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

Study Overview
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Brief Summary
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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

Detailed Description
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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.

Official Title
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Relapse in Previously Irradiated Prostate Bed : a Phase I/II Study of Stereotactic Ablative Reirradiation Potentiated by Metformin

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Metformin
* Radiation: Stereotactic Body Radiation Therapy (SBRT) 30 Gray (Gy)
* Radiation: Stereotactic Body Radiation Therapy (SBRT) 36 Gy
* Radiation: Stereotactic Body Radiation Therapy (SBRT) 25 Gy


Participation Criteria
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Eligibility Criteria
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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 of the prostate lodge and/or 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 2 successive assays) and radiological (lesion visible on MRI and/or Choline PET and/or Prostate-Specific Membrane Antigen (PSMA) PET) or histological examinations. Recurrence without rectal invasion Remote recurrence from vesico-urethral anastomosis (> 10 mm) to limit urinary toxicity Macroscopic Target Volume (GTV) ≤ 27cm3 to limit toxicity 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 PSA ≤ 10 ng / ml 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 Volume of the GTV > 27 cm3 Presence of grade 3 rectal telangiectasia classified by the Vienna Rectoscopy score (Rectoscopy required) (Appendix 7) Rectal surgery history Diabetic patient with HBA1C > laboratory normal value 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin + SBRT at total dose of 30 Gray (Gy)<br>Metformin: 850 mg per day (day -15 to day 0) 1700 mg per day (day 1 to day 75) Stereotactic Body Radiation Therapy (SBRT): Dose escalation 5 x 6 Gy, (day 0 to day 10) | Drug: Metformin<br>* Metformin: 850 mg per day (day -15 to day 0) 1700 mg per day (day 1 to day 75)<br>Radiation: Stereotactic Body Radiation Therapy (SBRT) 30 Gray (Gy)<br>* Stereotactic Body Radiation Therapy (SBRT): Dose escalation 5 x 6 Gy day 0 to day 10<br>* Other names: SBRT;|
| Experimental: Metformin + SBRT at total dose of 36 Gy<br>Metformin: 850 mg per day (day -15 to day 0) 1700 mg per day (day 1 to day 75) Stereotactic Body Radiation Therapy (SBRT): Dose escalation 6 x 6 Gy (day 0 to day 12) | Drug: Metformin<br>* Metformin: 850 mg per day (day -15 to day 0) 1700 mg per day (day 1 to day 75)<br>Radiation: Stereotactic Body Radiation Therapy (SBRT) 36 Gy<br>* Stereotactic Body Radiation Therapy (SBRT): Dose escalation 6 x 6 Gy day 0 to day 12<br>* Other names: SBRT;|
| Experimental: Metformin + SBRT at total dose of 25 Gy<br>Metformin: 850 mg per day (day -15 to day 0) 1700 mg per day (day 1 to day 75) Stereotactic Body Radiation Therapy (SBRT): Dose escalation 5 x 5 Gy (day 0 to day 10) | Drug: Metformin<br>* Metformin: 850 mg per day (day -15 to day 0) 1700 mg per day (day 1 to day 75)<br>Radiation: Stereotactic Body Radiation Therapy (SBRT) 25 Gy<br>* Stereotactic Body Radiation Therapy (SBRT): Dose escalation 5x 5 Gy day 0 to day 10<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| For phase 1:. Select the recommended dose for SBRT (either 5 x 6 Gy, 6 x 6 Gy, or 5 x 5 Gy), in combination with Metformin | SBRT toxicity will be reported during the 12 weeks following the initiation of SBRT. | 12 weeks | 
| For phase 2: estimate the efficacy of re-irradiation SBRT in combination with Metformin in terms of biochemical relapse-free survival rate. | PSA levels will be assessed every 3 months within 3 years after SBRT. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimate the efficacy of re-irradiation SBRT in combination with Metformin in terms of biochemical relapse-free survival and biochemical response | PSA levels will be assessed every 3 months within 5 years after SBRT. For all patients, visits will be made at 6, 9, 12, 18, 24, 36 months, 4 years, and 5 years will be made from the start of SBRT. The end of the trial is defined by the last visit of the last included patient. | 5 years | 
| Estimation of the efficacy of SBRT re-irradiation in combination with Metformin in terms of progression-free survival and overall survival | Clinical progression-free survival is defined as the time interval between the date of SBRT start and the date of clinical progression (local progression assessed by the physical examination, or appearance of metastatic lesions), start of hormonal therapy or death irrespective of the cause. | 5 years | 
| Evaluation of acute and late genitourinary and gastrointestinal toxicities of the SBRT re-irradiation | Acute and late genitourinary toxicities over the first 5 years will be assessed according to the NCI-CTCAE V5.0 classification | 5 years | 
| Evaluation of Quality of life after SBRT re-irradiation in combination with Metformin | Quality of life will be assessed based on EORTC Quality of life questionnaire (QLQ)-C30 scale at week 4; 8; 12; and month M6; M9; M12; M18; M24; M36; 4 years and 5 years. The Time Until Definitive Deterioration (TUDD) will be computed from registration until the first observation of a definitive deterioration of the quality of life, defined as a score decreased by 10 points (in the case of global health scale and functional scales) or increased by 10 points (in the case of symptom scales) compared to the score at baseline, without later improvement superior to 10 points compared to baseline score. | 5 years | 
| Evaluation of Quality of life after SBRT re-irradiation in combination with Metformin | Quality of life will be assessed based on EORTC Quality of life questionnaire in prostate cancer (QLQ-PR25) scale at week 4; 8; 12; and month M6; M9; M12; M18; M24; M36; 4 years and 5 years. The Time Until Definitive Deterioration (TUDD) will be computed from registration until the first observation of a definitive deterioration of the quality of life, defined as a score decreased by 10 points (in the case of global health scale and functional scales) or increased by 10 points (in the case of symptom scales) compared to the score at baseline, without later improvement superior to 10 points compared to baseline score. | 5 years | 
| Evaluation of urinary symptoms | Urinary symptoms over the first 5 years will be assessed by Internationnal Prostatic Symptom Score (IPSS). This score evaluates the severity of prostate symptoms in the last month on a scale of 0 to 35 (total of 7 items rated 0 to 5).The distributions of this score will be described at inclusion, at follow-up visits (M6 M9 M12 M18 M24 M36 4 and 5 years) and at the end of the study visit according to the following categories: 0 - 7: Poorly symptomatic ; 8 - 19: Moderately symptomatic ; 20 - 35: Severe symptoms. | 5 years | 
| Evaluation of erectile function | Erectile function will be assessed by International Index of Erectile Function (IIEF5). This score assesses erectile function over the past 6 months on a scale of 1 to 25 (total of 5 items rated 0/1 to 5). The distributions of this score will be described at baseline, at follow-up visits (M6 M12 M18, M24,M36 4 and 5 years old) and at the end of the study visit according to the following categories: 1 - 4: Non-interpretable ; 5 - 10: Severe erectile dysfunction ; 11 - 15: Moderate erectile dysfunction ; 16 - 20: Mild erectile dysfunction ; 21 - 25: Normal erectile function. | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prostate Cancer, Stereotactic Body Radiation Therapy, SBRT, Metformin, Previously Irradiated Prostate Bed, Biochemical recurrence