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

NCT02755844 | Completed Phase 1 DMC

• 1 other identifier: 69HCL15_0321
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 6

Brief Summary

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.

Conditions

Recurrent Endometrial Cancer

Keywords

endometrial carcinomas; metronomic cyclophosphamide; metformin; olaparib; dose-escalation study

Outcome Measures

Primary Outcomes (1)

• Recommended phase 2 trial (RP2D) dose of olaparib combined to metronomic cyclophosphamide and metformin

  through the 6th week of treatment (cycle 1)

Secondary Outcomes (5)

• Efficacy of olaparib combined to metronomic cyclophosphamide and metformin

  at 10 weeks

• Number of patients with adverse events relative to the study treatment olaparib combined to metronomic cyclophosphamide and metformin

  through treatment completion (a median of 12 months)

• Pharmacodynamic effects of the 3 drugs on circulating tumor DNA (ctDNA),

  through treatment completion (a median of 12 months)

• Pharmacodynamic effects of the 3 drugs on circulating Insulin Growth Factor (IGF-1)

  through treatment completion (a median of 12 months)

• Pharmacodynamic effects of the 3 drugs on circulating (Cancer Antigen) CA-125 values

  through treatment completion (a median of 12 months)

Study Arms (1)

Olaparib, metformin and metronomic cyclophosphamide

EXPERIMENTAL

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.

Drug: Olaparib; Drug: metformin; Drug: metronomic cyclophosphamide

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.

Olaparib, metformin and metronomic cyclophosphamide

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

Olaparib, metformin and metronomic cyclophosphamide

metronomic cyclophosphamide DRUG

from week 2 Metronomic cyclophosphamide will be given continuously on an oral daily basis at 50 mg qd

Olaparib, metformin and metronomic cyclophosphamide

Eligibility Criteria

• Age: 18 Years - 81 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Woman older than 18 years and younger than 81 year old
• Patients with histologically and/or cytologically documented endometrial carcinoma (type I or type II), recurrent after platinum-based chemotherapy.
• Patients with Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Archival tumor tissue available, or tumor lesion biopsy feasible
• There is no limitation to prior number of therapies
• Patients who have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
• Patients with adequate bone marrow function
• Absolute neutrophile count ≥ 1.5 x 10 9 /L
• Platelet count ≥ 100 x 10 9 /L
• Haemoglobin ≥ 9 g/dL
• Patients with adequate renal function :
• \* Calculated creatinine clearance, using the MDRD formula, according to the standardized IDMS method (http://www.sfndt.org/sn/eservice/calcul/eDFG.htm by ticking IDMS standardized measurement).\>= 60 ml/min
• Patients with adequate hepatic function
• \*Serum total bilirubin \< 1.25 x upper normal limit (UNL) and aspartate aminotransferase (AST)/Alanine Amino transferase (ALT) ≤ 2.5 X UNL (≤ 5 X UNL for patients with liver metastases)
• Patients must have a life expectancy ≥ 16 weeks

You may not qualify if:

• Illness, incompatible with metformin treatment, in particular those associated with a risk of hypoperfusion or hypoxia (not limited to): acute or chronic renal failure (creatinine clearance \< 60 ml/min, using the MDRD formula according to the standardized IDMS method); lactic ketoacidosis; septic shock; congestive heart failure; respiratory distress; liver failure; chronic alcoholism; uncontrolled seizures; age \> 80 years; allergy/hypersensitivity to metformin.
• Previous treatment with cyclophosphamide; or allergy/hypersensitivity to cyclophosphamide or one of its excipients or one of its metabolits.
• Illness incompatible with cyclophosphamide treatment: pre-existing hemorrhagic cystitis and urinary tract obstruction
• Any previous treatment with a poly-adenosine diphosphate ribose (ADP) ribose polymerase (PARP) inhibitor, including olaparib.
• Patients with second primary cancer, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for ≥ 5 years.
• Patients receiving any systemic chemotherapy, radiotherapy (except for palliative reasons), within 2 weeks from the last dose prior to study treatment. The patient can receive a stable dose of bisphosphonates for bone metastases, before and during the study as long as these were started at least 4 weeks prior to treatment with study drug.
• Concomitant use of known CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin boceprevir, telaprevir and nelfinavir and inducers such phenobarbital, phenytoin, carbamazepine, rifampicin.
• Persistent toxicities (\>=CTCAE grade 2) with the exception of alopecia, caused by previous cancer therapy.
• Treatment with other investigational agents.
• Bowel occlusive syndrome or other gastro-intestinal disorder that does not allow oral medication such as malabsorption.
• Female patients who are pregnant or lactating, Active infection to HIV, hepatitis B or C, or have other forms of hepatitis or cirrhosis.
• Symptomatic uncontrolled brain metastases. The patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 28 days prior to treatment.
• Major surgery within 14 days of starting study treatment
• Patients must have recovered from any effects of any major surgery.
• Resting ECG with corrected QT interval (QTc) \> 470msec on 2 or more time points within a 24 hour period or family history of long QT syndrome.

Sponsors & Collaborators

• Hospices Civils de Lyon: lead

Study Sites (6)

Service d'Oncologie Médicale, Centre François Baclesse

Caen, 14076, France

Location

Département de Cancérologie Cervico-Faciale et Thoracique, Centre Oscar Lambret

Lille, 59000, France

Location

Département d'Oncologie Médicale, Centre Antoine Lacassagne

Nice, 06189, France

Location

Service d'Oncologie Médicale, Institut Curie

Paris, 75248, France

Location

Centre Hospitalier Lyon Sud

Pierre-Bénite, 69495, France

Location

Comité Gynécologique, Institut Gustave Roussy

Villejuif, 94800, France

Location

Related Publications (1)

• Piffoux M, Leary A, Follana P, Abdeddaim C, Joly F, Bin S, Bonjour M, Boulai A, Callens C, Villeneuve L, Alexandre M, Schwiertz V, Freyer G, Rodrigues M, You B. Olaparib combined to metronomic cyclophosphamide and metformin in women with recurrent advanced/metastatic endometrial cancer: the ENDOLA phase I/II trial. Nat Commun. 2025 Feb 20;16(1):1821. doi: 10.1038/s41467-025-56914-7.

  PMID: 39979249 BACKGROUND

MeSH Terms

Conditions

Endometrial Neoplasms

Interventions

olaparib; Metformin

Condition Hierarchy (Ancestors)

Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Study Officials

• Benoit YOU, Doctor

  Hospices Civils de Lyon

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 14, 2016
• First Posted: April 29, 2016
• Study Start: September 23, 2016
• Primary Completion: November 1, 2018
• Study Completion: June 1, 2020
• Last Updated: October 2, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

FR (6)