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

Inclusion Criteria:

* 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
* Female patients who are of childbearing potential: evidence of non-childbearing status, practicing practicing two medically acceptable methods of birth control since consent signature during the study and 12 months after the end of treatment
* Patients who gave its written informed consent to participate to the study
* Patients affiliated to a social insurance regime

Exclusion Criteria:

* 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.
* Concomitant treatment with vitamin K antagonists
* Patients under guardianship.

A diabetic patient may be included in the study. In that case:

\- If the patient is treated with metformin: Keep metformin at the usual dosage. There will be no prescription or dispensation in the study.

\- If the patient is being treated with another medicine (ex Stagid): Take the advice of a diabetologist or the referring physician for the patient's diabetes for the continuation of the same treatment and the addition of metformin to 500 mg/day.