Cyclacel Pharmaceuticals, Inc. announced that it has opened enrolment of the Seamless pivotal phase III trial for the company’s sapacitabine oral capsules as a front-line treatment of elderly patients aged 70 years or older with newly diagnosed Acute Myeloid Leukaemia (AML) who are not candidates for intensive induction chemotherapy.

The study is being conducted under a Special Protocol Assessment (SPA) agreement that Cyclacel reached with the US Food and Drug Administration (FDA). Seamless builds on promising 1-year survival observed in elderly patients aged 70 years or older with newly diagnosed AML or AML in first relapse enrolled in a phase II study of single agent sapacitabine.

“The opening of the Seamless study for patient enrollment marks an important milestone for Cyclacel as this is the first pivotal phase III trial ever conducted by the Company,” said Spiro Rombotis, president and chief executive officer of Cyclacel. “If it reaches the market, sapacitabine will become an important treatment option for many elderly patients who are suffering from this life-threatening disease. We also look forward to interim data from the phase II study of sapacitabine in Non-Small Cell Lung Cancer (NSCLC). Sapacitabine may be one of few cancer drugs with activity against both haematological malignancies and solid tumours.”

The Seamless study is chaired by Hagop M. Kantarjian, MD, chairman and Professor, Department of Leukaemia, The University of Texas MD Anderson Cancer Centre, Houston, Texas. Seamless is a multi-centre, randomized, phase III study comparing three treatment arms. In arm A sapacitabine is administered in alternating cycles with decitabine, in arm B sapacitabine is administered alone and in arm C decitabine is administered alone.

The primary efficacy endpoint is overall survival. The study is designed to demonstrate an improvement in overall survival of either of two pair wise comparisons: arm A versus arm C or arm B versus arm C. Approximately 150 patients per arm or a total of 450 patients from approximately 50 centres will be enrolled. Seamless will be monitored by a Data Safety Monitoring Board (DSMB). A pre-specified interim analysis for futility will be performed and reviewed by the DSMB.

“We chose decitabine as an active control arm as it is one of the treatment options recommended by the National Comprehensive Cancer Network’s Clinical Practice Guidelines. We are pleased to learn that this active control arm is acceptable to AML investigators.” said Judy Chiao, MD, vice president of Clinical Development and Regulatory Affairs of Cyclacel. “AML in the elderly is a life-threatening disease with high unmet medical need. Patients with AML aged 70 years or older have a poor prognosis, as the majority of these patients are not candidates for intensive induction chemotherapy because of poor tolerability to such therapy and a high risk of relapse because of the lack of effective consolidation and maintenance therapy. If the Seamless study is successful, sapacitabine may significantly improve the outcome of this devastating disease in elderly patients.”

The treatment regimen of sapacitabine administered in alternating cycles with decitabine has been found to be safe and efficacious in an on-going pilot study conducted at The University of Texas MD Anderson Cancer Centre. In addition, Seamless has a lead-in stage to further confirm the safety and efficacy of the alternating treatment regimen in the multi-centre setting. The FDA has designated sapacitabine as an orphan drug for the treatment of both AML and Myelo-Dysplastic Syndromes (MDS).

AML is a cancer of the blood cells that progresses rapidly and if not treated, could be fatal in a few months. AML is generally a disease of older people and is uncommon before the age of 40. The average age of a patient with AML is about 67 years. There are more than 12,300 new cases of AML, of which about half are elderly and nearly 9,000 deaths caused by this cancer each year in the United States.

A Special Protocol Assessment is a binding written agreement with the FDA that the sponsor’s proposed trial protocol design, clinical endpoints and statistical analyses are acceptable to support regulatory approval. Final marketing approval depends on efficacy results, adverse event profile and an evaluation of the benefit/risk of a treatment as demonstrated in the trial.

Sapacitabine (CYC682), an orally-available nucleoside analogue, is currently being evaluated in a phase III trial in elderly AML under a SPA agreement with the US Food and Drug Administration and phase II trials in patients with haematological malignancies and solid tumours. Sapacitabine acts through a dual mechanism, interfering with DNA synthesis by causing single-strand DNA breaks and inducing arrest of cell cycle progression mainly at G2-phase.

Both sapacitabine and CNDAC, its major metabolite, have demonstrated potent anti-tumour activity in preclinical studies. Over 200 patients have received sapacitabine in phase II studies in AML, MDS, Cutaneous T Cell Lymphoma (CTCL) and NSCLC. Sapacitabine has been administered to approximately 170 patients in five phase I studies with both haematological malignancies and solid tumours. Sapacitabine is part of Cyclacel’s pipeline of small molecule drugs designed to target and stop uncontrolled cell division.

Cyclacel is a biopharmaceutical company developing oral therapies that target the various phases of cell cycle control for the treatment of cancer and other serious diseases. Cyclacel’s strategy is to build a diversified biopharmaceutical business focused in haematology and oncology based on a portfolio of commercial products and a development pipeline of novel drug candidates.