A Phase 1b/2 clinical trial testing Onxeo’s AsiDNA as a potential treatment to overcome resistance to Zejula (niraparib) in ovarian cancer patients is set to begin, part of an agreement between Onxeo and Gustave Roussy, a leading European cancer center.
The REVOCAN trial plans to enroll 26 women who have been using Tesaro‘s Zejula as a second-line maintenance therapy for at least six months, and who experienced an elevation in the ovarian cancer biomarker CA125. This rise may signal the cancer is progressing while on Zejula.
Led by Patricia Pautier at Gustave Roussy, the trial aims to achieve a drop in CA125 levels after the addition of AsiDNA to Zejula, suggesting that resistance has been overcome. Survival and time to disease progression will also be assessed as main efficacy outcomes.
Researchers expect to enroll its first patients by June, and to present the first findings by year’s end.
“Gustave Roussy and Onxeo will conduct an original proof-of-concept study of the reversion of the mechanism of resistance to a major therapeutic class,” Pautier, MD, oncologist, head of the Gynecological Cancers Committee at Gustave Roussy, said in a press release.
“If positive, this first study … may pave the way for further combination studies with this therapeutic class, in ovarian cancer but also in other pathologies, and offer patients who benefit from these treatments an additional opportunity to control their disease,” she added.
As cancer cells divide at a faster pace, they are prone to accumulating more errors in their genome than healthy cells. Cells have a specific machinery — called DNA Damage Response (DDR) — dedicated to finding these errors and correcting them, preventing additional cellular damage.
Among the critical components of this corrective mechanism are PARP enzymes, without which cells are unable to fix these cumulative genetic errors.
PARP inhibitors, like Zejula, were developed to stop cancer cells from repairing their DNA, so that errors accumulate and eventually kill cancer cells. Zejula is approved for two ovarian cancer indications, one of which is as a maintenance therapy for patients who responded to second-line or later platinum-based chemotherapy.
It is a once-daily pill and can be used in women with or without germline, or inherited, mutations in BRCA genes. However, some people develop resistance to Zejula during treatment, likely because tumors establish new pathways through which they repair their DNA errors.
AsiDNA is made of short DNA fragments (called oligonucleotides) designed to mimic damage to DNA. In this manner, it attracts DNA repair proteins, working as a decoy that prevents their recruitment to actual DNA damage sites. Eventually, cancer cells accumulate enough damage and die.
The mechanism of action of AsiDNA is different from that of Zejula, because it does not inhibit PARP enzymes but rather targets the whole DNA repair process. This prevents cancer cells from acquiring resistance to other DNA inhibitors, and is likely to increase responses to PARP inhibitors and chemotherapy.
Preclinical studies support the use of AsiDNA as a means of preventing resistance to PARP inhibitors like Zejula, and to improve the effectiveness of other DNA repair inhibitors. Another Phase 1 trial (NCT03579628) in Europe is underway, looking into the addition of AsiDNA to chemotherapy agents that target the DNA in people with advanced tumors.
“This is a major clinical milestone for Onxeo as we embark in this key study aiming to demonstrate that the addition of AsiDNA abrogates the tumor resistance to PARP inhibitors, which would in turn improve patients’ progression-free survival,” said Olivier de Beaumont, chief medical officer of Onxeo.