A Phase I Study of Duvelisib in Combination with Oral Azacitidine (BMS-986345) in Mature T Cell Lymphoma

Introduction: Relapsed/refractory mature T-cell lymphoma (RR TCL) is a poor prognosis disease with limited treatment options. Several single agent targeted therapies, such as duvelisib (DUV) or azacitidine (AZA), have been used but have either limited efficacy or difficult administration schedules. We aimed to evaluate a novel combination of the oral PI3K inhibitor DUV with the oral hypomethylating AZA in patients with RR TCL. To our knowledge, this is the first approach using two oral agents to treat this disease. Methods: In this single-center, phase I study, patients with RR TCL were enrolled. Adult patients had to have progressed on at least one line of therapy prior to enrollment. The trial followed a 3+3 design, with three doses levels (DL) of DUV selected: DL1=25 mg, DL2=50 mg, and DL3=75 mg twice daily for the first 2 cycles, followed by 25 mg twice daily thereafter. AZA was studied in a dosing schedule of 100 mg, 200 mg, and 300 mg daily on days 1-14 of 28-day cycles. For cycle 1, patients were started on 1 week of AZA followed by DUV starting in week 2. The primary endpoint of the study was to determine the maximum tolerated dose (MTD) and the recommended phase 2 trial dosing (RP2D). Responses were assessed by standard lymphoma assessment criteria. To evaluate the synergism of AZA+DUV, we studied changes in AKT phosphorylation at 4 hours following the administration of single-agent DUV, AZA, and the combination in cycle 1. Results A total of 14 patients were enrolled. The median age of the patients was 63.5 years (range 44-68), with an equal distribution of males and females. Most of the patients enrolled were Caucasian 64% (n=9), we enrolled a Hispanic cohort of 21% (n=3). Patients with T follicular helper (TFH) phenotype comprised 35% of the cohort, while 2 patients had cutaneous T-cell lymphoma (CTCL). Most patients had primary refractory disease (78%, n=11), with a median LDH of 334 U/L (range: 126-947 U/L). The median number of prior therapies was 2 (range 1-21). The RP2D was selected as DL2 of DUV (50 mg) BID for the first 2 cycles, followed by DUV (25 mg) BID thereafter, in combination with AZA (100 mg) daily on days 1-14 of 28-day cycles. There were two cases of grade 3 transaminitis at DL3, warranting the selection of the RP2D. Among patients at the DL2 or below, there was only one case of grade 3 transaminitis following progressive disease and sepsis in a patient after being off therapy for 1 week. Other toxicities were mostly hematological and were not dose-limiting (leukopenia n=1, neutropenia n=4, anemia n=3 and thrombocytopenia n=2). Most other toxicities, including gastrointestinal toxicities such as anorexia, nausea, and vomiting, were grade 1-2 and controllable with oral medications, they were reported in (n=3, 10, and 6 respectively). The median number of cycles administered was 2.3 (range: 0.83-19.87). Two patients discontinued treatment due to grade 3 transaminitis in dose cohort 3 (DUV 75 mg, AZA 100 mg), and one patient discontinued due to a rash after 19 cycles of therapy. The overall response rate (ORR) was 46% (complete response [CR] 31%, partial response [PR] 15%). Three patients proceeded to allogenic hematopoietic stem cell transplant. TFH phenotype patients had a CR of 100% (n=4). The median progression-free survival (PFS) was 2.2 months (95% CI: 1.8-NE), and the median overall survival (OS) was 10.2 months (95% CI: 6.3-NE). Phosphorylation of AKT was more suppressed during the combined administration of the two oral targeted therapies compared to administering them separately during the first cycle of therapy. Conclusions: The combination of DUV+AZA is safe and tolerable, with an acceptable toxicity profile. Our study demonstrates the synergism of the two mechanisms of action, showing promising activity in TFH subsets of RR TCL.