Cyclacel Pharmaceuticals has announced the completion of enrollment in Cohort 8 of its Phase 2 clinical trial (065-101) evaluating fadraciclib in patients with advanced solid tumors and lymphoma characterized by CDKN2A and/or CDKN2B abnormalities. Fadraciclib is an investigational CDK2/9 inhibitor.
The trial, designed as a proof-of-concept study, enrolled 12 patients in approximately six months, reflecting the urgent need for effective treatments for cancers with these specific genetic mutations. Enrollment in Cohort 5, which focuses on patients with T-Cell Lymphoma, is ongoing.
Early Clinical Observations
Interim Chief Medical Officer of Cyclacel, Brian Schwartz, M.D., noted encouraging early results, stating, "We are excited to observe stable disease and tumor shrinkage in a Phase 2 squamous cell cancer patient with unknown primary and CDKN2A abnormalities after two cycles of fadra oral tablets." He also referenced earlier findings from a Phase 1 study where a patient with squamous non-small cell lung cancer (NSCLC) and CDKN2A/B abnormalities experienced a 22% reduction in tumor burden after four weeks of treatment with oral fadraciclib, according to RECIST 1.1 criteria.
Trial Design and Objectives
The Phase 2 portion of the 065-101 study is evaluating the safety and efficacy of oral fadraciclib across eight cohorts defined by histology and/or biomarkers. These cohorts include various cancer types such as endometrial, ovarian, cholangiocarcinoma, hepatocellular, breast, T-Cell lymphoma, B-Cell lymphoma, and colorectal cancers. Cohort 8 is specifically designed for patients with CDKN2A and/or CDKN2B abnormalities. The study employs a Simon 2-stage design, aiming to demonstrate a response in molecular subtypes that showed sensitivity in Phase 1 data.
The Phase 1 dose-escalation study enrolled 48 patients with advanced solid tumors and lymphoma, establishing the recommended Phase 2 dose (RP2D) as 100mg twice daily for five days per week, on a four-weeks-on/four-weeks-off schedule.
Fadraciclib's Mechanism and Potential
Cyclacel believes that fadraciclib's dual inhibition of CDK2 and CDK9 may offer advantages over selective inhibition of either target alone. Oral administration with repeat dosing has shown transient suppression of anti-apoptosis proteins with generally good tolerability and no Grade 3 or higher hematological toxicity in the first cycle.
CDKN2A/B Abnormalities in Cancer
CDKN2A and CDKN2B are tumor suppressor genes frequently deleted or inactivated in various cancers. CDKN2A deletions are observed in over 40% of several solid tumors, including glioma, head and neck, pancreatic, esophageal, lung (including squamous cell), bladder, and melanoma. CDKN2B deletions are present in over 30% of tumors such as bladder, glioma, pancreatic, esophageal, lung (including squamous cell), head and neck, and melanoma.
