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.

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.

Men

Individual participant data that underlie the results reported in the primary study manuscript after deidentification (text, tables, figures and appendices)

Beginning 6 months and ending 3 years following article publication

Researchers who provide a methodologically sound proposal not overlapping with any planned secondary publications from the research team will be able to access the IPD. To achieve aims in the approved proposal. Proposals should be directed to Chief Investigator who will discuss such requested with the Department of Clinical Research and Innovation (DRCI):

Valentine.guimas@ico.unicancer.fr. To gain access, data requesters will need to sign a data access agreement. Data will be available for 3 years at Institut de Cancérologie de l'Ouest.