OBI-3424

P1/2, N=67, Recruiting, SWOG Cancer Research Network | Phase classification: P2 --> P1/2 | N=39 --> 67 | Trial completion date: Aug 2032 --> Aug 2028 | Trial primary completion date: Aug 2028 --> Aug 2026

P1/2, N=51, Active, not recruiting, Ascentawits Pharmaceuticals, Ltd | Recruiting --> Active, not recruiting

P2, N=39, Recruiting, SWOG Cancer Research Network | Trial completion date: Aug 2027 --> Aug 2032 | Trial primary completion date: Aug 2026 --> Aug 2028

The results showed that AST-3424 exhibited enhanced in vitro cytotoxicity and superior and durable in vivo anti-tumor effects in cells deficient of DNA repair protein BRCA2. In summary, we report here that when DNA repair capacity is reduced, the in vitro and in vivo activity of AST-3424 can be further enhanced, thus providing supporting evidence for the further evaluation of AST-3424 in the clinic.

P1/2, N=68, Terminated, OBI Pharma, Inc | N=104 --> 68 | Trial completion date: Dec 2024 --> Mar 2024 | Recruiting --> Terminated | Trial primary completion date: Dec 2024 --> Feb 2024; Little evidence of clinical activity in tumor types enrolled

P2, N=39, Recruiting, SWOG Cancer Research Network | Active, not recruiting --> Recruiting

Prior nelarabine therapy is not required, but patients who do not receive nelarabine during initial induction or post-remission treatment are eligible only if the physician does not feel they would benefit from other, multi-agent chemotherapy. Patients must not have had chemotherapy within 14 days prior to registration except for steroids, oral 6-mercaptopurine, oral methotrexate, vincristine, intrathecal chemotherapy, or hydroxyurea...This dose level temporarily closed on December 22, 2022, to fully assess the safety profile of the cohort. Three additional patients will be enrolled at dose level 3 after the study is reopened with a protocol amendment to relocate the MRD testing lab.

Prior nelarabine therapy is not required, but patients who do not receive nelarabine during initial induction or post-remission treatment are eligible only if the physician does not feel they would benefit from other, multi-agent chemotherapy. Patients must not have had chemotherapy within 14 days prior to registration except for steroids, oral 6-mercaptopurine, oral methotrexate, vincristine, intrathecal chemotherapy, or hydroxyurea...This dose level temporarily closed on December 22, 2022, to fully assess the safety profile of the cohort. Three additional patients will be enrolled at dose level 3 after the study is reopened with a protocol amendment to relocate the MRD testing lab.

However, enhancement of AST-3424 cytotoxicity by G2 arrest inhibitors, including adavosertib, AZD7762 and ceralasertib was only observed in HT29 but not in H460 cells. Conclusions DNA repair plays an essential role in AST-3424-mediated in vitro biological activities and in vivo anti-tumor activity. The preclinical data presented in this study support a new approach for cancer treatment.

The RP2D is 12 mg/m once every 3 weeks. OBI-3424 was well tolerated; dose-dependent, noncumulative thrombocytopenia and anemia were dose-limiting.

AST-3424 had a promising effect against HCC in PDTX model and orthotopic model with good safety. It could promote the sensitivity of other drugs without increasing toxicity. Clinical trials are warranted to further certify its antitumor effect and safety.