Novel CXCR4 Antagonist Enters Clinical Testing for CML
News | May 08, 2014 | Chronic Myeloid Leukemia, Hematologic Malignancies, Leukemia & Lymphoma
By Dave Levitan
A novel agent known as BL-8040 will enter phase I/II testing for the treatment of chronic myeloid leukemia (CML), according to BioLineRx, the company developing the drug. The study will evaluate BL-8040 in combination with imatinib in patients with a sub-optimal response to imatinib monotherapy.
Tyrosine kinase inhibitors such as imatinib have proven to be extremely effective treatments for CML, and survival has improved dramatically in these patients since the drugs' introduction more than a decade ago. But approximately 15% of patients do not respond well to imatinib, and as many as 40% eventually develop resistance.
"The bone marrow has a protective effect on CML stem cells, and enables them to evade eradication by existing drugs," said Arnon Nagler, MD, of the Sheba Medical Center in Israel, who will lead the new study. "Preclinical data have shown that BL-8040 efficiently synergizes with imatinib in vitro and in vivo, overcoming the protective effect of the bone marrow, and we therefore hope that the combination of these two drugs will override drug resistance and suppress residual disease."
The study referenced by Dr. Nagler was published this month in Molecular Cancer Therapeutics, and showed that the combination suppressed tumor growth by as much as 95%. BL-8040 is an antagonist for the chemokine receptor CXCR4, which has been implicated in relation to tumor progression, angiogenesis in tumors, and metastasis. According to the BioLineRx press release, it is overexpressed in more than 70% of all human cancers.
The new study of BL-8040 will be a phase I/II, randomized, dose-escalation trial for patients in the chronic phase of CML. The primary endpoints are the safety and tolerability of the drug, and secondary endpoints include cytogenetic and molecular responses.
Along with the phase I/II trial in CML patients, the company is also evaluating BL-8040 in a phase II trial of patients with relapsed or refractory acute myeloid leukemia (AML). In that study, BL-8040 will be administered in combination with cytarabine. Another phase I trial is testing the drug for stem cell mobilization, as a pre-treatment for stem cell transplantation.
"It is conceivable that adding BL-8040 to imatinib therapy in CML patients who have not achieved optimal cytogenetic or molecular responses may improve their response to imatinib by directly inducing apoptosis of the tumor cells and by mobilizing leukemic stem cells from the bone marrow's protective niches and sensitizing them to imatinib-induced cell death," Dr. Nagler said.
- See more at: http://www.cancernet...h.zfzeK4sL.dpuf