Cyclacel Pharma (CYCC) Presents Phase 1 Data of Sapacitabine Regimen in Patients With BRCA Mutant Breast Cancer at AACR 2019

In Clinical Trials by Barbara Jacoby


Cyclacel Pharmaceuticals, Inc. (NASDAQ: CYCC) announced Phase 1 clinical data from the company’s DNA damage response program with an oral, sequential regimen of sapacitabine and seliciclib as a treatment in patients with BRCA mutant metastatic breast cancer. Data from the study was presented today at the 2019 American Association for Cancer Research (AACR) Annual Meeting and demonstrated that the regimen was safe and led to a clinical benefit rate of 30%. All eight PARP inhibitor naïve patients, half of the patients previously treated with platinum agents and one on previous PARP inhibitor responded. Progression on previous platinum or PARP inhibitors was associated with lack of benefit. Both sapacitabine and PARP inhibitors are more effective in cancer cells with BRCA mutations or other homologous recombination repair deficiencies. Based on these data, the investigators are enrolling a Phase 1b/2 study of sapacitabine in combination with a PARP inhibitor in PARP inhibitor-naïve patients with BRCA mutant breast cancer.

“We are encouraged by the durable responses and stable disease in PARP inhibitor-naïve patients with BRCA mutant metastatic breast cancer,” said Sara M. Tolaney, MD, MPH, Senior Physician, Director, Clinical Trials, Breast Oncology, Dana-Farber Cancer Institute, Boston and Principal Investigator of the study. “We are very excited about the ongoing evaluation of the combination of sapacitabine and the PARP inhibitor olaparib in PARP inhibitor-naïve patients with metastatic BRCA mutant breast cancer.”

Study Details

The study evaluated an oral, sequential regimen of sapacitabine, a nucleoside analog prodrug, and seliciclib, a 1st generation CDK2/9 inhibitor, in patients with metastatic breast cancer harboring BRCA1/2 mutations. Patients received seven days of sapacitabine followed by three days of seliciclib. Of 20 patients treated, six progressed on prior platinum therapy and seven on prior PARP inhibitor.

  • Two patients achieved confirmed PR and four SD of at least 6 months duration for an overall clinical benefit rate of 30%. Of the two patients achieving PR, one progressed previously on platinum treatment and one had received no prior platinum or PARP inhibitor.
  • Responses (PR or SD regardless of duration) occurred in 12 patients: 8/8 without prior progression on platinum or a PARP inhibitor (1 PR, 7 SDs), 3/6 patients who progressed on platinum (1 PR, 2 SDs), and 1/7 patients who progressed on a PARP inhibitor (1 SD).
  • The most frequent grade 3 adverse events were neutropenia (15%), AST/ALT elevation (20%), and rash (10%). The only grade 4 adverse events were neutropenia in 2 patients.
  • Progression on previous platinum agents or PARP inhibitors was associated with lack of benefit, putatively associated in some cases with BRCA reversion alterations.

The poster abstract at the 2019 AACR titled “Expansion cohort of Phase I study of oral sapacitabine and oral seliciclib in patients with metastatic breast cancer and BRCA1/2 mutations” is available at (!/6812/presentation/9865).

Both sapacitabine and PARP inhibitors are more effective in cancer cells with BRCA mutations or other homologous recombination repair deficiencies and combine synergistically in preclinical models. As a result of these findings, a concomitant administration regimen of sapacitabine and olaparib PARP inhibitor is now being evaluated in an investigator-sponsored trial in approximately 64 patients with PARP inhibitor-naïve, metastatic HER2-negative breast cancer with germline BRCA1/2 mutation (

CYC065 AACR Poster Details

Preclinical data for Cyclacel’s CYC065 CDK2/9 inhibitor will also be presented at the 2019 AACR in a poster titled “Next generation CDK2/9 inhibitor CYC065 triggers anaphase catastrophe in diverse aneuploid cancers and markedly inhibits growth and metastasis.” Researchers from MD Anderson Cancer Center and Frederick National Laboratory for Cancer Research report that CDK2 inhibition preferentially targets aneuploid cancer cells and that CYC065 induces cell death in diverse cancer cell lines and animal models, irrespective of KRAS mutation status. This CYC065 activity is demonstrated to be a consequence of CDK2/9 inhibition, resulting in anaphase catastrophe, Mcl-1 down-regulation and suppression of proteins that regulate metastasis (!/6812/presentation/5901).

About sapacitabine

Sapacitabine (CYC682), an orally-available nucleoside analogue, acts through a novel DNA single-strand breaking (SSB) mechanism, leading to production of DNA double strand breaks (DSBs) and/or checkpoint activation. Unrepaired DSBs cause cell death. Repair of sapacitabine-induced DSBs is dependent on the homologous recombination repair (HRR) pathway. Both sapacitabine and its major metabolite, CNDAC, have demonstrated potent anti-tumor activity in preclinical studies. Sapacitabine has been studied in the SEAMLESS Phase 3 study in elderly patients with AML who were unfit or refused intensive induction chemotherapy, Phase 2 studies in patients with myelodysplastic syndromes (MDS), cutaneous T cell lymphoma (CTCL) and non-small cell lung cancer (NSCLC), Phase 1/2 studies in sequential administration with seliciclib and concomitant administration with olaparib in patients with BRCA mutant cancers.

About CYC065

CYC065 is a highly-selective, 2nd generation inhibitor of cyclin dependent kinases (CDK) 2 and 9. CYC065 is in an ongoing Phase 1, first-in-human study in patients with advanced solid tumors. In this study target engagement and durable suppression of the Mcl-1 biomarker were observed after a single dose of CYC065 at the recommended phase 2 dose. CYC065 is also being evaluated in a Phase 1 study in combination with venetoclax in patients with relapsed/refractory CLL. Preclinical data suggest that CYC065 may benefit patients with adult and pediatric hematological malignancies such as CLL, AML, ALL, B-cell lymphomas, multiple myeloma and certain cyclin E-addicted or MYC-amplified solid tumors, including HER2+ breast cancer, uterine serous carcinoma and neuroblastoma.