OBI-3424

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.

No abstract available

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.

P1/2, N=104, Recruiting, OBI Pharma, Inc | Trial completion date: Apr 2024 --> Dec 2024 | Trial primary completion date: Feb 2024 --> Dec 2024

No abstract available

No abstract available

P1/2, N=104, Recruiting, OBI Pharma, Inc | Trial completion date: Mar 2023 --> Apr 2024 | Trial primary completion date: Jan 2023 --> Feb 2024

AST-3424 is a prodrug of a potent nitrogen mustard, which targets the tumor by its specific and selective mode of activation and results in the concentration of the drug in the tumor and plays a higher intensity of antitumor effect with reduced side effects...The inhibition of AST-3424 was significantly higher than OXA, 5-Fu, Sor (sorafenib), and Apa (apatinib) in both HCC cells...The in-vitro studies revealed that AST-3424 in combination with both OXA and 5-Fu showed an increased antitumor effect, and the combination with OXA resulted in a synergistic effect. Together with the in-vitro results, additional in-vitro and in-vivo studies are warranted to further certify its antitumor effects and explore more potential antitumor mechanisms.

Background: OBI-3424 is a novel nitrogen mustard prodrug that can be selectively converted in the presence of the AKR1C3 enzyme into the bis-alkylating agent OBI-2660, which forms intra- and inter-strand DNA crosslinks resulting in cell death. We completed the dose-escalation portion of the study. The RP2D was determined to be 12 mg/m2 once every 3 weeks. OBI-3424 was well tolerated.

The results suggest that a combination therapy of OBI-3424 and anti-PD-1 in human clinical study is warranted. OBI-3424 is currently in Phase 1/2 clinical trials for solid tumor and acute lymphoblastic leukemia (NCT03592264 and NCT04315324).

No abstract available

No abstract available

In the combination therapy, we showed that 3424 could enhance the efficacy of the standard care of chemotherapy in the CDX models. The results described here highlight that 3424 exhibits AKR1C3-dependent cytotoxicity in vitro and anti-tumor activity in vivo in a wide range of human cancer types, which support further development of 3424 as an anti-cancer agent for treating different types of cancers and the use of AKR1C3 as a biomarker to profile cancer patients and further guide patient selection for therapy with 3424.

This indicates that clonal selection of CLL cells would involve additional oncogenic events. This raises the question whether detected subsets could represent B lymphocytes naturally prone to B-cell transformation.