Relapse in Previously Irradiated Prostate Bed : Stereotactic Ablative Reirradiation Potentiated by Metformin

This phase I/II escalation dose study is assessing the efficacy of the recommended dose of stereotactic re-irradiation (SBRT) of relapses within the prostatectomy bed, potentiated by metformin

The purpose of this escalation study is, first to select the recommended dose of re-irradiation SBRT in combination with Metformin (based on treatment toxicity monitoring) and then to estimate the efficacy of re-irradiation SBRT in combination with Metformin.

Five or six fractions, at a level of 5 or 6 Gray (Gy) per session (either 5 x 6 Gy, 6 x 6 Gy, or 5 x 5 Gy), will be delivered over a maximum of 12 days (from day 1 to day 10 or 12) to provide a total dose of 25 to 36 Gy.

Patient receive oral Metformin treatment from Day -15 and Day 75.

Patient will be followed for 5 years: patients visits will be planned at week 2; 4; 8; 12; and month M6; M9; M12; M18; M24; M36; 4 years and 5 years.

Eligibility Criteria:
Inclusion Criteria:

* Written informed consent according to International Conference on Harmonisation (ICH)/ Good Clinical Practice (GCP) regulations before registration and prior to any trial specific procedures.
* Biochemical recurrence occurring at least 2 years after external radiotherapy to the prostate lodge and the end of hormone therapy, for prostatic adenocarcinoma previously treated by radical prostatectomy.
* Local recurrence in irradiated areas proven by biological (PSA \> 0.2 ng/ml and ascending confirmed by at least 2 successive assays) and radiological (lesion visible on MRI and/or Choline PET and/or Prostate-Specific Membrane Antigen (PSMA) PET).
* Recurrence without rectal invasion
* Pelvic and prostate MRI evaluation
* Absence of pelvic lymph node or metastatic recurrence proven by choline PET or PSMA PET scan
* World Health Organisation (WHO) performance status 0-1
* Low risk, intermediate risk and high risk with a single risk factor
* PSA doubling time \> 6 months
* No anti-cancer treatments planned for the current relapse, including hormone therapy.
* Age \> 18 years old.
* Life expectancy greater than or equal to 5 years.
* Patient registered with a health insurance system.
* Patients willing and able to comply with the planned visits, treatment plan, laboratory tests and other study procedures indicated in the protocol.

Exclusion Criteria:

* Metastatic disease (bone, lymph node or other)
* Late radiotherapy urinary or gastrointestinal toxicity (grade ≥ 2) (after radiotherapy of prostate lodge)
* History of cancer in the 5 years prior to trial entry other than cutaneous basal cell carcinoma
* Inflammatory bowel disease
* Contraindications for performing MRI
* Rectal surgery history
* Patient treated for Diabetes
* Creatinine clearance \< 45 mL/min
* Treatment with metformin in the last 3 months prior to inclusion
* Severe comorbidity that may affect treatment, for example :

  * Acute bacterial or fungal infection requiring intravenous antibiotics at the time of inclusion.
  * Unstable angina, myocardial infarction and/or congestive heart failure requiring hospitalization within the last 6 months
  * Myocardial infarction in the last 6 months.
  * Exacerbation of Chronic Obstructive Pulmonary Disease (COPD) or other respiratory conditions requiring hospitalization or preventing metformin therapy at the time of inclusion.
* Any condition associated with an increased risk of lactic acidosis (e.g., alcohol abuse, New York Heart Association (NYHA) III or IV congestive heart failure).
* Clinically significant history of hepatopathy with Child-Pugh B or C score, including viral infection or hepatitis, alcohol abuse or cirrhosis.
* Any acute or chronic condition that may result in tissue hypoxia (e.g. heart or respiratory failure, shock).
* Bilateral hip prosthesis
* Treatment with any investigational drug or participation in a clinical trial within 30 days prior to inclusion.
* Known hypersensitivity to metformin or any of its components
* Inability or reluctance to swallow oral medications
* Persons deprived of liberty, under a measure of safeguard of justice, under guardianship or under the tutor authority
* Inability to undergo medical monitoring of the trial for geographical, social or psychological reasons.