A phase 1 study evaluating the safety, pharmacokinetics, and efficacy of fadraciclib, an oral CDK2/9 inhibitor, in patients with advanced solid tumors and lymphoma.

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3125 Background: Fadraciclib (formerly CYC065)is a highly selective inhibitor of CDK2 (IC50= 5 nM) and CDK9 (IC50=26 nM) causing mitotic catastrophe and apoptotic death of cancer cells at sub-micromolar concentrations. In a previous Phase 1 study of intravenous fadraciclib monotherapy, a heavily pretreated endometrial cancer patient with CDNK2A, CDKN2B and PRMT5 loss achieved confirmed CR. This is the first study to evaluate oral fadraciclib monotherapy. Methods: A global Phase 1/2, open-label, dose-escalation study in subjects with advanced solid tumors or lymphoma (NCT04983810). The Phase 1 portion is exploring both schedule and dose of oral fadraciclib monotherapy in 28-day cycles to identify MTD and/or RP2D using a standard 3+3 design. Results: As of January 31, 2024, 45 subjects have received fadraciclib at 8 dose levels (DL1-6a: 50-150 mg, bid given 3-5 days per week for 3-4 out of 4 weeks or DL6b: 125 mg, daily for 4/4 weeks). Heavily pretreated patients with breast, colorectal, gynecological cancers, and T cell lymphoma with ECOG PS 0:1 (9:36) were enrolled. Fadraciclib was well tolerated at dose levels 1 to 5 (up to 100 mg bid). Adverse events reported were nausea (n=31), vomiting (n=23), thrombocytopenia (n=6). Grade 3 DLT of hyperglycemia (1/2 DL6 and 2/6 DL6a) and nausea (1/2 DL6) was observed at doses above 125mg bid M-F, 4/4 weeks. Hyperglycemia was controlled after dose interruption and blood glucose levels returned to normal range after treatment. Preliminary PK analysis suggests dose dependent exposure. At DL5 and above, plasma concentration was above target concentration from CDK2 and CDK9 target engagement studies. Preliminary PD analysis of treated patient samples showed suppression of expression in multiple target genes, including MYC, MCL1, CCNE/cyclin E, CDKN2A, CDKN2B, and PRMT5. Preliminary efficacy data are available for 31 evaluable patients. Two PRs after the first cycle were observed in one patient with CTCL and one with angioimmunoblastic T-Cell Lymphoma (AITL). Twenty patients showed SD. Tumor size reduction was observed in 10 patients. A squamous NSCLC patient harboring a CDK2NB loss of function mutation and prior chemo- and immunotherapy achieved reduction of 22% in the sum of all target lesions after 1 cycle of treatment. Conclusions: Based on data from the CYC065-101 study, fadraciclib appears well tolerated from DL1 to 5. The MTD for the bid dosing schedule is 100mg bid, M-F, 4/4 weeks. The trial is ongoing with evaluation of a daily dosing schedule. Clinical trial information: NCT04983810 .