US-based clinical-stage biopharmaceutical firm Calithera Biosciences has initiated dosing patients in its first Phase I trial of CB-839, a potent, selective, orally bioavailable inhibitor of glutaminase, to treat patients with advanced solid tumours.
Glutaminase is a new target in cancer metabolism and the trials will help the company evaluate the safety, pharmacokinetics and pharmacodynamics of the new agent.
The company said that CB-839 interferes with tumour metabolism and blocks cancer cell growth and survival.
Calithera Biosciences founder, president and chief executive officer Susan Molineaux said: "CB-839 has demonstrated significant anti-tumour activity in both solid and hematological tumour models and we look forward to reporting initial clinical results with this compound."
Two additional Phase I trials are currently being carried out in parallel, one in patients with advanced multiple myeloma and non-Hodgkin’s lymphoma and the second in patients with acute leukemias.
The company said that all three single-arm, open-label dose escalation Phase I clinical studies will allow for expansion in specific tumour types once the maximum tolerated dose is reached.
Primary objectives of each of the trials are to determine the safety and tolerability of CB-839 and to establish a dose for Phase II trials, while secondary endpoints include pharmacokinetics, pharmacodynamics and evidence of anti-tumour response.
Predictive biomarkers are also being evaluated under the trials, which are being carried out at clinical sites in the US.
Glutaminase is the first enzyme in the glutamine metabolism pathway that controls the conversion of glutamine to glutamate.
The company said that in glutamine-requiring cancer cells, inhibition of glutaminase with CB-839 results in depletion of intracellular pools of TCA cycle intermediates, glutathione and amino acids leading to inhibition of cell growth as well as induction of apoptosis.
The preclinical trials have shown that CB-839 is effective against a significant fraction of tumour cells from a variety of solid and haematologic tumour cell types, including triple-negative breast cancer, non-small cell lung cancer, renal cell carcinoma, mesothelioma, multiple myeloma, diffuse large B-cell lymphoma and acute leukemias.
Image: Intermediate magnification micrograph of mantle cell lymphoma of the terminal ileum. Photo: courtesy of Nephron.