50 (PB040) - A phase 1/2, open-label, multicenter study to investigate the safety, pharmacokinetics, and efficacy of fadraciclib (CYC065), an oral CDK2/9 inhibitor, in subjects with advanced solid tumors and lymphoma

Abstract

Background: Fadraciclib is a highly selective, orally- and intravenously-available, 2nd generation amino-purine inhibitor of CDK2 and CDK9. Translational biology supports the development of fadraciclib as a therapeutic agent for cancers dependent on MCL1 and MYC through the inhibition of CDK9, and for cancers associated with CCNE1 amplification, a known resistance factor for trastuzumab and CDK4/6 inhibitors, through the inhibition of CDK2. By inhibiting CDK2 and 9, fadraciclib causes apoptotic death of cancer cells at sub-micromolar concentrations. In an earlier Phase 1 study of IV fadraciclib, confirmed CR has been achieved in a subject with MCL1-amplified endometrial cancer. Oral fadraciclib is highly bioavailable allowing flexibility of dosing and schedule. Methods: Fadraciclib is being evaluated in a global, open-label, non-randomized, dose-escalation (phase 1) study in subjects with advanced solid tumors or lymphoma, and proof of concept (phase 2) in subjects with targeted indications, designated CYC065-101, (NCT04983810). Phase 1 explores both schedule and dose of oral fadraciclib monotherapy in 28-day cycles to identify MTD and/or RP2D. Once RP2D is established, phase 2 will enroll 12 to 40 subjects in seven specific tumor-type groups and a basket cohort, utilizing a Simon two-stage optimal design to evaluate clinical activity. Phase 2 groups include endometrial or ovarian cancer, biliary tract cancer, hepatocellular carcinoma, breast cancer, B-cell lymphoma, T-cell lymphoma, metastatic colorectal cancer and a basket cohort for tumors with MCL1, MYC or CCNE amplification/overexpression. Results: CYC065-101 study started enrolling subjects in July 2021 and is ongoing at City of Hope National Cancer Center, MD Anderson Cancer Center, Seoul National University Hospital, and Vall d’Hebron Institute of Oncology. As of June 2022, 17 subjects have received fadraciclib at dose levels 1 to 5. Fadraciclib was well tolerated at all dose levels with no DLT and no SUSAR observed. Preliminary efficacy data are available for 16 patients. One patient with CTCL showed PR per mSWAT response criteria. At dose level 5, a patient with endometrial cancer showed 15% reduction of target lesions after first cycle of treatment, and a patient with Angioimmunoblastic T-Cell Lymphoma (AITL) showed extensive reduction in multiple lesions after first cycle of treatment. PK, PD, and PGx including NGS and RNA-Seq are being evaluated in phase 1 subjects. Preliminary PK analysis suggests dose dependent exposure. Studies on MYC, MCL1, and PPP1R10 mRNA in peripheral blood samples after fadraciclib treatment will be shown. Conclusion: Based on data from the CYC065-101 study, fadraciclib appears to be well tolerated from dose levels 1 to 5. No drug related SAEs, SUSAR or DLTs were reported. The trial is ongoing with a primary endpoint of defining MTD and RP2D. Conflict of interest: Advisory Board: D. Oh: AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA M. Villanona-Calero: Eli Lilly Corporate-sponsored Research: S. Piha-Paul: AbbVie, ABM Therapeutics, Acepodia, Alkermes Aminex Therapeutics Amphivena Therapeutics, BioMarin Pharmaceutical, Boehringer Ingelheim Bristol Myers Squib Cerulean Pharma, Chugai Pharmaceutical, Curis, Cyclacel Pharmaceuticals Daiichi Sankyo Eli Lilly ENB Therapeutics Five Prime Therapeutics F-Star Beta Limited F-Star Therapeutics Gene Quantum Genmab A/S Gilead Sciences, GlaxoSmithKline Helix BioPharma, HiberCell, Immunomedics, Incyte, Jacobio Pharmaceuticals, Lytix Biopharma AS Medimmune, Medivation, Merck Sharp and Dohme, Novartis Pharmaceuticals Pieris Pharmaceuticals, Pfizer Phanes Therapeutics Principia Biopharma, Puma Biotechnology, Purinomia Biotech, Rapt Therapeutics, Seattle Genetics Silverback Therapeutics Synlogic Therapeutics Taiho Oncology Tesaro, TransThera Bio ZielBio, NCI/NIH, P30CA016672 – Core Grant (CCSG Shared Resources) Consulting: CRC Oncology D. Oh: Research Grant: AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, Handok E. Garralda: Research: Novartis/Roche/Thermo Fisher/AstraZeneca/Taiho/ BeiGene Consultant/Advisor: Roche/Genentech - F.Hoffmann/La Roche/ Ellipses Pharma/Neomed Therapeutics1 Inc/Boehringer Ingelheim/Janssen Global Services/SeaGen/Alkermes/Thermo Fisher/Bristol-Mayers Squibb/ MabDiscovery/Anaveon/F-Star Therapeutics/Hengrui Speakers Bureau: Merck Sharp & Dohme/Roche/Thermo Fisher/Lilly/Novartis Clinical Trials PI or Co-PI (Institution): Affimed Gmbh - Amgen SA – Anaveon AG – AstraZeneca AB – Biontech Gmbh – Catalym Gmbh - Cytomx - F.Hoffmann La Roche Ltd – F-Star Beta Limited - Genentech Inc - Genmab B.V. – Hutchison Medipharma Limited – Icon - Imcheck Therapeutics – Immunocore Ltd – Janssen-Cilag SA – Medimmune Llc – Merck Kgga – Novartis Farmacéutica, S.A – Peptomyc – Ribon Therapeutics – Roche Farma SA – Seattle Genetics Inc – Symphogen A/S – Taiho Pharma Usa Inc M. Vieito: Travel grants: Roche, EMD/Serono Consulting: Roche, Debiopharm M. Villanona-Calero: Speakers Bureau: Amgen Other Substantive Relationships: J. Huang: Employee of Cyclacel, the trial sponsor M. Kirschbaum: Employee of Cyclacel, the trial sponsor M. Villanona-Calero: Stocks: Moderna