Safety and Efficacy of Metronomic Cyclophosphamide, Metformin and Olaparib in Endometrial Cancer Patients

Sponsor
Hospices Civils de Lyon
Study ID
NCT02755844
Phase
PHASE1/PHASE2
Status
Completed

Conditions

  • Recurrent Endometrial Cancer

Eligibility Criteria

Sex
FEMALE
Age
18 Years - 81 Years
Healthy Volunteers
Not accepted

Interventions

  • Olaparib — DRUG
    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.
  • metformin — DRUG
    From week 3 metformin will be gradually escalated from 500 mg/day to 1500 mg/day with weekly 500 mg dose escalation levels
  • metronomic cyclophosphamide — DRUG
    from week 2 Metronomic cyclophosphamide will be given continuously on an oral daily basis at 50 mg qd

Study Details

Endometrial cancer ranks 11th in terms of incidence (7275 / year) and mortality (2025 deaths/ year). The 5-year overall survivals of patients at diagnosis with locally advanced and metastatic carcinomas are about 50% and 15% respectively. Beyond first line treatment with platinum-based chemotherapy, there is lack of effective drug in this disease, which explains the poor prognosis of patients. The prognosis of metastatic endometrial cancer patients is poor, and few drugs have been shown to be effective beyond first chemotherapy line. Endometrial carcinomas are characterized by frequent alterations of PI3K-AKT-mTor; IGF1R and of DNA repair pathways. Phosphatase and tensin homologue (PTEN)-phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTor) and DNA repair pathways interact, and inhibition of PI3K-AKT-mTor signaling pathway may alter DNA damage repair. Metronomic cyclophosphamide regimen may increase the anti-proliferative effects of olaparib because it is an alkylating agent, and it exerts anti-angiogenic effects, with a favorable toxicity profile. Metformin may increase the anti-proliferative effects of olaparib because it downregulates IGF1R and PI3K-AKT-mTor pathways, with no additive toxicity.

Key Dates

Start date
Sep 23, 2016
Status verified
Sep 2025
Primary completion
Nov 30, 2018
Completion
Jun 30, 2020

Study Design

Enrollment
35 participants (actual)
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT

Arms

  • Experimental: Olaparib, metformin and metronomic cyclophosphamide
    Phase 1: Dose escalation scheme: a continual reassessment method (CRM) will be used to guide inclusion of patients in drug dose levels pre-specified based on observations of dose-limiting toxicity. Phase 2 (expansion of cohort): once RP2D will be determined, additional patients will be enrolled, in order to obtain preliminary data about efficacy in a 2 stage Simon's design.

Primary Outcome Measure

Recommended phase 2 trial (RP2D) dose of olaparib combined to metronomic cyclophosphamide and metformin [ Time Frame: through the 6th week of treatment (cycle 1) ]

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