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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

NCT02733042

Description:

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 were to be enrolled into 4 treatment arms, including durvalumab monotherapy; durvalumab in combination with lenalidomide± rituximab; ibrutinib; or rituximab ± bendamustine. Originally the study had 3 parts: dose finding, dose confirmation, and dose expansion. Subjects receiving monotherapy could receive combination therapy or involved-field radiation to a single nodal site at time of documented progressive disease. On 05-Sep-2017, the US FDA issued a Partial Clinical Hold on the study Arm A. Following this Partial Clinical Hold no more subjects were enrolled into study Arm A. Arm B and C completed dose confirmation. No dose expansion followed the completion of dose confirmation for Arm B and C. Accrual was completed on Feb-2018 with 106 subjects enrolled into the study.

Related Conditions:
  • B-Cell Non-Hodgkin Lymphoma
  • Chronic Lymphocytic Leukemia
  • Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
  • Hodgkin Lymphoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: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

Clinical Trial IDs

  • ORG STUDY ID: MEDI4736-NHL-001
  • NCT ID: NCT02733042

Trial Conditions

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

Trial Interventions

DrugSynonymsArms
DurvalumabMEDI4736Arm A: Durvalumab plus Lenalidomide and Rituximab
LenalidomideArm A: Durvalumab plus Lenalidomide and Rituximab
RituximabArm A: Durvalumab plus Lenalidomide and Rituximab
IbrutinibArm B: Durvalumab Plus Ibrutinib
BendamustineArm C: Durvalumab Plus Bendamustine and Rituximab

Trial Purpose

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, 253 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.

Detailed Description

Trial Arms

NameTypeDescriptionInterventions
Arm A: Durvalumab plus Lenalidomide and RituximabExperimentalSubjects 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 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 on Days 2, 8, 15 and 22 of Cycle 1 and on Day 1 from Cycles 2 through 5. One cycle is 28-day.
  • Durvalumab
  • Lenalidomide
  • Rituximab
    Arm B: Durvalumab Plus IbrutinibExperimentalSubjects 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.
    • Durvalumab
        • Ibrutinib
      Arm C: Durvalumab Plus Bendamustine and RituximabExperimentalSubjects 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.
      • Durvalumab
        • Rituximab
          • Bendamustine
      Arm D: Durvalumab MonotherapyExperimentalSubjects 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.
      • Durvalumab

        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/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 following laboratory requirements

        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.

        Maximum Eligible Age:N/A
        Minimum Eligible Age:18 Years
        Eligible Gender:Both
        Healthy Volunteers:No

        Primary Outcome Measures

        Measure:Adverse Events (AEs)- Phase
        Time Frame:Up to approximately 5 years
        Safety Issue:Yes
        Description:Number of participants with adverse events

        Secondary Outcome Measures

        Measure:Overall Response Rate- Phase 1
        Time Frame:Up to approximately 1 year
        Safety Issue:No
        Description: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
        Measure:Adverse Events (AEs) - Phase 2
        Time Frame:Up to approximately 5 years
        Safety Issue:Yes
        Description:Number of participants with adverse events
        Measure:Overall Response Rate-Phase1/2
        Time Frame:Up to approximately 5 years
        Safety Issue:No
        Description: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
        Measure:Duration of response (DoR)- Phase1/2
        Time Frame:Up to approximately 5 years
        Safety Issue:No
        Description:Time from first response (CR/PR) to progressive disease (PD) or death
        Measure:Progression free survival (PFS) - Phase 1/2
        Time Frame:Up to approximately 5 years
        Safety Issue:No
        Description: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
        Measure:Pharmacokinetics - AUC
        Time Frame:Up to approximately 2 months
        Safety Issue:No
        Description:Area under the concentration-time curve
        Measure:Pharmacokinetics - Tmax
        Time Frame:Up to approximately 2 months
        Safety Issue:No
        Description:Time to maximum concentration
        Measure:Pharmacokinetics - t1/2
        Time Frame:Up to approximately 2 months
        Safety Issue:No
        Description:Terminal half-life
        Measure:Pharmacokinetics - CL/F
        Time Frame:Up to approximately 2 months
        Safety Issue:No
        Description:Apparent total body clearance
        Measure:Pharmacokinetics - Vz/F
        Time Frame:Up to approximately 2 months
        Safety Issue:No
        Description:volume of distribution
        Measure:Pharmacodynamics - Phase 1
        Time Frame:Up to approximately 1 year
        Safety Issue:No
        Description:Individual soluble PDL-1 levels [pg/mL] in blood with durvalumab monotherapy

        Trial 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