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

Celgene

Status and phase: Completed; Phase 2

Conditions: Lymphoma, Large B-Cell, Diffuse

Treatments: Drug: Vincristine; Drug: Cyclophosphamide; Drug: Rituximab; Drug: Prednisone; Drug: Durvalumab; Drug: Lenalidomide; Drug: Doxorubicin

Study type: Interventional

Funder types: Industry

Identifiers

NCT03003520

MEDI4736-DLBCL-001

2015-005173-20 (EudraCT Number)

Details and patient eligibility

About

This Phase 2, two-arm, open-label study is designed to evaluate the safety, clinical activity, and predictive biomarkers of durvalumab in combination with R-CHOP or R2-CHOP, followed by durvalumab consolidation therapy in previously untreated subjects with high-risk diffuse large B-cell lymphoma (DLBCL). Induction treatment with R-CHOP (± lenalidomide) will last for a total of up to 6 to 8 treatment cycles (21 day cycles), 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 enrollment into Arm B (Durvalumab + Lenalidomide + R-CHOP). After the US FDA Partial Clinical Hold, new eligible participants have been enrolled in Arm A (Durvalumab + R-CHOP).

Full description

This research study is conducted in participants 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) 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 augment the anti-tumor activity of R-CHOP against high-risk DLBCL sub-types.

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
• An Expansion Stage to analyze the clinical activity of the treatment combinations

Results posted following Primary Outcome Completion date are based on a database cut-off of August 2, 2018.

Enrollment: 46 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
8. Adequate hematology laboratory results (absolute neutrophil count ≥ 1.5 * 10^9/L, platelet count ≥ 75 * 10^9/L, hemoglobin ≥ 10.0 g/dL).
9. Adequate biochemistry laboratory results (aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 3.0 * 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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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46 participants in 2 patient groups

DUR + R-CHOP

Experimental group

Description:

On Day 1 of each 21-day cycle, participants received durvalumab 1125 mg intravenously (IV) followed by R-CHOP (IV rituximab 375 mg/m\^2, doxorubicin 50 mg/m\^2, vincristine 1.4 mg/m\^2 (maximum dose of 2.0 mg total), and cyclophosphamide 750 mg/m\^2); Participants also were administered daily oral or IV prednisone/prednisolone 100 mg from Day 1 to 5. Induction treatment continued for a total of 6-8 cycles. Participants who achieve a complete response or partial response continue with consolidation therapy treatment consisting of durvalumab monotherapy 1500 mg by IV on Day 1 of each 28-day cycle for up to a total of 12 months.

Treatment:

Drug: Doxorubicin

Drug: Durvalumab

Drug: Prednisone

Drug: Cyclophosphamide

Drug: Rituximab

Drug: Vincristine

DUR + R2-CHOP

Experimental group

Description:

Participants start the study on durvalumab in combination with R-CHOP (as described in Arm DUR + R-CHOP). Based on their DLBCL Cell-of-Origin subtype (test typically done between cycles 1 and 2), participants with ABC subtype continue the study taking durvalumab in combination with R2-CHOP. On Day 1 of each 21-day cycle, participants received durvalumab 1125 mg intravenously (IV) followed by R-CHOP. Participants were also administered daily oral or IV prednisone/prednisolone 100 mg from Day 1 to 5. In addition, a daily oral lenalidomide 15 mg was administered from Day 1 to 14 of each 21-day cycle. Induction treatment continued for a total of 6-8 cycles. Participants who achieve a complete response or partial response continue with consolidation therapy treatment consisting of durvalumab monotherapy 1500 mg by IV on Day 1 of each 28-day cycle for up to a total of 12 months. Enrollment into Arm B was discontinued.

Treatment:

Drug: Doxorubicin

Drug: Lenalidomide

Drug: Durvalumab

Drug: Prednisone

Drug: Cyclophosphamide

Drug: Rituximab

Drug: Vincristine