ONC201 is a selective antagonist of the G-protein coupled receptor (GPCR) dopamine receptor domain 2 (DRD2) that is overexpressed in endometrial cancer (EC) due to its p53-independent control of the Akt/ERK signaling pathways. ONC201 is a first-in-class small molecule exhibits anticancer efficacy in a wide range of refractory cancers, including p53 mutant cells, by simultaneously inactivating Akt and ERK signaling, resulting in cell cycle arrest and apoptosis. Type II EC comprises non-endometrioid histology (i.e. serous, clear cell and mucinous) that are generally associated with more aggressive clinical behavior. This proposal supports a clinical trial of ONC201 in Type II EC patients with recurrent disease, who have mutations in p53 as well as deregulated Akt and ERK pathways in their tumors. In clinical trials, ONC201 has been exceptional well tolerated, possessed a therapeutic pharmacokinetic profile, and exhibited sustained pharmacodynamics and anti-cancer activity in advanced cancer patients. No > Grade 1 drug-related adverse events were observed in the first-in-human trial, despite achieving therapeutic blood levels and demonstrating signs of biological activity. Of the 28 evaluable patients in that trial, there were 5 advanced endometrial cancer patients and several exhibited clinical benefit and all expressed DRD2 in their archival tumor specimens. Among these heavily-pretreated 5 patients, the median number of prior treatments was 5 (3-6), 3 patients had prior radiation and all patients had prior surgery. After 2 doses of ONC201, one patient with clear cell EC had a mixed response with >50% decrease in lymphadenopathy. Two EC patients experienced prolonged stable disease lasting for 18 and 42 weeks, including a 56 year-old patient with serous- papillary EC who also had a significant and sustained reduction in the size of a metastatic lung lesion. Thus, EC emerged as the most promising tumor type from a preliminary efficacy perspective in this first-in-human trial in advanced solid tumors. Based on the clinical responses observed in this patient population, in this fast-track application we propose to first evaluate a pilot cohort of patients to evaluate the preliminary single agent efficacy profile in Type II EC patients. Depending on these clinical results, we will then conduct a larger study enrolling an additional 30 patients to determine the efficacy of ONC201 either as a single agent or in combination with paclitaxel. Phase/Aim#1: Evaluation of preliminary single agent efficacy profile in Type II EC patients. Phase/Aim #2: Determine the efficacy of ONC201 in Type II EC. This proposal seeks to provide a safe and durable treatment for patients with a disease that has few treatment options and a dismal prognosis.
Public Health Relevance Statement: Project Narrative This proposal seeks to develop a new cancer drug called ONC201, which has a new way of killing cancer cells that no longer respond to other treatments, for patients who have Type II endometrial cancer. In a previous first-in-human advanced solid tumor study, patients with this type of cancer had their tumors shrink and target of this new drug was expressed in their tumors. These patients have very poor prognoses and limited treatment options, with no new drugs approved by the FDA in almost 20 years for this disease and therefore ONC201 represents an important treatment option for these patients.
Project Terms: Acetates; Advanced Malignant Neoplasm; Adverse event; antagonist G; Apoptosis; Archives; Atrophic; base; Behavior; Biological; Biological Assay; Blood; cancer cell; Cancer Histology; Cancer Model; Cancer Patient; cancer therapy; cancer type; Cell Cycle Arrest; Cells; Cessation of life; Clear Cell; Clinical; clinical application; clinical efficacy; Clinical Trials; cohort; combinatorial; Data Set; Development; Disease; Dopamine Receptor; Dose; Drug Kinetics; effective therapy; efficacy evaluation; Endometrial; Endometrial Carcinoma; Enrollment; ERBB2 gene; Estrogens; Evaluable Disease; Evaluation; Exhibits; experience; FDA approved; G-Protein-Coupled Receptors; Histology; Human; human study; In Vitro; in vivo; Institutional Review Boards; Investigation; Killings; Lead; Lesion; Lung; Lymphatic Diseases; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Megestrol; member; Molecular Target; mortality; Mucinous; mutant; Mutate; Mutation; new therapeutic target; novel; novel anticancer drug; novel therapeutics; oncology; Operative Surgical Procedures; Oral; outcome forecast; overexpression; Paclitaxel; Papillary; Pathway interactions; patient population; Patients; Pharmaceutical Preparations; pharmacodynamic biomarker; Pharmacodynamics; Phase; phase II trial; predictive marker; Radiation; Ras Signaling Pathway; receptor; Recurrence; Recurrent disease; Refractory; Reporting; response; Safety; screening; Serous; Signal Pathway; Signal Transduction; small molecule; Solid Neoplasm; Specimen; Stable Disease; Structure; Survival Rate; Therapeutic; Tissues; TP53 gene; tumor; United States; Validation
