Cyclacel Pharmaceuticals Presents New Phase 2 Oral Fadraciclib Data at 2024 EORTC-NCI-AACR Symposium

Cyclacel Pharmaceuticals, Inc., a biopharmaceutical company known for developing cancer treatments, has released preliminary safety and efficacy data from twelve patients with advanced solid tumors involved in the Phase 2 segment of the 065-101 clinical trial of fadraciclib, also referred to as "fadra." This data was unveiled at the 2024 EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics held in Barcelona, Spain.

The patients in this trial were part of Cohort 8, selected based on the presence of CDKN2A and/or CDKN2B abnormalities. Spiro Rombotis, the President and CEO of Cyclacel, expressed optimism about the interim results from both Cohorts 6 and 8 of the Phase 2 trial. He acknowledged that although the data from Cohort 8 is still preliminary, the observed efficacy and tolerability in patients with CDKN2A/B abnormalities are promising. He also extended gratitude to the investigators, patients, and their families for their participation and support.

The interim findings indicated that fadraciclib was generally well-tolerated by patients in Cohort 8, with common drug-related adverse effects such as diarrhea, nausea, and vomiting, consistent with those observed in the Phase 1 trial. Crucially, there were no Grade 3 or higher treatment-emergent adverse events reported in the Phase 2 study up to this point. The patients had a median of three prior therapies and predominantly exhibited an ECOG performance status of 1.

Within Cohort 8, the patient pool included individuals with various types of cancer, such as pancreatic, cholangiocarcinoma, duodenal, melanoma, cervical, laryngeal, ovarian, squamous cell cancer with an unknown primary source (CUP), and thymus cancer. Among the six patients evaluable for efficacy, two achieved stable disease – one melanoma patient had a treatment duration of 125 days, and a squamous cell CUP patient experienced an 11% tumor reduction over 85 days of ongoing treatment. Additionally, two other patients with ovarian and laryngeal cancer are still undergoing treatment but have yet to receive their first scan.

The molecular characteristics frequently observed in Cohort 8 patients included the loss of function or deletion of the CDKN2A and/or CDKN2B tumor suppressor genes. Other notable pharmacogenomic observations involved mutations in CDKN2A/B, KRAS, and/or TP53.

The 065-101 study incorporated two Phase 2 dose expansion cohorts. Cohort 8 included 12 patients with known CDKN2A/B genetic alterations, enrolled between April and September 2024. The study aimed to further investigate clinical activity observed in Phase 1 patients with these genetic alterations. Cohort 6 includes patients with T-cell lymphoma, with two treated so far, to evaluate partial responses observed in Phase 1 patients with T-cell lymphoma. All patients were administered oral fadraciclib at 100mg BID (twice daily), Monday to Friday, in a four-week cycle, which was the Recommended Phase 2 Dose (RP2D).

The primary objectives of the 065-101 study's Dose Escalation stage are to determine the maximum tolerated dose (MTD) and/or RP2D. In the Phase 2 Proof of Concept stage, the main goal is to evaluate preliminary efficacy, measured by the overall response rate (ORR). Secondary objectives include assessing safety, tolerability, pharmacokinetics, and ORR during Dose Escalation, while Phase 2 aims to evaluate safety, tolerability, disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Additionally, the study uses a Simon two-stage optimal design to evaluate clinical activity, with exploratory objectives focusing on clinical pharmacodynamics (PD) and pharmacogenomics (PGx).

Fadraciclib is recognized as a selective inhibitor of CDK2 and CDK9, leading to mitotic catastrophe and apoptotic death of cancer cells at sub-micromolar concentrations. Clinical activity in patients with known CDKN2A or CDKN2B genetic alterations was previously suggested during the Phase 1 dose escalation studies. Notably, a heavily pretreated endometrial cancer patient with CDKN2A, CDKN2B, and PRMT5 loss in a Phase 1 intravenous study achieved a confirmed complete response (CR).

Cyclacel Pharmaceuticals continues to develop innovative cancer medications, with fadraciclib and plogosertib (a PLK1 inhibitor) undergoing evaluation for both solid tumors and hematological malignancies. The company aims to build a diversified portfolio of oncology and hematology drug candidates.