Cyclacel Pharmaceuticals to initiate phase II trials

Drug discovery company Cyclacel Pharmaceuticals based in Berkeley Heights, New Jersey, is to open a multicenter randomised Phase II clinical trial later this month looking at the use of oral sapacitabine in elderly patients with acute myeloid leukemia who are previously untreated or in first relapse.

The move comes as the company posts promising data from a phase I clinical trial of the novel nucleoside CYC682 at the 49th annual meeting of the American Society of Hematology, in Atlanta, Georgia.

Dr Hagop Kantarjian, a lead investigator in the trial and professor of medicine and chairman of the leukemia department, said updated results based on a study of sapacitabine offered promising anti-leukemic activity in patients with relapsed and refractory acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS) when administered by two different dosing schedules.

Sapacitabine interferes with DNA synthesis by causing single-strand DNA breaks and also induces arrest of cell cycle progression mainly at G2/M-Phase. Both sapacitabine and CNDAC, its major metabolite or a substance into which the drugs converts after ingestion by patients, have demonstrated potent anti-tumor activity in preclinical studies.

The primary objective of the study is to determine the maximum tolerated dose (MTD) of sapacitabine administered twice daily for seven consecutive days every 21 days or three consecutive days per week for two weeks every 21 days.

The MTD was reached at 375mg on the seven-day schedule and 475mg on the three-day schedule. Dose-limiting toxicity was gastrointestinal, which included abdominal pain, diarrhoea, small bowel obstruction and neutropenic colitis. One patient treated at the MTD of 375mg on the seven-day schedule died of complications from neutropenic colitis.

Among 46 patients with AML (n=42) or MDS (n=4) in this dose escalating study, the best responses were complete remissions (CR) or complete remissions without platelet recovery (CRp) in six patients.

In addition, 15 patients had a significant decrease in bone marrow blasts including seven with blast reduction to 5% or less.

The study is ongoing at The University of Texas M. D. Anderson Cancer Center and is led by Kantarjian, Professor and Dr William Plunkett, professor and chief at the section of molecular and cellular oncology at the department of experimental therapeutics.

The new Phase II study will evaluate the one-year survival rate of three dosing schedules. The study will use a selection design to identify a dosing schedule that produces a better one-year survival rate in the event that all three dosing schedules are active.