Interim data published by Mateon Therapeutics, a biopharmaceutical company developing vascular targeted therapy, including vascular disrupting agents or VDAs and?anti-angiogenic agents for the treatment of orphan oncology indications, confirmed that CA4P, known as combretastatin A4-phosphate or fosbretabulin, in combination with a checkpoint inhibitor, significantly reduced tumor size in a CT-26 colon cancer animal model.
The results showed that CA4P in combination with anti-CTLA-4 antibodies resulted in 77% reduction in tumor size compared to anti-CTLA-4 antibodies alone and 89% reduction compared to control.
Fosbretabulin is a potent, tubulin-binding vascular disrupting agent (VDA). Upon administration, fosbretabulin is dephosphorylated to its active metabolite, combretastatin A4, which targets and binds to tubulin dimers and prevents microtubule polymerization, thereby resulting in mitotic arrest and apoptosis in endothelial cells. As apoptotic endothelial cells detach from their substrata, tumor blood vessels collapse, as a result, acute disruption of tumor blood flow may result in tumor necrosis.
Researchers at Mateon evaluated the company’s lead investigational drug CA4P, which is also currently being studied in a phase II/III clinical trial in platinum-resistant ovarian cancer, in a syngeneic mouse model in combination with a checkpoint inhibitor.
Focus
This clinical study, called FOCUS (NCT02641639), is designed to test whether CA4P improves Progression Free Survival (PFS) when combined with bevacizumab (Avastin?; Genentech/Roche) and physician?s choice chemotherapy or PCC.
Table 1.0: Results following two weeks of treatment CA4P in combination with anti-CTLA-4 antibodies.The trial is a randomized double-blind placebo-controlled study divided into 2 parts to maximize the speed of data collection. During part 1 (n=80 patients), several interim analyses will be conducted to initially assess the efficacy and safety of the combination regimen when compared to standard-of-care. Part 2 (n=356 patients) is a confirmatory Phase III study which would begin immediately after evidence of safety and efficacy are initially demonstrated in part 1.
The FOCUS trial was designed to build upon data from the GOG-0186I study, which demonstrated that CA4P improves PFS in women with recurrent ovarian cancer when combined with bevacizumab compared to bevacizumab alone. The treatment effect observed in this study was strongest in the subgroup of ovarian cancer patients with platinum-resistant disease.
Difficult-to-treat tumors
In order to assess the effects of CA4P on more advanced and difficult-to-treat tumors, tumors in this study were allowed to grow for 13 days prior to treatment. Consequently, beginning tumor sizes were approximately three times larger than those generally evaluated in pre-clinical studies.
Table 2.0: Mean Tumor Volume in CT-26 Colorectal Mouse Model?CA4P increases the effects of checkpoint inhibitors because it rapidly causes tumor cell death, which likely increases tumor antigen presentation and T-cell activation and the overall immunologic response,? explained William D. Schwieterman, M.D., President and Chief Executive Officer of? Mateon Therapeutics.
?These new results reinforce similar results observed in other studies and, importantly, the animals in the combination CA4P and anti-CTLA-4 antibody treatment group are continuing to show declines in tumor volume beyond Day 14. We look forward to additional data from this study and other on-going preclinical work over the next several months,? Schwieterman added.
This is the second study and tumor type to demonstrate robust complementary effects when Mateon?s CA4P is provided in combination with a checkpoint inhibitor; results obtained approximately four months ago in a smaller tumor EMT-6 mammary model also showed strong synergy when anti-CTLA-4 antibodies were combined with CA4P.
Last editorial review: June 28, 2017
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