A Phase 1-2, Open-Label Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Activity of Tolinapant in Combination with Oral Decitabine/Cedazuridine and Oral Decitabine/Cedazuridine Alone in Subjects with Relapsed/Refractory Peripheral T-Cell Lymphoma

Rationale

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 Advances, 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 hypomethylating agents (HMAs) in PTCL, a recent 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. There are minimal overlapping toxicities between the study drugs and no expected drug-drug interactions. Oral decitabine/cedazuridine (ASTX727; fixed-dose combination of 35mg decitabine/100 mg cedazuridine) 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 recently approved in the US, Canada, and Australia for the treatment of intermediate and high-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML).

Study Design

ASTX660-03 (NCT05403450) is a Phase 1-2, open-label study investigating the safety and efficacy of combination tolinapant and oral decitabine/cedazuridine treatment in relapsed/refractory PTCL. 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, be ineligible for, or intolerant to 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 have 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. Study initiated in May 2022.

Shortt:Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Ostuka: Membership on an entity's Board of Directors or advisory committees. Poligone:Innate Pharma: Research Funding; Tubulis: Consultancy; Biogen: Research Funding; Replimmune: Research Funding; Malinckrodt: Speakers Bureau; Helsinn: Research Funding; Astex Pharmaceuticals, Inc.: Research Funding; Sogligenix: Consultancy, Research Funding. Ribrag:BMS: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; AZ: Membership on an entity's Board of Directors or advisory committees; Abbvie: Speakers Bureau; GSK: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Epizyme: Research Funding; Astex: Research Funding. Zinzani:Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Secura Bio: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; University of Bologna: Current Employment. El-Sharkawi:AbbVie: Consultancy, Honoraria; Astex: Consultancy; AstraZeneca: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Gilead: Honoraria; Janssen: Consultancy, Honoraria; Kyowa Kirin: Consultancy; Lilly: Consultancy; Novartis: Honoraria; Roche: Consultancy, Honoraria; Takeda: Honoraria. Walewski:AstraZeneca: Research Funding; Celgene/BMS: Research Funding; Epizyme: Research Funding; Gilead: Research Funding; GSK: Research Funding; Incyte: Research Funding; Janssen-Cilag: Research Funding; Karyopharm: Research Funding; Morphosys: Research Funding; MSD: Research Funding; Nanovector: Research Funding; Novartis: Consultancy; Regeneron: Research Funding; Roche: Honoraria; Seagen: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Prica:Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees. Wilson:Astex Pharmaceuticals, Inc.: Current Employment. Souza:Astex Pharmaceuticals, Inc.: Current Employment. Keer:Astex Pharmaceuticals, Inc.: Current Employment. Taylor:Astex Pharmaceuticals, Inc.: Current Employment. Marchi:Myeloid Therapeutics: Ended employment in the past 24 months, Membership on an entity's Board of Directors or advisory committees; University of virginia: Patents & Royalties: 3062/170 PROV; Merck: Research Funding; Celgene/BMS: Research Funding; Astex Pharmaceuticals: Research Funding; NomoCan Pharmaceuticals: Research Funding; Kyowa Kirin: Honoraria; Daiichi Sankyo: Other: Participation at advisory board.

INQOVI (35 mg decitabine and 100 mg cedazuridine) is a prescription medicine approved in the United States to treat adults with myelodysplastic syndromes and chronic myelomonocytic leukemia. In this study, INQOVI is referred as ASTX727 or oral decitabine and cedazuridine due to the off-label investigational use in this study in combination with tolinapant (ASTX660). Tolinapant is an investigational drug and has not been approved by any regulatory agency anywhere in the world.