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Cyclacel Pharmaceuticals Announces First Patient Treated in a Phase 1/2 Study of Sapacitabine and Venetoclax in Relapsed or Refractory AML or MDS Patients
“Sapacitabine is an oral nucleoside analogue that is active in AML and MDS that is relapsed or refractory to prior therapy such as cytarabine or hypomethylating agents. Combining sapacitabine with venetoclax may offer an effective, oral treatment regimen for patients who have failed front-line therapy,” said
The Phase 1/2 study (NCT01211457) is intended to enroll up to 40 patients with relapsed or refractory AML or MDS with the objective of determining the safety and efficacy of the combination. Secondary objectives include duration of response, CR, CRp, PR, or major HI, transfusion requirements, number of hospitalized days and overall survival.
Preclinical Data on Combinations of Sapacitabine and BCL2 Inhibitors in AML
Oral sapacitabine is metabolized to CNDAC which causes single stranded breaks in the DNA of growing cells, resulting in double stranded breaks and cancer cell death when DNA is not repaired. The combination effect of CNDAC and the BCL2 inhibitor ABT-737 was studied in vitro in AML cellular models. A synergistic increase in induction of apoptosis of cancer cells was observed when MV4-11 AML cells were treated simultaneously with CNDAC and the BCL2 inhibitor. Treatment with cytarabine and BCL2 inhibitors resulted in similar synergy (Frame S et al., 14th
About Venetoclax in AML
About Sapacitabine Clinical Studies in AML/MDS
Sapacitabine is active in relapsed or refractory AML or MDS. In a Phase 1 dose escalation trial of single agent sapacitabine 11 patients with relapsed or refractory AML or MDS responded (4 CR, 2 CRp, 5 CRi). In a Phase 2 single agent study of 63 patients with MDS who had progressed or relapsed after decitabine or azacitidine 9 patients responded (2 CR, 2 CRp, 5 major HI).
Sapacitabine as a single agent is active in previously untreated AML. In a randomized Phase 2 study of sapacitabine of 105 patients aged 70 years or older with untreated or first relapse AML, 28 out of 86 previously untreated patients responded (9 CR, 1 CRp, 3 CRi, 2 PR and 13 HI). In a Pilot/Lead-in study of sapacitabine alternating with decitabine 46 newly diagnosed AML patients aged 70 or older were administered the same regimen as the experimental arm in SEAMLESS. Nineteen patients responded (10 CR, 4 PR and 5 HI).
The randomized, open-label, Phase 3 SEAMLESS study enrolled 482 patients, aged 70 or older, with newly diagnosed AML who were not candidates for or refused intensive therapy. Patients were stratified by peripheral baseline white blood cell count (WBC), antecedent hematologic disease (AHD) and bone marrow blasts and randomized 1:1 to receive either intravenous decitabine administered in alternating cycles with oral sapacitabine or intravenous decitabine alone. The primary endpoint of demonstrating statistically significant improvement in overall survival (OS) was not met. A higher CR rate, a secondary endpoint, was observed on the decitabine-sapacitabine arm (17% versus 11%). Other endpoints and safety were similar between the arms. Stratified subgroup analyses showed that in a large subgroup of patients (n=319) with low WBC a trend towards improved OS (HR=0.84 [0.66, 1.06], nominal p=0.14) and a significantly higher CR rate (21% versus 9%, nominal p=0.0017) were observed favoring decitabine-sapacitabine. The opposite effect was observed in the high WBC subgroup.
This news release contains certain forward-looking statements that involve risks and uncertainties that could cause actual results to be materially different from historical results or from any future results expressed or implied by such forward-looking statements. Such forward-looking statements include statements regarding, among other things, the efficacy, safety and intended utilization of Cyclacel's product candidates, the conduct and results of future clinical trials, plans regarding regulatory filings, future research and clinical trials and plans regarding partnering activities. Factors that may cause actual results to differ materially include the risk that product candidates that appeared promising in early research and clinical trials do not demonstrate safety and/or efficacy in larger-scale or later clinical trials, trials may have difficulty enrolling, Cyclacel may not obtain approval to market its product candidates, the risks associated with reliance on outside financing to meet capital requirements, and the risks associated with reliance on collaborative partners for further clinical trials, development and commercialization of product candidates. You are urged to consider statements that include the words "may," "will," "would," "could," "should," "believes," "estimates," "projects," "potential," "expects," "plans," "anticipates," "intends," "continues," "forecast," "designed," "goal," or the negative of those words or other comparable words to be uncertain and forward-looking. For a further list and description of the risks and uncertainties the Company faces, please refer to our most recent Annual Report on Form 10-K and other periodic and other filings we file with the
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