720TiP - Phase I, open-label, first-in-human (FIH) study of JZP815 in advanced or metastatic solid tumors harboring mitogen-activated protein kinase (MAPK) alterations

Background

MAPK activation by RAS and RAF mutations often drives human cancer. Targeting MAPK represents a promising route for drug development. JZP815 is a potent, selective pan-RAF kinase inhibitor that binds RAF proteins which inhibits MAPK signaling and tumor cell growth. Preclinically, JZP815 inhibited solid tumor growth in xenograft models harboring RAS/BRAF mutations, repressed a MAPK signaling marker, and generated synergy with other MAPK inhibitors.¹ JZP815 also inhibited BRAF-CRAF dimer activity, representing a known resistance mechanism to BRAF ^V600E -specific inhibitors. The profile of JZP815 supports its progress into this FIH study.

Trial design

This phase I, open-label, multicenter study (NCT05557045) investigates the safety, dosing, and JZP815 antitumor activity in patients ≥18 years old with advanced or metastatic solid tumors harboring a documented, clinically significant alteration in MAPK. The study comprises a dose exploration phase (Part A) to characterize safety and tolerability, determine maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), and pharmacokinetic (PK) profile; Part B is an expansion phase to further assess RP2D and examine antitumor activities across patient subsets based on mutation and/or tumor type, including NRAS ^Q61 -mutated melanoma. The starting dose is 20 mg twice daily (oral capsules). In Part A, MTD will be based on dose-limiting toxicities (DLTs) using a Bayesian optimal interval design. Patients (n≤6) may then be enrolled in pre-expansion cohorts at doses at or below MTD to obtain further safety, PK, and pharmacodynamics data before identifying RP2D. Patients will be treated until disease progression, death, unacceptable toxicity, or withdrawal. Primary endpoints include incidence and nature of DLTs (Part A), objective response rate per RECIST 1.1 (Part B), duration of response (Part B), and adverse events, changes in laboratory values or vital signs, and dose interruptions and reductions (Parts A and B). The study is enrolling with planned enrollment up to 332 patients. 1 Hauptschein R, et al. Cancer Res. 2022;82:2677. https://doi.org/10.1158/1538-7445.AM2022-2677

Clinical trial identification

NCT05557045, Release date: 27 September 2022.

Editorial acknowledgement

Editorial support was provided by Katie Groschwitz, PhD, of CMC AFFINITY, a division of IPG Health Medical Communications, with funding from Jazz Pharmaceuticals.

Legal entity responsible for the study

Jazz Pharmaceuticals.

Funding

Jazz Pharmaceuticals.

Disclosure

A. Naqash: Financial Interests, Personal, Other, Social Media Editor and Consultant: JCO Precision Oncology; Financial Interests, Institutional, Local PI: Loxo, Surface Oncology, ADC Therapeutics, IGM Biosciences, Nikang Therapeutics, Inspirna, Revolution Medicine, Jacobio, Pionyr, Jazz, NGM; Financial Interests, Institutional, Coordinating PI: EMD Serono, Aravive; Non-Financial Interests, Other, Social Media Consultant and Scientific Committee Member: ASCO; Non-Financial Interests, Other, Educational Activity: OncLive; Non-Financial Interests, Leadership Role, Scientific Committee Co-Chair: ORIEN; Non-Financial Interests, Leadership Role, Early Career Scientist Committee: SITC. J.S. Wang: Financial Interests, Personal, Invited Speaker, Previous Member of Speaker's Bureau for Tagrisso and Imfinzi, stopped in 2021: AstraZeneca; Financial Interests, Personal, Invited Speaker, Previous Member of Speaker's Bureau for Lenvima, stopped 2021: Eisai; Financial Interests, Institutional, Local PI: 7,8 Pharma, Accutar, Adagene, Artios Pharma, AstraZeneca, Blueprint, Boehringer Ingelheim, Celgene/BMS, Clovis Pharma, Cyteir, Daiichi Sankyo, Forty Seven, Genentech/Roche, Hotspot, ImmunoOnc, Janssen, Kymab, LSK BioPartners, MabSpace, Macrogenics, Moderna, Novartis, Nurix, ORIC, Olema Therapeutics, Prelude Therapeutics, Ribon Therapeutics, Syndax, Teneobio, Zymeworks; Financial Interests, Institutional, Coordinating PI: Astellas, Bayer Healthcare, BeiGene, Bicycle Therapeutics, BioNTech, BioTheryX, Biosplice, Cullinan, Erasca, GSK, H3 Biomedicine, Hutchinson MediPharma, IGM Biosciences, Immuno-Gen, Jazz Pharma, Klus Pharma, Medikine, NGM Bio, Phoenix Molecular Designs, Pionyr, PureTech Health, Pyxis, Qilu Pugent Sound, Relay Therapeutics, Revolution Medicines, Sanofi, StingThera, TopAlliance, Treadwell Therapeutics, Xencor. C.A. Perez: Financial Interests, Institutional, Local PI: Accutar Biotech, Artios Pharma, Dracen Pharmaceuticals, Elpiscience Biopharmaceuticals, Elucida Oncology, Genentech, Inc., Hyamab Inc., Jazz Pharmaceuticals, Kinnate Biopharma, Kura Oncology, Mirati Therpeutics, Relay Therapeutics, Ribbon Therapeutics, Seagen Inc., Tallac Therapeutics, Xilio Therapeutics, Zhuhai Yufan Biotechnologies Co. J.T. Henry: Financial Interests, Personal, Full or part-time Employment, Associate Director/Oncologist: Sarah Cannon Research Institute; Financial Interests, Personal, Stocks/Shares: HCA; Financial Interests, Institutional, Local PI: Abbiscko Therapeutics, ABl bio, Accutar biotech ADC therapeutics, Agenus, Aileron Therapeutics, Amgen Inc., Artios, Astrazenaca, Bicycle therapeutics, BioAlta, BioInvent pharma, Biosplice therapeutics, Black diamond therapeutics, Boehringer, Ingelheim, Cyteir, Daiichi Sankyo, Eli Lilly, Epizyme, Erasca, Exelixis, FujiFilm, GSK, Hutchison MediPharma, ICON plc, IGM Biosciences, Immunogen, Jacobio pharmaceuticals, Jounce pharma, Jubilant therapeutics, Loxo Oncology, Merck& CO, Metabomed, Molecular templates, Navire Pharma, Nikang pharmaceuticals, Oncorus, Prelude therapeutics, Poseida, PureTech, Pyramid, Rascal Therapeutics, Regeneron, Relay Therapeutics, Rgenix Inc., Ribon therapeutics, Sapience, Sarah Cannon Development Innovations, Sarah Cannon Research Institute, Seagen, Simcha Therapeutics, Siranomics, Stingthera, Synthorx Inc., Takeda pharmaceuticals, Tallac therapeutics, Tarveda, Teneothree, Tesaro, Turning point pharma, Xencor, Immunitas, Mirati, Pyxis, Jazz Pharmaceuticals, Nikang, Bayer, Kineta, NGM Bio, Roche, Tarus Therapeutics. B. Bashir: Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Institutional, Other, Clinical Trial Research: Eisai, Amgen, Artios, Bicycle Therapeutics, Boehringer Ingelheim, Gritstone Bio, Ikena Oncology, Jazz Pharmaceuticals, KAHR Medical, Lyell immunopharma, Merck, Pionyr Immunopharma, RASCAL Therapeutics, Syros Pharmaceuticals, Tarveda Therapeutics. A. Panneerselvam, S. Markova, R.S. Cheung: Financial Interests, Personal, Full or part-time Employment: Jazz Pharmaceuticals; Financial Interests, Personal, Stocks or ownership: Jazz Pharmaceuticals. All other authors have declared no conflicts of interest.