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A Study of Durvalumab in Combination With R-CHOP or Lenalidomide Plus R-CHOP in Previously Untreated High-Risk Diffuse Large B-Cell Lymphoma

NCT03003520

Description:

This Phase 2, two-arm, open-label study is designed to evaluate the safety, clinical activity, predictive biomarkers and pharmacokinetics/ pharmacodynamics of durvalumab in combination with R-CHOP (Arm A) or R2-CHOP (Arm B), followed by durvalumab consolidation therapy in previously untreated subjects with high-risk DLBCL. Induction treatment with R-CHOP (± Lenalidomide) will last for a total of up to 6 to 8 treatment cycles (21 days cycle), and the total time on study treatment, including durvalumab consolidation, will last up to 12 months. On 05-Sep-2017, the US FDA has issued a Partial Clinical Hold on this study resulting in the discontinuation of enrolment into Arm B (Durvalumab + Lenalidomide + R-CHOP). After the US FDA Partial Clinical Hold, new eligible subjects have been enrolled in Arm A (Durvalumab + R-CHOP).

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of Durvalumab in Combination With R-CHOP or Lenalidomide Plus R-CHOP in Previously Untreated High-Risk Diffuse Large B-Cell Lymphoma
  • Official Title: A PHASE 2, OPEN-LABEL, MULTICENTER STUDY TO EVALUATE THE SAFETY AND CLINICAL ACTIVITY OF DURVALUMAB IN COMBINATION WITH RITUXIMAB, CYCLOPHOSPHAMIDE, DOXORUBICIN, VINCRISTINE, PREDNISONE (R-CHOP) OR WITH LENALIDOMIDE PLUS R CHOP (R2 CHOP) IN SUBJECTS WITH PREVIOUSLY UNTREATED, HIGH RISK DIFFUSE LARGE B CELL LYMPHOMA

Clinical Trial IDs

  • ORG STUDY ID: MEDI4736-DLBCL-001
  • SECONDARY ID: 2015-005173-20
  • NCT ID: NCT03003520

Conditions

  • Lymphoma, Large B-Cell, Diffuse

Interventions

DrugSynonymsArms
DurvalumabArm A (non-ABC DLBCL): Durvalumab in combination with R-CHOP
RituximabArm A (non-ABC DLBCL): Durvalumab in combination with R-CHOP
DoxorubicinArm A (non-ABC DLBCL): Durvalumab in combination with R-CHOP
VincristineArm A (non-ABC DLBCL): Durvalumab in combination with R-CHOP
CyclophosphamideArm A (non-ABC DLBCL): Durvalumab in combination with R-CHOP
PrednisoneArm A (non-ABC DLBCL): Durvalumab in combination with R-CHOP
LenalidomideArm B (ABC DLBCL): Durvalumab in combination with R2-CHOP

Purpose

This Phase 2, two-arm, open-label study is designed to evaluate the safety, clinical activity, predictive biomarkers and pharmacokinetics/ pharmacodynamics of durvalumab in combination with R-CHOP (Arm A) or R2-CHOP (Arm B), followed by durvalumab consolidation therapy in previously untreated subjects with high-risk DLBCL.

Patients with non-ABC subtype (determined by gene expression profiling) will be allocated to Arm A while patients with ABC (activated B-cell type) subtype will be allocated to Arm B. Approximately 120 patients may be enrolled and assigned into the appropriate treatment arms dependent upon their cell of origin status.

Induction treatment with R-CHOP (± Lenalidomide) will last for a total of up to 6 to 8 treatment cycles (21 days cycle), and the total time on study treatment, including durvalumab consolidation, will last up to 12 months.

Detailed Description

This research study is conducted in patients with previously untreated, high-risk Diffuse Large B-cell Lymphoma (DLBCL). Patients with high-risk DLBCL typically have insufficient therapeutic outcomes. Therefore, the addition of novel agents to the currently used induction therapy (R-CHOP backbone) is a rational approach to improve therapeutic outcomes in this disease setting.

Based on pre-clinical and clinical observations, it is hypothesized that durvalumab will have activity in DLBCL because the PD 1/PD L1 pathway is involved in the pathophysiology of DLBCL. In particular, the addition of durvalumab may significantly augment the anti-tumor activity of R-CHOP against high-risk DLBCL subtypes.

There are different subtypes of DLBCL which are distinguished by their Cell of Origin (ABC, GCB, unclassifiable). About a third of DLBCL is of the ABC subtype and as those patients have a worse outcome when treated with R-CHOP, lenalidomide plus R-CHOP (R2-CHOP) will be used for patients with the ABC subtype.

The safety of durvalumab has already been explored. However, as there is limited clinical experience with durvalumab in DLBCL, the study is divided into two stages:

- A Safety Run-in Stage to evaluate the safety of the treatment combinations until at least 10 subjects are included in each of the two treatment arms for a total of 20 subjects

- An Expansion Stage to analyze the clinical activity of the treatment combinations in up to 100 additional subjects

Trial Arms

NameTypeDescriptionInterventions
Arm A (non-ABC DLBCL): Durvalumab in combination with R-CHOPExperimentalDurvalumab 1125 mg intravenously (IV) on Day 1 of each 21-day cycle in combination with 6 to 8 cycles R-CHOP (IV rituximab, doxorubicin, vincristine, and cyclophosphamide on Day 1; daily oral/IV prednisone/prednisolone from Day 1 to 5) followed by durvalumab monotherapy for up to a total of 12 months after start of study treatment.
  • Durvalumab
  • Rituximab
  • Doxorubicin
  • Vincristine
  • Cyclophosphamide
  • Prednisone
    Arm B (ABC DLBCL): Durvalumab in combination with R2-CHOPExperimentalDurvalumab 1125 mg IV on Day 1 of each 21-day cycle in combination with 6 to 8 cycles R2-CHOP (IV rituximab, doxorubicin, vincristine and cyclophosphamide on Day 1; daily oral/IV prednisone/prednisolone from Day 1 to 5; daily oral lenalidomide 15 mg from Day 1 to 14) from Cycle 2 until end of induction therapy (Cycle 6 or Cycle 8), or starting Cycle 1 if ABC subtype is identified prior to Cycle 1 Day 1 (C1D1) followed by durvalumab monotherapy for up to a total of 12 months after start of study treatment.
    • Durvalumab
    • Rituximab
    • Doxorubicin
    • Vincristine
    • Cyclophosphamide
    • Prednisone
    • Lenalidomide

    Eligibility Criteria

    Inclusion Criteria:

    1. CD20+Diffuse Large B-Cell Lymphoma.

    2. Ann Arbor stage 3 or 4 or stage 2 with bulky disease

    3. High or high-intermediate disease risk.

    4. No prior anti-lymphoma treatment.

    5. Subject is willing and able to undergo biopsy.

    6. Investigator considers R-CHOP immunochemotherapy appropriate.

    7. ECOG performance status of 0-2.

    8. Adequate hematology laboratory results (absolute neutrophil count ≥ 1.5 x 10^9/L, platelet count ≥ 75 x 10^9/L, hemoglobin ≥ 10.0 g/dL).

    9. Adequate biochemistry laboratory results (AST/SGOT and ALT/SGPT ≤ 3.0 x upper limit of normal; bilirubin ≤ 2.0 mg/dL; creatinine clearance of ≥ 40 mL/min).

    10. Bi-dimensionally measurable disease (> 2.0 cm).

    11. Subject is using effective contraception.

    Exclusion Criteria:

    1. Diagnosis of lymphoma other than Diffuse Large B-Cell Lymphoma.

    2. Composite lymphoma or transformed lymphoma.

    3. Primary or secondary Central Nervous System involvement by lymphoma.

    4. Seropositive or active viral infection with hepatitis B virus, human immunodeficiency virus or hepatitis C virus.

    5. History of other malignancies, unless disease-free for ≥ 5 years.

    6. Left ventricular ejection fraction < 50%.

    7. Peripheral neuropathy ≥ Grade 2.

    8. Prior use of lenalidomide, or monoclonal antibodies against CTLA-4, PD-1, or PD-L1.

    9. High risk of developing thromboembolic events, who are unwilling to take venous thromboembolism prophylaxis.

    10. Active or prior documented autoimmune or inflammatory disorders within the past 3 years.

    11. Current or prior use of immunosuppressive medication within 28 days before start of treatment.

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

    Primary Outcome Measures

    Measure:Progression Free Survival at 24 months
    Time Frame:Up to 24 months after last patient is enrolled
    Safety Issue:
    Description:Subjects who have not experienced disease progression or death within 24 months after start of study treatment

    Secondary Outcome Measures

    Measure:Treatment-Emergent Adverse Events (AEs)
    Time Frame:Up to 15 months after last patient is enrolled
    Safety Issue:
    Description:Number of participants with adverse event
    Measure:Clinical response to study treatment in biomarker-defined subpopulations
    Time Frame:Up to 24 months after last patient is enrolled
    Safety Issue:
    Description:Identification and development of biomarkers predictive of clinical response to study treatment

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Celgene

    Trial Keywords

    • Lymphoma
    • Diffuse-large B-Cell Lymphoma
    • Durvalumab
    • Anti-PD-L1 Antibody
    • MEDI4736
    • Immune Checkpoint
    • Rituximab
    • Cyclophosphamide
    • Doxorubicin
    • Vincristine
    • Prednisone/Prednisolone
    • Lenalidomide

    Last Updated

    February 13, 2017