Cancer Research UK (CRUK) has kicked off a Phase I/II trial to see if a DNA methyltransferase (DNMT) inhibitor can stop bladder cancers developing resistance to chemotherapy. The study will give Astex Pharmaceuticals’ DNMT inhibitor in combination with chemotherapy.
In the first phase of the study, CRUK, working out of its clinical trial unit in Southampton, U.K., will give small doses of the DNMT inhibitor guadecitabine to up to 36 patients with advanced solid tumors. In doing so, CRUK expects to confirm the safety of the drug and identify the most effective dose, setting it up to advance into the second phase of the clinical trial. This second phase represents the critical stage for the program.
CRUK plans to enroll 20 patients with bladder cancer who are scheduled to have three or four cycles of chemotherapy before undergoing surgery. Some of the participants will be randomized to receive this standard-of-care treatment. Another cohort will receive the cycles of chemotherapy plus Astex’s experimental DNMT inhibitor guadecitabine, also known as SGI-110. Preclinical research suggests the combination could be more effective than chemotherapy alone.
This line of thinking is underpinned by knowledge of the mechanism of action of guadecitabine and the process that causes bladder cancers to develop resistance to chemotherapy. As DNMTs facilitate epigenetic modifications that researchers have for decades linked to the development of resistance to chemotherapy, CRUK is hoping the inhibition of the process will result in tumors of patients in the guadecitabine arm remaining more susceptible to the standard-of-care treatment.
CRUK is running the trial as part of the Combinations Alliance, an initiative that brings the nonprofit together with the Experimental Cancer Medicine Centres Network and drug developers to see which treatments work well when given together. In this instance, the drug developer is Astex, a biotech run out of Cambridge, U.K. and Pleasanton, CA, that was bought out by Otsuka for $886 million (€786 million) in 2013.
Astex has advanced guadecitabine furthest down the pipeline as a treatment for blood cancers--in April it teamed with Genentech for an anti-PD-L1 combination study in acute myeloid leukemia--but it has also explored its effect on solid tumors. Many of the solid tumor trials, like the CRUK study, are sponsored by third parties that want to assess the effect of guadecitabine in combination with other drugs in indications such as melanoma and colorectal cancer.
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