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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)

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ClinicalTrials.gov Identifier: NCT02733042
Recruitment Status : Completed
First Posted : April 11, 2016
Results First Posted : March 18, 2020
Last Update Posted : January 10, 2023
Sponsor:
Information provided by (Responsible Party):
Celgene

Tracking Information
First Submitted Date  ICMJE April 5, 2016
First Posted Date  ICMJE April 11, 2016
Results First Submitted Date  ICMJE March 4, 2020
Results First Posted Date  ICMJE March 18, 2020
Last Update Posted Date January 10, 2023
Actual Study Start Date  ICMJE May 11, 2016
Actual Primary Completion Date March 6, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 4, 2020)
  • Part 1: Number of Participants With Dose Limiting Toxicities (DLTs) [ Time Frame: 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 [ 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. ]
    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).
Original Primary Outcome Measures  ICMJE
 (submitted: April 5, 2016)
  • Adverse Events (AEs)- Phase [ Time Frame: Up to approximately 5 years ]
    Number of participants with adverse events
  • Dose Limiting Toxicity (DLT) - Phase 1 [ Time Frame: Up to approximately 1 month ]
    Number of participants with a DLT
  • Non-Tolerated Dose (NTD)- Phase 1 [ Time Frame: Up to approximately 1 month ]
    A dose will be considered to be a non-tolerated dose (NTD) if ≥ 2 of 3 or 6 evaluable subjects in a dose level experience a Dose Limiting Toxicity (DLT).
  • Maximum Tolerated Dose (MTD)- Phase 1 [ Time Frame: Up to approximately 1 month ]
    Is defined as the highest dose level below the NTD with 0 of 3 or 1 of 6 (ie, < 1/3 of subjects) evaluable subjects experiencing DLTs during the DLT evaluation period.
  • Overall Response Rate (ORR)- Phase 2 [ Time Frame: Up to approximately 1 year ]
    Number of subjects with best disease response of complete response (CR) or partial response (PR) during durvalumab treatment based on the International Working Group (IWG) Response Criteria for Malignant Lymphoma (the Lugano Classification) (Cheson, 2014) or the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Response Criteria (Hallek 2008; 2012; 2013)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 4, 2020)
  • Overall Response Rate (ORR) During Durvalumab Treatment [ Time Frame: 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 [ 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. ]
    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 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. ]
    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 [ 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. ]
    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) [ 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. ]
    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 Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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. ]
  • Terminal Elimination Phase Half-Life (t½) of Durvalumab [ Time Frame: 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. ]
  • Clearance (CL) of Durvalumab [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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. ]
  • Time to Maximum Observed Plasma Concentration (Tmax) of Lenalidomide [ Time Frame: 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 [ Time Frame: Cycle 1 Day 1 at predose and 1, 2, 4, and 24 hours post-dose ]
  • Maximum Observed Plasma Concentration (Cmax) of Ibrutinib [ Time Frame: 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. ]
  • Time to Maximum Observed Plasma Concentration (Tmax) of Ibrutinib [ Time Frame: 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 Ibrutinib [ Time Frame: 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 [ Time Frame: 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).
Original Secondary Outcome Measures  ICMJE
 (submitted: April 5, 2016)
  • Overall Response Rate- Phase 1 [ Time Frame: Up to approximately 1 year ]
    Number of subjects with best disease response of CR or PR during durvalumab treatment based on the IWG Response Criteria for Malignant Lymphoma (the Lugano Classification) or the IWCLL Response Criteria
  • Adverse Events (AEs) - Phase 2 [ Time Frame: Up to approximately 5 years ]
    Number of participants with adverse events
  • Overall Response Rate-Phase1/2 [ Time Frame: Up to approximately 5 years ]
    Number of subjects with best disease response of CR or PR during study treatment based on the IWG Response Criteria for Malignant Lymphoma (the Lugano Classification) or the IWCLL Response Criteria
  • Duration of response (DoR)- Phase1/2 [ Time Frame: Up to approximately 5 years ]
    Time from first response (CR/PR) to progressive disease (PD) or death
  • Progression free survival (PFS) - Phase 1/2 [ Time Frame: Up to approximately 5 years ]
    Time from first study treatment dose to the first documented PD or death due to any cause, whichever occurs first time from first study treatment dose to the first documented PD or death due to any cause, whichever occurs first
  • Pharmacokinetics - AUC [ Time Frame: Up to approximately 2 months ]
    Area under the concentration-time curve
  • Pharmacokinetics - Tmax [ Time Frame: Up to approximately 2 months ]
    Time to maximum concentration
  • Pharmacokinetics - t1/2 [ Time Frame: Up to approximately 2 months ]
    Terminal half-life
  • Pharmacokinetics - CL/F [ Time Frame: Up to approximately 2 months ]
    Apparent total body clearance
  • Pharmacokinetics - Vz/F [ Time Frame: Up to approximately 2 months ]
    volume of distribution
  • Pharmacodynamics - Phase 1 [ Time Frame: Up to approximately 1 year ]
    Individual soluble PDL-1 or other soluble factors levels in blood with durvalumab monotherapy
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
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.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Lymphoma
  • Leukemia, Lymphocytic, Chronic, B-Cell
Intervention  ICMJE
  • Drug: Durvalumab
    Administered as an IV infusion (250 mL) over approximately 1 hour in duration
    Other Names:
    • MEDI4736
    • IMFINZI®
  • Drug: Lenalidomide
    Administered orally
    Other Name: Revlimid®
  • Drug: Rituximab
    Administered by intravenous infusion
    Other Names:
    • Rituxan®
    • MabThera®
  • Drug: Ibrutinib
    Administered orally
    Other Name: Imbruvica®
  • Drug: Bendamustine
    Administered as a 30-minute intravenous infusion
    Other Names:
    • Treanda®
    • Bendeka®
    • Levact®
Study Arms  ICMJE
  • Experimental: Arm A: Durvalumab + Lenalidomide ± 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.

    Interventions:
    • Drug: Durvalumab
    • Drug: Lenalidomide
    • Drug: Rituximab
  • Experimental: Arm B: Durvalumab + 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.

    Interventions:
    • Drug: Durvalumab
    • Drug: Ibrutinib
  • Experimental: Arm C: Durvalumab + Rituximab ± 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.

    Interventions:
    • Drug: Durvalumab
    • Drug: Rituximab
    • Drug: Bendamustine
  • Experimental: Arm D: Durvalumab Monotherapy
    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: Drug: Durvalumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 18, 2018)
106
Original Estimated Enrollment  ICMJE
 (submitted: April 5, 2016)
253
Actual Study Completion Date  ICMJE August 21, 2022
Actual Primary Completion Date March 6, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE France,   Germany,   Italy,   Japan,   Netherlands,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02733042
Other Study ID Numbers  ICMJE MEDI4736-NHL-001
2015-003516-21 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Celgene
Original Responsible Party Celgene Corporation
Current Study Sponsor  ICMJE Celgene
Original Study Sponsor  ICMJE Celgene Corporation
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
PRS Account Celgene
Verification Date December 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP