and Efficacy of Durvalumab as Monotherapy and in Combination Therapy in Subjects With Lymphoma or Chronic Lymphocytic Leukemia
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
Overall status: COMPLETED
Phase: PHASE1
PHASE2
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
Lead sponsor: Celgene
Sponsor class: INDUSTRY
First posted: 2016-04-11
Enrollment: 106
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention 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.
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Part 1: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Cycle 1 (28 days)
measure: Number of Participants With Treatment-emergent Adverse Events
timeFrame: 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:
measure: Overall Response Rate (ORR) During Durvalumab Treatment
timeFrame: Up to 13 cycles (12 months)
measure: Overall Response Rate During the Entire Study
timeFrame: 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.
measure: Time to First Response
timeFrame: 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.
measure: Kaplan-Meier Estimate of Duration of Response
timeFrame: 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.
measure: Kaplan-Meier Estimate of Progression-free Survival (PFS)
timeFrame: 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.
measure: Maximum Observed Plasma Concentration (Cmax) of Durvalumab
timeFrame: 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.
measure: Time to Maximum Plasma Concentration (Tmax) of Durvalumab
timeFrame: 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.
measure: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUClast) of Durvalumab
timeFrame: 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.
measure: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) of Durvalumab
timeFrame: 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.
measure: Terminal Elimination Phase Half-Life (t½) of Durvalumab
timeFrame: 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.
measure: Clearance (CL) of Durvalumab
timeFrame: 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.
measure: Volume of Distribution (Vz) of Durvalumab
timeFrame: 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.
measure: Maximum Observed Plasma Concentration (Cmax) of Lenalidomide
timeFrame: 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.
measure: Time to Maximum Observed Plasma Concentration (Tmax) of Lenalidomide
timeFrame: 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.
measure: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUClast) of Lenalidomide
timeFrame: Cycle 1 Day 1 at predose and 1, 2, 4, and 24 hours post-dose
measure: Maximum Observed Plasma Concentration (Cmax) of Ibrutinib
timeFrame: 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.
measure: Time to Maximum Observed Plasma Concentration (Tmax) of Ibrutinib
timeFrame: 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.
measure: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUClast) of Ibrutinib
timeFrame: Cycle 1 Day 1 at predose and 1, 2, 4, and 24 hours post-dose
measure: Change From Baseline in Soluble Programmed Cell Death Ligand-1 (sPD-L1) Concentration
timeFrame: Baseline (Cycle 1 Day 1 predose) and Day 1 of Cycles 2 to 13
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center
state: Arizona
city: Scottsdale
country: United States
facility: Pinnacle Oncology Hematology
state: Arizona
city: Aurora
country: United States
facility: University of Colorado Cancer Center
state: Colorado
city: Gainesville
country: United States
facility: Shands Cancer Center University of Florida
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: Northwestern University Feinberg School of Medicine
state: Illinois
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Hackensack
country: United States
facility: John Theurer Cancer Center at Hackensack University Medical Center
state: New Jersey
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: Rochester
country: United States
facility: Local Institution - 005
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Peggy and Charles Stephenson Cancer Center
state: Oklahoma
city: Philadelphia
country: United States
facility: Jefferson Medical Oncology Associates
state: Pennsylvania
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Houston
country: United States
facility: Houston Methodist Cancer Center
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Bobigny Cedex
country: France
facility: Centre Hospitalier Universitaire d'Avicennes
city: Creteil
country: France
facility: Hopital Henri Mondor
city: Dijon Cedex
country: France
facility: Centre Hospitalier
city: Marseille Cedex 9
country: France
facility: Institut Paoli Calmettes
city: Montpellier Cedex 5
country: France
facility: CHU Montpellier
city: Montpellier Cedex 5
country: France
facility: Local Institution - 102
city: Nantes
country: France
facility: Centre Hospitalier Universitaire de Nantes
city: Nantes
country: France
facility: Local Institution - 105
city: Pessac Cedex
country: France
facility: Hopital Haut Leveque
city: Pierre-Benite CEDEX
country: France
facility: Centre Hospitalier Lyon-Sud
city: Pierre-Benite CEDEX
country: France
facility: Local Institution - 103
city: Rennes
country: France
facility: CHRU Rennes
city: Rouen Cedex
country: France
facility: Centre Henri Becquerel
city: Essen
country: Germany
facility: Universitatsklinikum Essen
city: GÃ¶ttingen
country: Germany
facility: UKG Universitatsklinikum Gottingen
city: Homburg-Saar
country: Germany
facility: Universitatsklinikum des Saarlandes
city: KÃ¶ln
country: Germany
facility: Universitatsklinik Koln
city: MÃ¼nchen
country: Germany
facility: Medizinische Klinik III Klinikum der UniversitÃ¤t MÃ¼nchen-GroÃŸhadern
city: Bologna
country: Italy
facility: University of Bologna
city: Brescia
country: Italy
facility: Local Institution - 306
city: Brescia
country: Italy
facility: Spedali Civili Di Brescia
city: Milano
country: Italy
facility: IEO- Istituto Europeo di Oncologia
city: Milano
country: Italy
facility: A.O. Ospedale Ca Granda - Niguarda
city: Napoli, Campania
country: Italy
facility: Istituto Nazionale Per Lo Studio E La Cura Dei Tumori Fondazione Giovanni Pascale
city: Napoli, Campania
country: Italy
facility: Local Institution - 304
city: Pavia
country: Italy
facility: I.R.C.C.S. Policlinico San Matteo
city: Rozzano (milano)
country: Italy
facility: IRCCS Humanitas Clinical Institute
city: Chuo-ku
country: Japan
facility: Local Institution - 602
state: Tokyo
city: Chuo-ku
country: Japan
facility: National Cancer Center Hospital
city: Isehara City, Kanagawa
country: Japan
facility: Tokai University Hospital
city: Nagoya
country: Japan
facility: Aichi Cancer Center
city: Amsterdam
country: Netherlands
facility: VU Academic Medical Center, Amsterdam
city: Groningen
country: Netherlands
facility: UMC Groningen
city: Leiden
country: Netherlands
facility: Leids Universitair Medisch Centrum
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center
city: Rotterdam
country: Netherlands
facility: Local Institution - 501
city: Plymouth
country: United Kingdom
facility: Local Institution - 402
state: Devon
city: Nottingham
country: United Kingdom
facility: Local Institution - 407
state: Nottinghamshire
city: Leeds
country: United Kingdom
facility: St James University Hospital
city: London
country: United Kingdom
facility: UCL Cancer Institute
city: Manchester
country: United Kingdom
facility: Christie Hospital NHS Trust
city: Manchester
country: United Kingdom
facility: Local Institution - 404
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust
city: Oxford
country: United Kingdom
facility: Local Institution - 406
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals NHS Trust- Churchill Hospital-Oxford Centre for Respiratory Medicine
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
city: Southampton
country: United Kingdom
facility: Southampton University Hospitals NHS Trust
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References: