Study Title: A051902: A Randomized Phase II Study of CHO(E)P Vs. CC-486-CHO(E)P Vs. Duvelisib-CHO(E)P in Previously Untreated CD30 Negative Peripheral T-cell Lymphomas

ClinicalTrials.Gov Number: NCT04803201

Sponsor: National Cancer Institute

Accrual Goal: 182

Participating Centers: National Clinical Trials Network (NCTN)

Study Design: This is a three-arm, open-label, randomized phase II study to evaluate whether the addition of duvelisib or CC-486 to CHOP (cyclosphosphamide, doxorubicin, vincristine, prednisone) or CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, prednisone) chemotherapy improves the rate of complete remission (CR) by positron emission tomography/computed tomography (PET/CT) in patients with peripheral T-cell lymphoma (PTCL) who have less than 10 percent CD30 expression by immunohistochemistry. As both CHOP and CHOEP are commonly given for the upfront treatment of PTCL, this study will compare the novel combination strategies to standard therapy with either regimen. Patients older than 60 years will receive a CHOP chemotherapy backbone, and those 60 years or younger will receive a CHOEP backbone. Patients will be randomized to standard chemotherapy or duvelisib with standard therapy, or to CC-486 with standard therapy. Patients will be stratified on age (≤ 60 years vs. > 60 years) and on the presence of angioimmunoblastic T-cell lymphoma (AITL) or T follicular-helper (TFH) PTCL phenotype (follicular T-cell lymphoma or nodal peripheral T-cell lymphoma with TFH phenotype), since preliminary data have shown that patients with T-cell lymphomas derived from TFH cells may be more responsive to these novel agents.1,2  Stratification based on TFH phenotype will be performed based on local review. TFH phenotype can be designated based on diagnosis of AITL or PTCL not otherwise specified (PTCL-NOS) with TFH phenotype (as defined by expression of two or more of the following markers: CD10, BCL6, CXCL13, ICOS, and PD1 by immunohistochemistry).3  The study will directly compare these regimens to CHOP/ CHOEP itself. Patients will be stratified on age (< 60 years vs. > 60 years). As duvelisib has not been studied in combination with CHOP or CHOEP chemotherapy, the study will evaluate the safety of the regimen at a dose of duvelisib 15 mg in combination with CHO(E)P in the first 12 patients as part of the safety lead-in. The study will be performed in the U.S. Intergroup and will enroll approximately 182 patients. The study is anticipated to be activated in August 2021. Additionally, this study plans to explore ways to better predict outcomes to frontline therapy in PTCL. These include the use of cell-free DNA as a tool to evaluate minimal residual disease in this patient population as well as imaging tools such as tumor metabolic volume and interim PET/CT.

Rationale: PTCLs are a rare subset of non-Hodgkin lymphomas, of which PTCL-NOS, AITL, and anaplastic large-cell lymphoma are the most common subsets. TFH PTCLs, including AITL, have a similar genetic landscape with a high proportion of mutations associated with chromatin modification. While patients are often treated with CHOP-based therapy for curative intent, registry studies have shown that the five-year survival remains at 20 to 30 percent.4  Patients aged 60 years or younger have been shown to have improved rates of CR with the addition of etoposide to CHOP (CHOEP).5  The ECHELON 2 study demonstrated a progression-free and overall survival benefit of brentuximab-CHP compared to CHOP in those with PTCL with 10 percent or greater CD30 expression, and suggested that well-tolerated and effective therapies added to a CHOP backbone can result in improved survival for this difficult-to-treat disease.6  Duvelisib is an oral PI3-kinase inhibitor that is well tolerated and approved for the treatment of relapsed/ refractory chronic lymphocytic leukemia and follicular lymphoma. Duvelisib has shown an overall response rate of 52 to 58 percent and a CR rate of 20 to 30 percent.2,7  CC-486 is an oral formulation of azacitidine now approved for treatment of acute myeloid leukemia. In a small series, azacitidine has shown a 75 percent response rate in patients with AITL with durable remission.8  Therefore, CC-486 was studied in combination with CHOP in PTCL and was found to be well tolerated with an 88 percent CR rate at the end of treatment.1  Given the promising activity of these agents in PTCL, and the fact that they are well tolerated, the researchers have developed this three-arm, open label, randomized phase II study to evaluate whether the addition of duvelisib or CC-486 to CHOP or CHOEP chemotherapy improves the rate of CR by PET/CT in patients with PTCL who have less than 10 percent CD30 expression by immunohistochemistry.

Comment: Outcomes for patients with PTCL remain inferior to those in patients with diffuse large B-cell lymphoma, and CHOP chemotherapy (with etoposide added for younger patients) remains the standard. Improvement in progression-free survival, with the substitution of brentuximab vedotin for vincristine was demonstrated in the ECHELON-2 study. However, the benefit is largely limited to patients with high CD30 expression, such as seen in T cell anaplastic large-cell lymphoma. There is a pressing need to improve outcomes in other types of PTCL. Duvelisib and CC-486 have shown promising activity in T-cell lymphomas and are rational agents to test in combination with standard therapy. The primary endpoint of this randomized phase II study will be the PET/CT CR rate, as an increase in CR by PET/CT has been associated with improved progression-free and overall survival in ECHELON-2 and other studies.6,9 

Trial Schema: Randomized Phase II Study of CHO(E)P vs. CC-486-CHO(E)P vs. Duvelisib-CHO(E)P in Previously Untreated CD30 Negative Peripheral T-cell Lymphomas.

Phase II Safety Check. The randomized study will have a safety check (the first 12 patients enrolled to each treatment arm) before expanding to the full phase II trial. In arms A, B, and C, the safety check will include six patients with CHOP chemotherapy and six with CHOEP chemotherapy.

Trial Schema: Randomized Phase II Study of CHO(E)P vs. CC-486-CHO(E)P vs. Duvelisib-CHO(E)P in Previously Untreated CD30 Negative Peripheral T-cell Lymphomas.

Phase II Safety Check. The randomized study will have a safety check (the first 12 patients enrolled to each treatment arm) before expanding to the full phase II trial. In arms A, B, and C, the safety check will include six patients with CHOP chemotherapy and six with CHOEP chemotherapy.

Competing Interests

Dr. Mehta-Shah is the principle investigator of A051902 and has served as a consultant for C4 Therapeutics, Kiowa Hakka Kirin, Karyopharma, Ono Pharmaceuticals, Secura Bio, and Daiichi Sankyo. She has received intstitutional research funding from Bristol Myers Squibb, Celgene, Secura Bio, Verastem Pharmaceuticals, Innate Pharmaceuticals, Roche/ Genentech, and Corvus Pharmaceuticals. Dr. Kahl reported consulting fees from Celgene/BMS.

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