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.