Etctn P10500: Phase 1 Study of Tazemetostat Plus Belinostat for the Treatment of Relapsed or Refractory Lymphoma

Given the critical importance of concurrent derangements in epigenetic modifiers (CREBBP, EP300, and EZH2) in germinal center (GC) B- and T-cell lymphomas, combined targeting of epigenetic machinery with tazemetostat (EZH2i) and belinostat (HDACi) may induce profound epigenetic modification, leading to the induction of cell death. Preclinical data generated in our lab has demonstrated that when combined in discrete subsets of DLBCL and T cell lymphomas, tazemetostat plus belinostat leads to highly synergistic interactions via modulation of both histone acetylation and methylation, leading to prolonged survival in murine models (Lue 2019). Based on these observations, the NCI/CTEP ETCTN P10500 clinical study was designed to study the combination of tazemetostat plus belinostat in R/R lymphoma (NCT05627245).

Patients with R/R non-Hodgkin lymphoma were eligible for this open-label phase 1 study. Patients must not be eligible for ASCT and have adequate organ function. Patients were enrolled based on a standard 3-by-3 phase 1 design and treated on a 21-day cycle with tazemetostat orally twice daily at doses between 600-800 mg, and belinostat intravenous daily for 5 days between doses of 600-1000mg. The primary endpoint is to determine the maximum tolerated dose and the dose limiting toxicities to find recommended phase 2 dose. Safety was assessed according to CTCAE v5.1. DLTs were assessed within the first cycle. Patients were treated until unacceptable toxicity or progression. Response was assessed per Lugano criteria. The pharmacokinetic profile was determined for the combination and paired peripheral blood samples were evaluated for T cell activation.

As of July 30, 2024, 11 patients were enrolled (DLBCL n=1, transformed DLBCL n=2, TCL n=7, PTLD/HGBCL n=1) across 3 dose cohorts (n=6 dose level (DL) 1, n=3 DL2, n=2 DL3). Median age was 62 y (range 31-88), 8 were male; 8 were White Non-Hispanic, 1 White Hispanic, 2 Black. Median baseline performance status was 1, and Stage 1 n=1, Stage 3 n=3, Stage 4 n=6 (missing n=1). Median number of prior therapies was 4 (1-7), including prior autologous SCT n=4, allogeneic SCT n=1 and CAR T n=2.

The median number of cycles received was 2.5 (1-12+). Reasons for discontinuation from study included transition to transplant (n=1), AE n=1, withdrawal of consent n=1, lack of clinical improvement despite SD n=1, and PD n=5. There was one DLT observed in DL1: grade 4 thrombocytopenia. It occurred in a heavily pretreated subject with transformed DLBCL (7 prior lines of therapy including both ASCT and CAR T) and whose baseline platelets (77,000/mcL) were just above the eligibility threshold (75,000/mcL). There were no observed DLTs in DL 2 and none to date in DL 3 however only 2 subjects have been evaluated for DLT at DL3. There were 81 TEAEs, 32 of which were considered related to study drug. There were 7 grade 3 AEs, however only 1 was considered related to study drug: hypoxia. The others included extremity pain, hypertension, anemia, supraventricular tachycardia, and sinusitis. There were 2 grade 4 AEs: neutropenia and thrombocytopenia. There was one grade 5 AE of COVID-19 infection that was not considered related to study drug and occurred in the same subject who triggered the DLT. Study drugs were interrupted in 2 subjects and reduced in 1 subject. In the subjects evaluable for response, the ORR was 33% (3/9 evaluable patients), CR n=2, PR n=1, SD n=3. Interestingly, in subjects with TCL the ORR was 43% (3/7) with CR n=2, PR n=1 and SD n=3. The mean duration of response is 24 weeks with 1 responder still in therapy at 12+ cycles to date and 1 responder bridged to proceed with allogeneic transplant after 6 cycles. Paired peripheral blood samples were collected in 3 subjects. Dual exposure to epigenetic therapy led to modulation in antigen presentation on B cells and expansion and activation of cytotoxic T cells.

The preliminary data suggest that dual epigenetic targeting with belinostat and tazemetostat is safe and well tolerated. The combination leads to modulation of T cell activity. The responses in T cell lymphoma are intriguing and likely represent recurrent epigenetic derangements in these diseases. Once the RP2D is established, the study will enroll an expanded cohort of LBCL stratified by EZH2 mutation status. The hope is to create a strategy to target discrete mutations, like EZH2, EP300 and CREBBP, driving GC-derived lymphomas. Funding: NCI #UM1CA186689