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

Lymphoma Clinical Trial

— 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02733042
• Other study ID #: MEDI4736-NHL-001
• Secondary ID: 2015-003516-21
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: May 11, 2016
• Est. completion date: August 21, 2022

Study information

• Verified date: October 2023
• Source: Celgene
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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 information / eligibility

• Status: Completed
• Enrollment: 106
• Est. completion date: August 21, 2022
• Est. primary completion date: March 6, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Lymphoma

Intervention

Drug:
• Durvalumab
Administered as an IV infusion (250 mL) over approximately 1 hour in duration
• Lenalidomide
Administered orally
• Rituximab
Administered by intravenous infusion
• Ibrutinib
Administered orally
• Bendamustine
Administered as a 30-minute intravenous infusion

Locations

Country	Name	City	State
France	Centre Hospitalier Universitaire d'Avicennes	Bobigny Cedex
France	Hopital Henri Mondor	Creteil
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	Centre Hospitalier Lyon-Sud	Pierre-Benite CEDEX
France	Local Institution - 103	Pierre-Benite CEDEX
France	CHRU Rennes	Rennes
France	Centre Henri Becquerel	Rouen Cedex
Germany	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
Italy	University of Bologna	Bologna
Italy	Local Institution - 306	Brescia
Italy	Spedali Civili Di Brescia	Brescia
Italy	A.O. Ospedale Ca Granda - Niguarda	Milano
Italy	IEO- Istituto Europeo di Oncologia	Milano
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)
Japan	Local Institution - 602	Chuo-ku	Tokyo
Japan	National Cancer Center Hospital	Chuo-ku
Japan	Tokai University Hospital	Isehara City, Kanagawa
Japan	Aichi Cancer Center	Nagoya
Netherlands	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
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	Local Institution - 407	Nottingham	Nottinghamshire
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	Local Institution - 402	Plymouth	Devon
United Kingdom	Southampton University Hospitals NHS Trust	Southampton
United States	Emory University	Atlanta	Georgia
United States	University of Colorado Cancer Center	Aurora	Colorado
United States	Northwestern University Feinberg School of Medicine	Chicago	Illinois
United States	The Ohio State University	Columbus	Ohio
United States	Shands Cancer Center University of Florida	Gainesville	Florida
United States	Banner MD Anderson Cancer Center	Gilbert	Arizona
United States	John Theurer Cancer Center at Hackensack University Medical Center	Hackensack	New Jersey
United States	Houston Methodist Cancer Center	Houston	Texas
United States	MD Anderson Cancer Center	Houston	Texas
United States	MD Anderson Cancer Center	Houston	Texas
United States	Weill Cornell Medical College	New York	New York
United States	University of Oklahoma Peggy and Charles Stephenson Cancer Center	Oklahoma City	Oklahoma
United States	Jefferson Medical Oncology Associates	Philadelphia	Pennsylvania
United States	Local Institution - 005	Rochester	New York
United States	Mayo Clinic	Rochester	Minnesota
United States	University of Rochester	Rochester	New York
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Pinnacle Oncology Hematology	Scottsdale	Arizona
United States	Moffitt Cancer Center	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Celgene

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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	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).	Up to 13 cycles (12 months)
Secondary	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).	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.
Secondary	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).	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.
Secondary	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.	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.
Secondary	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.	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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
Secondary	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.
Secondary	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.
Secondary	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
Secondary	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).	Baseline (Cycle 1 Day 1 predose) and Day 1 of Cycles 2 to 13

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