Clinical Efficacy Evaluation of First in class Imipridone ONC in Recurrent Type II Endometrial Cancer

Project Summary ONC is a selective antagonist of the G protein coupled receptor GPCR dopamine receptor domain DRD that is overexpressed in endometrial cancer EC due to its p independent control of the Akt ERK signaling pathways ONC is a first in class small molecule exhibits anticancer efficacy in a wide range of refractory cancers including p 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 ONC in Type II EC patients with recurrent disease who have mutations in p as well as deregulated Akt and ERK pathways in their tumors In clinical trials ONC has been exceptional well tolerated possessed a therapeutic pharmacokinetic profile and exhibited sustained pharmacodynamics and anti cancer activity in advanced cancer patients No andgt Grade 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 evaluable patients in that trial there were advanced endometrial cancer patients and several exhibited clinical benefit and all expressed DRD in their archival tumor specimens Among these heavily pretreated patients the median number of prior treatments was patients had prior radiation and all patients had prior surgery After doses of ONC one patient with clear cell EC had a mixed response with andgt decrease in lymphadenopathy Two EC patients experienced prolonged stable disease lasting for and weeks including a 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 patients to determine the efficacy of ONC either as a single agent or in combination with paclitaxel Phase Aim Evaluation of preliminary single agent efficacy profile in Type II EC patients Phase Aim Determine the efficacy of ONC 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 Project Narrative This proposal seeks to develop a new cancer drug called ONC 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 years for this disease and therefore ONC represents an important treatment option for these patients