Fadraciclib Demonstrates Safety, Early Efficacy Signals in CDKN2A/B+ Advanced Solid Tumors

Treatment with the highly selective CDK2 and CDK9 inhibitor fadraciclib (CYC065) was well tolerated and showed signs of clinical activity in patients with advanced solid tumors harboring CDKN2A or CDKN2B alterations, according to interim data from the phase 2 065-101 trial (NCT04983810).¹

Findings announced by Cyclacel Pharmaceuticals and presented at the 2024 EORTC-NCI-AACR Annual Meeting showed that among efficacy-evaluable patients in cohort 8 (n = 6), 2 experienced stable disease, including 1 patient with melanoma who received treatment for 125 days and another patient with squamous cell carcinoma of unknown primary site (CUP) who achieved an 11% tumor shrinkage in the sum of all lesions. The latter patient received treatment for 85 days and was ongoing at data cutoff.

Cohort 8 included patients with pancreatic cancer (n = 4), as well as cholangiocarcinoma, duodenal, melanoma, cervical, laryngeal, ovarian, squamous cell CUP, and thymus cancer (n = 1 each). At the data cutoff, 2 additional patients with ovarian and laryngeal cancer started treatment but did not undergo their first scan.

Regarding safety, the most common treatment-related adverse effects (TRAEs) included diarrhea, nausea, and vomiting; TRAEs were similar to toxicities reported during phase 1 of the study. No grade 3 or higher TRAEs have been observed in phase 2.

“We are encouraged by the interim data of cohorts 6 and 8 in our phase 2 study of fadraciclib,” Spiro Rombotis, president and CEO of Cyclacel Pharmaceuticals, stated in a news release. “Although the data in cohort 8 [are] immature with ongoing patients still to have a first scan and being followed up, we continue to see good tolerability and signals of efficacy in patients with CDKN2A/B abnormalities [who] have had their first scan and follow-up evaluation. We are grateful to our investigators, the patients and their families for their support of this important study.”

Previously reported data from the phase 1 portion of the study showed that 7 of 38 treated patients harbored known CDKN2A/B alterations. Among the 6 patients evaluable for efficacy from this subgroup, the overall response rate (ORR) was 17%, and the disease control rate (DCR) was 100%. One patient with peripheral T-cell lymphoma harboring a CDKN2A P114L mutation achieved a partial response. Another patient with squamous non–small cell lung cancer with CDKN2B loss had stable disease and a 22% reduction in tumor volume in the sum of all target lesions. One patient with metastatic, testicular Leydig germ cell cancer harboring CDKN2A, CDKN2B, and MTAP loss experienced a 12% reduction in tumor volume in the sum of all target lesions.

Thus far, the phase 2 expansion portion of the study has included 2 cohorts. Cohort 8 has enrolled patients with advanced solid tumors harboring CDKNA/B alterations, and cohort 6 has included 2 patients with T-cell lymphoma.

Phase 2 will include 8 cohorts in total, which are enrolling patients at least 18 years of age with locally advanced, recurrent, or metastatic, histologically confirmed advanced solid tumors or lymphoma.²

• Cohort 1: Endometrial or ovarian cancer
• Cohort 2: Biliary tract cancer
• Cohort 3: Hepatocellular carcinoma
• Cohort 4: HER2-positive refractory metastatic breast cancer; hormone receptor–positive, HER2-negative, metastatic breast cancer after a CDK4/6 inhibitor; and triple-negative breast cancer
• Cohort 5: B-cell lymphoma
• Cohort 6: T-cell lymphoma
• Cohort 7: Metastatic colorectal cancer
• Cohort 8: Other tumor types suspected to have a related mechanism of action, such as MCL1, MYC, or CCNE amplification/overexpression, that were not included in other cohorts

Key inclusion criteria for all patients include an ECOG performance status of 0 or 1. Patients are being excluded if they have a history of brain metastases or who have signs/symptoms attributable to brain metastases; notably, patients with asymptomatic treated brain metastases that have been clinically stable for at least 4 weeks are eligible.

In phase 2 of the study, fadraciclib is being given at the recommended phase 2 dose of 100mg twice per day Monday through Friday for weeks 1 to 4 of 28-day cycles.^1,2

The primary end point of phase 2 is ORR. Secondary end points include safety and tolerability; DCR; duration of response; progression free survival; and overall survival Pharmacodynamics and pharmacogenomics are exploratory end points.¹

References

1. Cyclacel Pharmaceuticals reports new clinical data from ongoing, phase 2 study of oral fadraciclib at the 2024 EORTC-NCI-AACR Symposium. News release. Cyclacel Pharmaceuticals. October 23, 2024. Accessed October 23, 2024. https://investor.cyclacel.com/news-releases/news-release-details/cyclacel-pharmaceuticals-reports-new-clinical-data-ongoing-phase
2. A study to investigate fadraciclib (CYC065), in subjects with advanced solid tumors and lymphoma. ClinicalTrials.gov. Updated January 25, 2024. Accessed October 23, 2024. https://clinicaltrials.gov/study/NCT04983810