Abstract CT033: Safety and early efficacy signals for COTI-2, an orally available small molecule targeting p53, in a phase I trial of recurrent gynecologic cancer

Abstract Background: Mutated p53 tumor suppressor protein is involved in >50% of all malignancies; however, only recently have candidate drugs designed to target p53 mutations entered clinical trials. COTI-2, an orally bioavailable "third-generation" thiosemicarbazone, was shown to restore the structure and function of mutant p53 proteins and induced growth inhibition in a number of p53 mutant cell lines. Thus, a three-part phase I dose escalation trial of COTI-2 was initiated with Part 1 reported herein. Methods: A multicenter, open label, 3+3 dose escalation trial enrolling patients with recurrent gynecological cancers with adequate performance status and bone marrow function. Patients could have unlimited prior therapies. Patients received COTI-2 5x/week orally over a 28-day cycle. Disease response was assessed by RECIST 1.1 every 8 weeks. Results: Twenty-four patients received study treatment: 19 ovarian, 3 cervical, and 2 endometrial cancers. Median age was 60 years (45-73 yrs) and patients had received a median of 5 prior chemotherapy regimens. After 4 dose cohorts (0.25, 0.5, 1.0, and 1.7 mg/kg), the Recommended phase II Dose (R2PD) for gynecologic cancer was 1.0 mg/kg. Dose-limiting toxicities (DLT) were encountered at 1.0 mg/kg (G3 abdominal pain, G3 sensory peripheral neuropathy, n=1) and 1.7 mg/kg, (G3 neuralgia n=1, G3 myalgia n=1). All DLTs resolved off treatment. Most common adverse events (> 10%) were nausea (67%), vomiting (67%), fatigue (54%), abdominal pain (46%), constipation (29%), anemia (29%), dyspnea (29%), anorexia (29%), urinary tract infection (21%), and hypokalemia (20%), myalgia (16%), diarrhea (16%), pyrexia (17%), peripheral neuropathy (17%), increased creatinine (13%), and weight loss (13%). Pharmacokinetic assessment showed oral administration of COTI-2 yielded a Tmax between 15-90 minutes and a half-life of 8-10 hours. Fifteen patients were evaluable for efficacy, having received at least one cycle of treatment. Of these, 13 had ovarian, 1 had cervical, and 1 had endometrial cancer. Eight patients had received one or more bevacizumab combinations, and two had received immune checkpoint inhibitors. Following COTI-2 treatment, 10 patients showed signs of possible activity: 1 patient had stable disease, 4 had stable target lesions, and 5 had stable non-target lesions. Twelve patients had comprehensive genomic profiling by next generation sequencing: 3 had wild-type p53 and 9 had either hotspot or non-hotspot mutations. Conclusions: COTI-2 was deemed generally safe and well-tolerated. Part 2 of the study is currently underway in HNSCC patients, with additional data expected in 2018, and Part 3 will follow with expansion to combination treatment of ovarian and HNSCC patients. Clinical trial information: NCT02433626. Citation Format: Shannon N. Westin, Wilberto Nieves-Neira, Christian Lynam, Kowthar Y. Salim, Alison D. Silva, Richard T. Ho, Gordon B. Mills, Robert L. Coleman, Filip Janku, Daniela Matei. Safety and early efficacy signals for COTI-2, an orally available small molecule targeting p53, in a phase I trial of recurrent gynecologic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT033.