PHASE 1-2 STUDY OF THE SAFETY, PK, PD, AND PRELIMINARY ACTIVITY OF TOLINAPANT IN COMBINATION WITH ORAL DECITABINE/CEDAZURIDINE AND ORAL DECITABINE/CEDAZURIDINE ALONE IN SUBJECTS WITH R/R PTCL.

Abstract

Background: There are limited treatment options for patients with Peripheral T-Cell Lymphoma (PTCL) after progression following front line therapy. Tolinapant (ASTX660) is a novel oral non-peptidomimetic, small-molecule antagonist of cellular/X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP), which also induces necroptosis in T-cell lymphoma models (Ferrari et al., Blood Adv., 2021). An ongoing Phase 1-2 study demonstrates an overall response rate (ORR) of >20% in relapsed/refractory PTCL with single agent tolinapant (Michot et al., EHA 2022). While there are limited studies using decitabine as a hypomethylating agent (HMA) in PTCL, a recent guadecitabine prospective study showed 40% ORR (Wong et al., Leukemia, 2022). Preclinical data demonstrate decitabine treatment leads to re-expression of genes critical for necroptosis and synergy between decitabine and tolinapant in T-cell tumor models (Ward et al. ASH 2021; Manavalan et al. EHA abstract 2022). These data suggest that this combination may have synergistic activity in PTCL. Oral decitabine/cedazuridine (ASTX727) is an oral DNMTi that provides equivalent PK exposure to intravenous decitabine at standard dosing (20 mg/m2 day 1-5 every 28 days). This combination of oral decitabine and cedazuridine was approved in the US, Canada, and Australia for the treatment of intermediate and high-risk myelodysplastic syndromes and chronic myelomonocytic leukemia. There are minimal overlapping toxicities between the study drugs and no expected drug-drug interactions. Aim(s): The Primary Aim of Phase 1 is to assess safety, and to identify the recommended Phase 2 dose of tolinapant in combination with oral decitabine/cedazuridine. The primary Aim of Phase 2 is to assess preliminary efficacy as determined by overall response rate. Secondary Aims of the trial include assessing safety and to identify the tolerated dosing of oral decitabine/cedazuridine alone in this population and determining the pharmacokinetic parameters of both tolinapant and oral decitabine/cedazuridine. Method(s): ASTX660-03 (NCT05403450) is a Phase 1-2, open-label study. To be eligible, subjects with ECOG PS <=2 must have received at least two prior systemic therapies with evidence of documented progressive disease with at least one measurable lesion by computerized tomography (CT). Subjects with CD30-positive disease must have received or be ineligible for brentuximab vedotin. Key exclusion criteria include ejection fraction <50%, QTc >=470 milliseconds, and the use of concomitant medications that are either strong or moderate CYP3A4 inhibitors/inducers. There is a lead-in phase to confirm tolerability of the MDS-approved regimen of oral decitabine/cedazuridine in a PTCL population. In Phase 1 subjects are randomized to oral decitabine/cedazuridine alone or to the combination of oral decitabine/cedazuridine with tolinapant. The combination arm will include escalation of tolinapant in dose ranges that have shown efficacy in PTCL. The oral decitabine/cedazuridine only arm will enroll 20-24 subjects. Once the combination arm reaches recommended Phase 2 dose/maximum tolerated dose, there will be a dose expansion of 20 subjects in the combination arm prior to the initiation of the combination dosing in Phase 2 which has an enrollment goal of 102 subjects. There will be no formal statistical analysis in Phase 1. In Phase 2, there will be efficacy analysis for every 34 subjects, without a pause in enrollment. Result(s): None to date Summary/Conclusion: The Study opened in June 2022 with primary completion estimated to be December 2025.