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Trial record 1 of 1 for:    MEDI4736-NHL-001
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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 : Recruiting
First Posted : April 11, 2016
Last Update Posted : August 30, 2017
Sponsor:
Information provided by (Responsible Party):

Study Description
Brief Summary:
This open-label, multicenter, global study is designed to determine the recommended phase 2 dose, safety, efficacy, and pharmacokinetics/pharmacodynamics of durvalumab in subjects with certain lymphoma subtypes or CLL. Globally, 265 subjects may be enrolled into 4 treatment arms, including durvalumab monotherapy; durvalumab in combination with lenalidomide± rituximab; ibrutinib; or rituximab ± bendamustine. The study will have 3 parts: dose finding, dose confirmation, and dose expansion. Subjects receiving monotherapy may receive combination therapy or involved-field radiation to a single nodal site at time of progressive disease.

Condition or disease Intervention/treatment Phase
Lymphoma Leukemia, Lymphocytic, Chronic, B-Cell Drug: Durvalumab Drug: Lenalidomide Drug: Rituximab Drug: Ibrutinib Drug: Bendamustine Phase 1 Phase 2

Study Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 265 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : May 11, 2016
Estimated Primary Completion Date : June 6, 2024
Estimated Study Completion Date : June 6, 2024


Arms and Interventions

Arm Intervention/treatment
Experimental: Arm A: Durvalumab and Lenalidomide plus or minus Rituximab

Subjects assigned to Arm A will receive:

  • Durvalumab 1500 mg (IV) infusion on Day 1 of Cycles 1 through 13 (ie, 12 months) and
  • Lenalidomide (oral) at assigned dose levels (10 mg, 15 mg or 20 mg) once daily on Days 1 to 21 (inclusive) of:

    • Cycles 1 through 13 in indolent Non-Hodgkin lymphoma (NHL) (ie, FL or MZL) 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 Schedule 1 (dose levels 2 and -1B) on Days 2, 8, 15 and 22 of Cycle 1 and on Day 1 from Cycles 2 through 5.

Rituximab 375 mg/m2 (IV) infusion Schedule 2 (dose levels -2 and -3) on Day 2 of Cycle 1 and on Day 1 from Cycles 2 through 8.

One cycle is 28-day.

Drug: Durvalumab
Other Name: MEDI4736
Drug: Lenalidomide Drug: Rituximab
Experimental: Arm B: Durvalumab and Ibrutinib

Subjects assigned to Arm B will receive:

  • Durvalumab (IV) infusion on Day 1 of Cycles 1 through 13
  • Ibrutinib (oral) at assigned dose levels (280 mg, 420 mg, or 560 mg)continuous once daily until disease progression, unacceptable toxicity or discontinuation for any other reason One cycle is 28-day.
Drug: Durvalumab
Other Name: MEDI4736
Drug: Ibrutinib
Experimental: Arm C: Durvalumab and Bendamustine plus or minus Rituximab

Subjects assigned to Arm C will receive:

  • Durvalumab 1500 mg (IV) infusion on Day 1 of Cycles 1 through 13
  • Bendamustine (IV) infusion at assigned dose levels (70 mg/m2 or 90 mg/m2) on Days 1 and 2 of Cycles 1 through 6
  • Rituximab 375 mg/m2 (IV) infusion on Day 2 Cycles 1 through 6 One cycle is 28-day.
Drug: Durvalumab
Other Name: MEDI4736
Drug: Rituximab Drug: Bendamustine
Experimental: Arm D: Durvalumab Monotherapy

Subjects assigned to Arm D will receive:

• Durvalumab (IV) infusion at a fixed dose of 1500 mg, on Day 1 of Cycles 1 through 13. One cycle is 28-day.

Drug: Durvalumab
Other Name: MEDI4736


Outcome Measures

Primary Outcome Measures :
  1. Adverse Events (AEs)- Phase [ Time Frame: Up to approximately 5 years ]
    Number of participants with adverse events

  2. Dose Limiting Toxicity (DLT) - Phase 1 [ Time Frame: Up to approximately 1 month ]
    Number of participants with a DLT

  3. 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).

  4. 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.

  5. 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)


Secondary Outcome Measures :
  1. 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

  2. Adverse Events (AEs) - Phase 2 [ Time Frame: Up to approximately 5 years ]
    Number of participants with adverse events

  3. 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

  4. 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

  5. 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

  6. Pharmacokinetics - AUC [ Time Frame: Up to approximately 2 months ]
    Area under the concentration-time curve

  7. Pharmacokinetics - Tmax [ Time Frame: Up to approximately 2 months ]
    Time to maximum concentration

  8. Pharmacokinetics - t1/2 [ Time Frame: Up to approximately 2 months ]
    Terminal half-life

  9. Pharmacokinetics - CL/F [ Time Frame: Up to approximately 2 months ]
    Apparent total body clearance

  10. Pharmacokinetics - Vz/F [ Time Frame: Up to approximately 2 months ]
    volume of distribution

  11. Pharmacodynamics - Phase 1/2 [ Time Frame: Up to approximately 1 year ]
    Individual soluble PDL-1 levels [pg/mL] in blood with durvalumab monotherapy

  12. Time to First Response(TTR)- Phase1/2 [ Time Frame: Up to approximately 1 year ]
    Time from first IP dose to the first documented response (PR or CR)


Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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/small lymphocytic lymphoma.
  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 PD-1 or PD-L1 and/or any prior:

    1. Arm A only: ImiDs (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.
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02733042


Contacts
Contact: Associate Director Clinical Trial Disclosure 1-888-260-1599 clinicaltrialdisclosure@celgene.com

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Sponsors and Collaborators
Celgene
Investigators
Study Director: Myron S Czuczman Celgene
More Information

Responsible Party: Celgene
ClinicalTrials.gov Identifier: NCT02733042     History of Changes
Other Study ID Numbers: MEDI4736-NHL-001
First Posted: April 11, 2016    Key Record Dates
Last Update Posted: August 30, 2017
Last Verified: August 2017

Keywords provided by Celgene:
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

Additional relevant MeSH terms:
Lymphoma
Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Lenalidomide
Rituximab
Thalidomide
Bendamustine Hydrochloride
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors
Immunosuppressive Agents
Leprostatic Agents
Anti-Bacterial Agents
Anti-Infective Agents
Antineoplastic Agents, Alkylating
Alkylating Agents