Safety and Efficacy of Metronomic Cyclophosphamide, Metformin and Olaparib in Endometrial Cancer Patients (ENDOLA)
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|ClinicalTrials.gov Identifier: NCT02755844|
Recruitment Status : Not yet recruiting
First Posted : April 29, 2016
Last Update Posted : April 29, 2016
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.
|Condition or disease||Intervention/treatment||Phase|
|Recurrent Endometrial Cancer||Drug: Olaparib Drug: metformin Drug: metronomic cyclophosphamide||Phase 1 Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||36 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase I/II Trial to Assess the Safety and Efficacy of Metronomic Cyclophosphamide, Metformin and Olaparib in Recurrent Advanced/Metastatic Endometrial Cancer Patients|
|Study Start Date :||April 2016|
|Estimated Primary Completion Date :||April 2018|
|Estimated Study Completion Date :||November 2019|
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.
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.
From week 3 metformin will be gradually escalated from 500 mg/day to 1500 mg/day with weekly 500 mg dose escalation levels
Drug: metronomic cyclophosphamide
from week 2 Metronomic cyclophosphamide will be given continuously on an oral daily basis at 50 mg qd
- Recommended phase 2 trial (RP2D) dose of olaparib combined to metronomic cyclophosphamide and metformin [ Time Frame: through the 6th week of treatment (cycle 1) ]
- Efficacy of olaparib combined to metronomic cyclophosphamide and metformin [ Time Frame: at 10 weeks ]non-progression rate at 10 weeks, calculated as the combination of stable disease, partial response and complete response defined according to RECIST v.1.1
- Number of patients with adverse events relative to the study treatment olaparib combined to metronomic cyclophosphamide and metformin [ Time Frame: through treatment completion (a median of 12 months) ]All adverse events relative to the study treatment will be recorded (NCI- Common Terminology for Adverse Events (CTAE) v.4 criteria) during the treatment.
- Pharmacodynamic effects of the 3 drugs on circulating tumor DNA (ctDNA), [ Time Frame: through treatment completion (a median of 12 months) ]The kinetics of circulating tumor DNA (ctDNA), serially measured will be assessed using population kinetic approach and mathematical modeling
- Pharmacodynamic effects of the 3 drugs on circulating Insulin Growth Factor (IGF-1) [ Time Frame: through treatment completion (a median of 12 months) ]The kinetics of Insulin Growth Factor (IGF-1) values serially measured will be assessed using population kinetic approach and mathematical modeling
- Pharmacodynamic effects of the 3 drugs on circulating (Cancer Antigen) CA-125 values [ Time Frame: through treatment completion (a median of 12 months) ]The kinetics of (Cancer Antigen) CA-125 values serially measured will be assessed using population kinetic approach and mathematical modeling
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02755844
|Contact: Benoit YOU, Doctor||4 788 643 18 ext +firstname.lastname@example.org|
|Contact: Marine DUPUIS||4 788 612 25 ext +email@example.com|
|Centre Hospitalier Lyon Sud||Not yet recruiting|
|Pierre Benite, France, 69495|
|Contact: Benoit YOU|
|Contact: Marine DUPUIS|
|Principal Investigator: Benoit YOU, MD|
|Principal Investigator:||Benoit YOU, Doctor||Hospices Civils de Lyon|