Apex Part 2 Trial in Progress: A Phase 2 Open-Label Clinical Study of Bezuclastinib in Adult Patients with Advanced Systemic Mastocytosis

Background and Significance:

Systemic mastocytosis (SM) is a rare heterogeneous disease characterized by the aberrant accumulation of neoplastic mast cells (MC). In about 95% of adult patients, SM is driven by a gain-of-function mutation (D816V) in exon 17 of KIT. Advanced SM (AdvSM) is a life-threatening form of SM and includes three subtypes: aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). Despite improvement in disease control with approval of tyrosine kinase inhibitors (TKIs), there is still unmet need for improved tolerability and efficacy in AdvSM treatments.

Bezuclastinib, an oral and selective type 1 TKI that potently inhibits KIT D816V, is being studied in patients diagnosed with AdvSM in the Apex study (NCT04996875). Results from the Part 1 dose optimization portion of Apex were presented previously. Part 1 randomized 32 patients 1:1:1:1 to receive bezuclastinib at 50, 100, or 200 mg BID or 400 mg QD. Initial results from the Part 1 dose optimization portion of the Apex trial in patients with AdvSM demonstrated encouraging safety profile and signs of clinical activity, as well as deep reductions across biomarkers of MC burden including bone marrow MC burden, serum tryptase levels, and KIT D816V variant allele fraction (VAF). In addition, 94%, 93%, and 100% of patients demonstrated ≥50% reduction in serum tryptase, KIT D816V VAF, and bone marrow MC burden, respectively. Exposure achieved with 100 mg BID of bezuclastinib original formulation resulted in optimal efficacy and safety outcomes. 150 mg QD of an optimized formulation is expected to deliver bezuclastinib exposures consistent with the 100 mg BID of the original formulation. Part 2 is further evaluating the efficacy and safety of bezuclastinib in patients with AdvSM at the selected Part 2 dose of 150mg QD of the optimized formulation.

Study Design and Methods:

Apex is a multicenter, Phase 2 open-label study of bezuclastinib in patients with AdvSM as defined per the WHO criteria. Enrollment includes previously treated and treatment-naïve patients.

Part 2 is enrolling approximately 65 patients including up to 15 patients without measurable mIWG C-findings. The Part 2 expansion portion of the Apex study is designed to evaluate the efficacy and safety of bezuclastinib in patients with AdvSM, including ASM, SM-AHN, or MCL. Key eligibility criteria include measurable disease (centrally adjudicated) according to modified IWG-MRT-ECNM criteria and clinically acceptable laboratory values including platelet count ≥50,000/µL. The primary efficacy endpoint of Part 2 is overall response rate (ORR = complete response [CR] + complete remission with partial hematologic recovery [CRh] + partial response [PR] + clinical improvement [CI]) per mIWG-MRT-ECNM criteria according to mIWG-MRT-ECNM response criteria and will be confirmed by a Central Response Review Committee. Secondary endpoints include further characterization of safety and tolerability, pure pathologic response, biomarker response (including changes in bone marrow MC burden, serum tryptase level, and KIT D816V mutational burden), duration of response, time to response, progression-free survival, and overall survival (OS). Apex Part 2 is actively enrolling. Study sites are enrolling in North America, Asia-Pacific, and Europe. In addition, a high-risk SM-AHN sub-study assessing the safety and feasibility of the combination of bezuclastinib 150 mg QD and azacitidine may enroll up to 20 patients who are currently receiving or indicated for azacitidine and have biopsy-proven SM with an associated high- or very high-risk myeloid neoplasm. Patients with SM-AHN from Part 1 or Part 2 who have demonstrated AHN progression may enroll in an additional rollover cohort to receive bezuclastinib with concomitant azacitidine or hydroxyurea.

Vachhani:Stemline: Consultancy; CTI BioPharma Corp (now Sobi): Consultancy, Research Funding; Kartos Therapeutics: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Research Funding; Cogent Biosciences: Consultancy; Pfizer: Consultancy; Gilead/Forty Seven: Research Funding; GlaxoSmith Kline: Consultancy; Karyopharm: Consultancy; Novartis: Consultancy; Astex Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding; Constellation Pharmaceuticals: Research Funding; GenenTech: Consultancy; Daiichi Sankyo: Consultancy; MorphoSys: Consultancy; Amgen: Consultancy, Research Funding; Blueprint Medicines: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding. Pullarkat:Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Speakers Bureau; Rigel: Consultancy, Honoraria; Alexion: Honoraria; Sobi: Speakers Bureau; Jazz: Speakers Bureau; Amgen: Speakers Bureau. DeAngelo:Incyte: Consultancy; Jazz: Consultancy; Kite: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Servier: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; Bristol-Meyers Squibb: Honoraria; Abvie: Research Funding; Glycomimetics: Research Funding; Daiichi-Sankyo: Other: DSMB; Fibrogen: Other: DSMB; MT Sinai MPN Consortium: Other: DSMB; Gilead: Consultancy; Curis: Consultancy; Blueprint: Consultancy, Research Funding; Autolos: Consultancy; Amgen: Consultancy, Honoraria. Sperr:Blueprint: Consultancy, Speakers Bureau; BMS-Celgene: Consultancy; Laboratories Delbert: Consultancy, Honoraria, Speakers Bureau; Otsuka: Consultancy; Pfizer: Consultancy, Speakers Bureau; Servier: Consultancy, Speakers Bureau; Stemline: Consultancy, Speakers Bureau; Thermo fisher: Speakers Bureau; Astellas: Consultancy; Abbvie: Consultancy, Speakers Bureau. Shoumariyeh:Blueprint: Honoraria. Panse:Apellis: Consultancy, Current equity holder in publicly-traded company, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Current equity holder in publicly-traded company, Honoraria; Sanofi: Consultancy, Current equity holder in publicly-traded company; Swiss Biopharma: Honoraria; Bristol Myers Squibb: Consultancy, Current equity holder in publicly-traded company, Honoraria; F Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: All authors received support for third-party writing assistance, furnished by Akshaya Srinivasan, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland., Speakers Bureau; Samsung Bioepis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria; Swedish Orphan Biovitrum AB: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ng:Spinnaker Health Research foundation: Research Funding; University hospital Geelong: Other: Project Grant; WA Health: Other: Fellowship Grant. Piris-Villaespesa:BluePrint: Consultancy, Research Funding, Speakers Bureau; GSK: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Tashi:CITI Biopharma: Honoraria; Italfarmaco: Research Funding; Cogent: Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaEssentia: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Telios: Research Funding; Blueprint: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Study Steering Committee, Research Funding. Hunter:GSK: Consultancy, Honoraria; PharmaEssentia: Consultancy, Honoraria; Blueprint Medicines: Consultancy, Honoraria, Research Funding; Sobi​ (formerly CTI biopharma): Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Cogent Biosciences: Research Funding; Ascentage Pharma: Research Funding; Syntrix Biosystems: Research Funding; Novartis: Research Funding; PharmaEssentia: Research Funding. Bose:Incyte: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; CTI: Consultancy, Honoraria, Research Funding; Kartos: Research Funding; Telios: Research Funding; Morphosys: Consultancy, Honoraria, Research Funding; Ionis: Consultancy, Honoraria, Research Funding; Disc: Consultancy, Honoraria, Research Funding; Geron: Consultancy, Honoraria, Research Funding; Janssen: Research Funding; Blueprint: Consultancy, Honoraria, Research Funding; Cogent: Consultancy, Honoraria, Research Funding; Sumitomo: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Pharma Essentia: Consultancy, Honoraria; Keros: Consultancy, Honoraria; Morphic: Consultancy, Honoraria; Jubilant: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. George:Incyte: Consultancy; Beckman Coulter: Consultancy; Celgene/BMS: Consultancy; Cogent Biosciences: Consultancy; Blueprint Medicines Corporation: Consultancy. Patel:BMS: Consultancy. Papayannidis:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria; Menarini/Stemline: Honoraria; BMS: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Blueprint: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Delbert Laboratories: Membership on an entity's Board of Directors or advisory committees. Cridtina:AS Science: Consultancy; BluePrint: Consultancy. Schwaab:AOP: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel reimbursement , Research Funding; Blueprint medicines: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel reimbursement , Research Funding; Cogent Biosciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel reimbursement , Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel reimbursement , Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel reimbursement , Research Funding. Lambert:Novartis: Honoraria; Kite-Gilead: Consultancy, Honoraria; Blueprint: Consultancy; Takeda: Honoraria. Jain:Bristol Myers Squibb, Incyte, Abbvie, CTI, Kite, Cogent Biosciences, Blueprint Medicine, Telios pharma, Protagonist therapeutics, Galapagos, Tscan therapeutics, Karyopharm, Morphosys: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma, Kartos therapeutics, Incyte, Bristol Myers Squibb: Research Funding. Wierzbicka-Hainaut:UCB: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Blueprint: Consultancy; Novartis: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Kyowa: Consultancy, Speakers Bureau; Kirin: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau. Hermine:Inatherys: Consultancy, Current equity holder in publicly-traded company, Patents & Royalties, Research Funding; AB Science: Consultancy, Current equity holder in publicly-traded company, Patents & Royalties, Research Funding; BMS: Research Funding; Alexion: Research Funding; Roche: Research Funding; MSD Avenir: Research Funding. Hobbs:Novartis: Honoraria; GSK: Honoraria; Sobi: Honoraria; Cogent: Honoraria; Abbvie: Honoraria; Pharmaessentia: Honoraria; Incyte: Honoraria, Research Funding; BMS: Honoraria; Pfizer: Honoraria; Regeneron: Other: spouse employment. Deininger:SPARC: Research Funding; Leukemia & Lymphoma Society: Research Funding; Fusion Pharma: Consultancy; DisperSol: Consultancy; Takeda: Honoraria, Other: Part of a study management committee, Research Funding; Sangamo: Consultancy, Honoraria; Medscape: Honoraria, Other: Case Author ; Incyte: Honoraria, Research Funding; Blueprint Medicines Corporation: Consultancy, Honoraria, Other: Part of a study management committee, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Grants, Travel, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Grants, travel, clinical trial support, Research Funding. Pilla:Cogent: Current Employment, Current equity holder in publicly-traded company. Carden:Cogent: Current Employment, Current equity holder in publicly-traded company. Radia:Novartis: Honoraria; Blueprint: Consultancy, Honoraria, Other: Study Steering Committee, Research Funding, Speakers Bureau; Cogent: Consultancy, Honoraria, Other: Study Steering Committee.