Date: 2016-06-06
Type of information: Presentation of results at a congress
phase: 1
Announcement: presentation of results at the American Society of Clinical Oncology (ASCO) annual meeting, in Chicago
Company: Cyclacel Pharmaceuticals (USA - NJ)
Product: seliciclib and sapacitabine
Action
mechanism: cyclin dependant kinase inhibitor/CDK inhibitor/nucleoside analogue. Sapacitabine is an oral nucleoside analogue prodrug whose metabolite generates single-strand DNA breaks, either leading to arrest of the cell cycle at G2 phase or development of double-strand DNA breaks. Repair of the double-strand DNA breaks is dependent on homologous recombination. BRCA mutations in cancer cells are a cause of homologous recombination deficiency, making them susceptible to cell death induced by sapacitabine. Seliciclib is an orally-available CDK (cyclin dependant kinase) inhibitor molecule that selectively inhibits enzyme targets, CDK2 and CDK9, which are central to the process of cell growth, survival and cell cycle control. Seliciclib treatment has been reported to inhibit the two major DNA double-strand break repair pathways, homologous recombination and non-homologous end joining, by reducing expression of components of each pathway. It may potentiate the activity of sapacitabine by compromising homologous recombination protein expression and activation or by potentiating apoptosis following sapacitabine-induced DNA damage.
Disease: advanced solid tumors
Therapeutic area: Cancer - Oncology
Country: USA
Trial
details: The primary objective of this phase 1 study is to determine the maximum tolerated dose (MTD) or recommended phase II doses of sapacitabine and seliciclib administered sequentially or concomitantly. The secondary objectives are to evaluate antitumor activity of this sequential or concomitant treatment and to explore the pharmacodynamic effect of this treatment in skin and peripheral blood mononuclear cells. (NCT00999401)
Latest
news: * On June 6, 2016, Cyclacel Pharmaceuticals reported updated Phase 1 data from its DNA damage response program evaluating a combination regimen of seliciclib, a cyclin dependent kinase (CDK) inhibitor, and sapacitabine, a nucleoside analogue. The regimen was orally-administered as sequential (Part 1) or concomitant (Part 2) treatment to 67 heavily-pretreated patients with advanced solid tumors. Antitumor activity was demonstrated in a subgroup of 45 patients with breast, ovarian and pancreatic cancers who tested positive for BRCA mutations (44 germline and 1 sporadic) with a 35.6% disease control rate (1 CR, 5 PR and 10 SD). Treatment durations in responders ranged between 16 and over 240 weeks. No CR or PR was observed in BRCA negative patients. Data were presented at an oral presentation at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago (abstract). A Part 3 extension of the study is currently enrolling advanced breast cancer patients with BRCA mutations. The trial is a dose escalation study conducted in patients with advanced and incurable solid tumors. The orally-administered regimen consists of sapacitabine administered twice daily for 7 days sequentially followed by seliciclib twice daily for 3 days over a 21 day cycle (Part 1, n=38); and sapacitabine dosed each morning followed by seliciclib each evening, each once daily for 5 days per week for 2 weeks of a 28 day cycle (Part 2, n=29). The primary objective of the trial is to determine the maximum tolerated dose with a secondary objective of antitumor activity of the combination. Sixty-seven patients have been treated in Parts 1 and 2 of the study, of which 44 were found to carry BRCA mutations and one a sporadic BRCA mutation. * One patient had a sporadic BRCA mutation. CR=complete response, PR=partial response, SD=stable disease. One CR and five PR were observed in BRCA mutation carriers with breast, ovarian and pancreatic cancers. Treatment durations for the 3 breast/ovarian cancer responders in Part 1 are 54, 93, over 240 weeks and the one breast cancer responder in Part 2 over 76 weeks respectively. Treatment durations for the two pancreatic cancer responders, one each in Parts 1 and 2, are 21 and 16 weeks respectively. Responders included patients who underwent prior treatment with PARP inhibitors and PARP naïve patients. SD was observed in 9 BRCA mutation carriers and 1 sporadic BRCA positive patient with treatment durations ranging from 16 to 88 weeks. Overall in BRCA positive patients (Parts 1 and 2, n=45), disease control rate is 35.6% and overall response rate (ORR) is 11% (Part 1 ORR 25% and Part 2 7%). The difference in Part 1 and Part 2 ORRs may suggest that the seliciclib dose in the Part 2 schedule may be too low for enhancing the activity of sapacitabine. Pharmacodynamic effects of the seliciclib and sapacitabine combination were observed in skin biopsies. Part 1 biopsies following treatment showed a 2.3-fold increase in DNA damage induced by sapacitabine, as measured by gamma-H2AX immunohistochemistry. Additional DNA damage occurred after treatment with seliciclib with a 0.58-fold further increase in gamma-H2AX staining. In Part 1 recommended Phase 2 doses (RP2D) are: sapacitabine 50 mg b.i.d./seliciclib 800 mg b.i.d. Most frequent grade 3/4 adverse events were neutropenia (16%) and elevation in AST (16%). In Part 2 RP2D are: sapacitabine 250 mg q.d./seliciclib 200 mg q.d. Most frequent grade 3/4 adverse events were neutropenia (28%) and elevation in AST (10%). Dose limiting toxicities were reversible elevations in transaminase and bilirubin, neutropenia or febrile neutropenia and pneumonia.Best Responses PART 1 PART 2 BRCA carriers Others BRCA carriers Others (n=16) (n=22) (n= 28) (n=1) CR 1 - - - PR 3 - 2 - SD 2 6 7 1* ORR (CR/PR) 25 % 0 % 7 % 0 % Disease Control (CR/PR/SD) 6 (37.5%) 6 (27.3%) 9 (32.1%) 1 (100.0 %)
