Duvelisib and Oral Azacitidine Under Study With CHO(E)P in Peripheral T-Cell Lymphoma

Duvelisib (Copiktra) and oral azacitidine are each being studied in combination with CHOP/CHOEP chemotherapy in patients with previously untreated CD30-negative peripheral T-cell lymphoma (PTCL) in the randomized phase 2 Alliance A059102 trial (NCT04803201).¹

The study, which was presented as a trial in progress at the 2022 ASCO Annual Meeting, was initiated on July 30, 2021, and is currently enrolling to the safety lead-in phase.

“Given that certain subtypes of PTCL seem to be sensitive to azacitidine or duvelisib, a PI3K inhibitor, we hope that these novel approaches could similarly improve the number of patients who achieve a complete remission [CR] at the end of treatment,” Neha Mehta-Shah, MD, lead study author and assistant professor at the Washington University School of Medicine in Saint Louis said in a statement to OncLive^®. “This is the first US intergroup study in frontline T-cell lymphoma to be conducted and has been a fantastic collaboration between our colleagues all over the country.”

CHOP-based therapy is associated with a 5-year overall survival (OS) rate of between 20% and 25% in PTCL. Brentuximab vedotin (Adcetris) plus CHP has shown improved progression-free survival (PFS) and OS in PTCL with CD30 expression of at least 10%.

“This served as proof of principle that biomarker driven therapy can lead to improved outcomes in this rare disease,” the study authors wrote in the abstract.

Duvelisib is a gamma delta PI3K inhibitor with an overall response rate (ORR) of 50% in PTCL that trends higher in patients with a T-follicular helper (TFH) phenotype. Azacitidine is a hypomethylating agent with an ORR of 75% in PTCL with the TFH phenotype.

Notably, oral azacitidine has been safely combined with CHOP, resulting in an ORR of 75% with a higher ORR in PTCL with the TFH phenotype.

The primary end point of the study is the comparison of the CR rate at the end of treatment. Secondary end points include ORR, duration of response, PFS, event-free survival, and OS. Additional secondary objectives included the prospective assessment of PET/CT biomarkers including total metabolic tumor volume, Lugano and RECIL scores at the interim analysis and end of treatment, and the delta-SUV at interim scan. Investigators will also evaluate the toxicity profile of each regimen using the Common Terminology Criteria for Adverse Events (CTCAE) and patient-reported outcomes CTCAE.

Exploratory objectives include the evaluation of cell-free DNA and use of gene expression profiling, immunophenotyping, and mutational analysis as prognostic tools in PTCL.

The study has 90% power to detect a 25% improvement in the CR rate with the duvelisib and oral azacitidine regimens compared with CHOP/CHOEP alone, with a type I error rate of 10%.

To be eligible for enrollment, patients must have untreated stage I to IV PTCL including nodal T-cell lymphoma with TFH phenotype, follicular T-cell lymphoma, PTCL not otherwise specified, angioimmunoblastic T-cell lymphoma (AITL), enteropathy associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma; CD30 expression of less than 10%; and a performance status of between 0 and 2.

CD30 expression will be evaluated via immunohistochemistry.

Patients with transformed mycosis fungoides or anaplastic large cell lymphoma will be excluded.

The study will consist of a safety lead-in (n = 12) and randomized (n = 159) phase.

In the safety lead-in phase, patients over the age of 60 will receive CHOP and those aged 60 years or younger will receive CHOEP. Here, patients will receive 6, 21-day cycles of 15 mg of duvelisib twice daily plus CHOP (n = 6) or duvelisib plus CHOEP (n = 6).

In the randomized phase, patients will be stratified by phenotype (PTCL-TFH or AITL), chemotherapy backbone (CHOP or CHOEP), and age (>60 or ≤60). Here, patients will be randomized 1:1:1 to 6, 21-day cycles of 25 mg of duvelisib twice daily plus CHO(E)P (n = 53), 300 mg of oral azacitidine once daily plus CHO(E)P (n = 53), or CHO(E)P alone (n = 53).

Notably, oral azacitidine will be administered daily in the 6 days leading up to cycle 1 and administered on days 8 through 21 thereafter.

G-CSF support will be mandated for standard CHO(E)P administration.

Reference

1. Mehta-Shah N, Geyer SM, Barta SK, et al. Alliance A059102: a randomized phase II U.S. intergroup study of CHO(E)P versus CC-486-CHO(E)P versus duvelisib-CHO(E)P in previously untreated, CD30-negative, peripheral T-cell lymphomas. J Clin Oncol. 2022;40(suppl 16):TPS7593. doi:10.1200/JCO.2022.40.16_suppl.TPS7593