Cyclacel Announces Phase II Trial of Sapacitabine

Cyclacel Pharmaceuticals, Inc. recently announced that the first patient has been dosed in an investigator-initiated, translational, Phase II clinical study at The University of Texas MD Anderson Cancer Center. The objective of the study is to learn if oral sapacitabine capsules given in combination with two standard injectable drugs, cyclophosphamide and rituximab, or the SCR regimen, can help control chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) in up to 40 relapsed patients with leukemia cells containing the 11q22-23 chromosome deletion. Deletion at chromosome 11q22-23 is associated with deletion of the Ataxia Telangiectasia Mutated (ATM) gene, an important element of the homologous recombination DNA repair (HRR) pathway. Previous findings show that cells with HRR pathway defects are particularly sensitive to sapacitabine. Sapacitabine may therefore be of particular benefit to patients with ATM-defective blood cancers.

“As gene-based, personalized medicine approaches have in certain cases been developed and approved faster than traditional methods, we are encouraged by the prospect of tailoring treatment with sapacitabine to the genetic profile of an individual’s cancer cells,” said Spiro Rombotis, President and CEO of Cyclacel. “We have collaborated with Dr. Wierda, Dr. Plunkett, and their teams for several years to study sapacitabine’s effects on the DNA repair pathway. We thus welcome the opportunity to explore the hypothesis that the presence of 11q22-23 deletion may translate into clinical benefit for patients treated with the sapacitabine-based SCR regimen, while doing so in a fiscally responsible and collaborative manner. We look forward to the eventual outcome of this unique study and building our value proposition on data from Cyclacel’s ongoing studies in both hematological malignancies and solid tumors, with emphasis on our SEAMLESS Phase III pivotal trial in patients with front-line acute myeloid leukemia (AML).”

The translational Phase II study is a single institution, single arm, trial of the SCR regimen in previously treated patients with CLL or SLL. The primary objective is to evaluate the overall response rate of the regimen based on the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria. Up to 40 patients will be enrolled at different dosing schedules under evaluation. Secondary endpoints include the evaluation of tolerability and toxicities, determination of duration of response, disease-free survival, and overall survival. In addition, the study will evaluate the association between response to the SCR regimen and ATM gene function in previously treated patients with CLL who have chromosomal deletion 11q22-23 by the fluorescence in-situ hybridization or FISH technique. The study will also evaluate other clinically correlated pretreatment indicators with response and time-to-event outcomes.

Patients enrolled in the study will be 18 years and older and have a diagnosis of CLL or SLL with leukemia cells containing the 11q22-23 deletion, have been previously treated with at least one prior regimen and have undergone FISH-evaluation within 3 months without intervening treatment. The latest previous dose of chemotherapy must have been administered at least 30 days prior to receiving treatment on this study.

Sapacitabine (CYC682), an orally available nucleoside analogue, is currently being evaluated in a registration-directed, Phase III trial in front-line elderly AML and Phase II trials in patients with hematological malignancies and solid tumors. 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-tumor activity in preclinical studies.

Over 300 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 hematological malignancies and solid tumors. In December 2009, Cyclacel reported data from a randomized Phase II study including promising 1-year survival in elderly patients with AML aged 70 years or older. Sapacitabine is part of Cyclacel’s pipeline of small molecule drugs designed to target and stop uncontrolled cell division.