ENDOLA : A GINECO-GINEGEPS French NCI sponsored phase I/II trial to assess the safety and efficacy of metronomic cyclophosphamide, metformin and OLAparib in recurrent advanced/metastatic ENDometrial cancer patients

Abstract

Background: Beyond first line treatment with platinum-based chemotherapy, there is lack of effective and well tolerated regimens for patients with metastatic endometrial carcinomas (EC). The combination of metronomic cyclophosphamide + metformin + olaparib may be effective because ECs are characterized by frequent alterations in the PI3K, IGF1R and f DNA repair pathways. In addition, PI3K signaling promotes effective DNA repair via homologous recombination (HR) and PI3K inhibition induces HR deficiency. Metronomic cyclophosphamide may be synergistic with olaparib via both its alkylating and anti-angiogenic effects, with a favorable toxicity profile. Finally, metformin may increase the anti-proliferative effects of olaparib because it suppresses IGF1R and PI3K-AKT-mTor pathways, with no additive toxicity. Trial design: Trial design: ENDOLA is a prospective multicenter phase I/II open-label dose-escalation study to assess the safety, the phase 2 trial recommended dose (RP2D), potential PD interactions, as well as the efficacy of olaparib combined with metronomic cyclophosphamide and metformin in patients with recurrent advanced ECs. Phase 1: Dose escalation: a continual reassessment method (CRM) will be used to guide inclusion of a maximum 23 patients in drug dose levels pre-specified based on observations of dose-limiting toxicity of olaparib. Phase 2 (expansion cohort): once RP2D is determined, additional 6 to 13 patients will be enrolled, in order to obtain preliminary data about efficacy in a 2-stage Simon's design. During cycle 1 only, the 3 drugs will be gradually given in gradual run-in periods. It will enable assessment of PD interactions induced by the 3 drugs in blood and PBMCs (PI3KCA-AKT-mTor, IGF-1 and PARP-1). Olaparib tablet dose will be dose-escalated on 4 dose levels, guided by a continual reassessment method (CRM). One cycle will be 28 days (4 weeks) in duration, except for cycle 1 which will be 6 weeks. The primary endpoint is safety based on NCICTAE v4 criteria in order to determine the RP2D.