Cyclacel Pharmaceuticals, Inc. 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 Centre. 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 Leukaemia (CLL) and Small Lymphocytic Lymphoma (SLL) in up to 40 relapsed patients with leukaemia 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.

The study is led by William G Wierda, MD, Ph.D., Associate Professor of Medicine, Leukaemia Department, Division of Cancer Medicine, and is based on translational work published by a group led by William Plunkett, Ph.D., Professor and Deputy Chair, Department of Experimental Therapeutics, both of MD Anderson. The trial is being funded by MD Anderson’s Leukaemia Department with Cyclacel contributing sapacitabine and a small grant to support the performance of certain exploratory diagnostic tests.

“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 haematological malignancies and solid tumours, with emphasis on our SEAMLESS phase III pivotal trial in patients with front-line Acute Myeloid Leukaemia (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 Leukaemia (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 leukaemia 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.

According to the American Cancer Society, CLL is a very common adult leukaemia, accounting for one-third of all leukaemias in the United States. Nearly 94,000 Americans are living with CLL, which mainly affects the elderly with an average age at the time of diagnosis around 72 years. The American Cancer Society projects 14,570 new cases of CLL and about 4,380 deaths from the disease in 2011. CLL is a type of cancer that starts from white blood cells (called lymphocytes) in the bone marrow and can spread through the blood to the lymph nodes, spleen, liver and other parts of the body. SLL, a subset of Non-Hodgkins Lymphoma (NHL) accounting for 5-10% of NHL cases, is a type of blood cancer that also starts from lymphocytes. In SLL, however, cancer cells are mainly located in the lymph nodes.

The presence of deletion 11q22-23 measured by FISH occurs in approximately 18% of CLL cases and is associated with high-risk disease with a poor prognosis. Deletion at chromosome 11q22-23 is associated with deletion of the Ataxia Telangiectasia Mutated (ATM) gene. ATM, an element of the homologous recombination DNA repair pathway, plays an important role in cellular responses to double strand DNA breaks. Previous findings show that cells with defects in this chromosome region, such as inactivation of ATM, are particularly sensitive to sapacitabine. In addition to ATM deletions, mutations of ATM are also common in CLL with deletion 11q22-23. Sapacitabine may be of particular benefit to patients with ATM-defective leukaemia cells.

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 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 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 haematological malignancies and solid tumours. In December 2009 at the 51st Annual Meeting of the American Society of Haematology (ASH), 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.

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.