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

Phase 1

Recruiting

• Conditions: Prostate Cancer
• Interventions: 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

• Registration Number: NCT04536805
• Lead Sponsor: Institut Cancerologie de l'Ouest

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2020-08-17
• Study First Submitted QC: 2020-08-27
• Study First Posted: 2020-09-03
• Study Start: 2020-11-17
• Status Verified: 2024-02
• Last Update Submitted: 2024-03-11
• Last Update Posted: 2024-03-13
• Primary Completion: 2028-11
• Study Completion: 2030-11

Recruitment & Eligibility

• Status: RECRUITING
• Sex: Male
• Target Recruitment: 44

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Metformin + SBRT at total dose of 30 Gray (Gy)	Metformin	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)
Metformin + SBRT at total dose of 30 Gray (Gy)	Stereotactic Body Radiation Therapy (SBRT) 30 Gray (Gy)	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)
Metformin + SBRT at total dose of 36 Gy	Stereotactic Body Radiation Therapy (SBRT) 36 Gy	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)
Metformin + SBRT at total dose of 25 Gy	Stereotactic Body Radiation Therapy (SBRT) 25 Gy	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)
Metformin + SBRT at total dose of 36 Gy	Metformin	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)
Metformin + SBRT at total dose of 25 Gy	Metformin	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)

Primary Outcome Measures

Name	Time	Method
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	12 weeks	SBRT toxicity will be reported during the 12 weeks following the initiation of SBRT.
For phase 2: estimate the efficacy of re-irradiation SBRT in combination with Metformin in terms of biochemical relapse-free survival rate.	3 years	PSA levels will be assessed every 3 months within 3 years after SBRT.

Secondary Outcome Measures

Name	Time	Method
Estimate the efficacy of re-irradiation SBRT in combination with Metformin in terms of biochemical relapse-free survival and biochemical response	5 years	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.
Estimation of the efficacy of SBRT re-irradiation in combination with Metformin in terms of progression-free survival and overall survival	5 years	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.
Evaluation of acute and late genitourinary and gastrointestinal toxicities of the SBRT re-irradiation	5 years	Acute and late genitourinary toxicities over the first 5 years will be assessed according to the NCI-CTCAE V5.0 classification
Evaluation of Quality of life after SBRT re-irradiation in combination with Metformin	5 years	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.
Evaluation of urinary symptoms	5 years	Urinary symptoms over the first 5 years will be assessed by International 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.
Evaluation of erectile function	5 years	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.

Trial Locations

Locations (11)

Institut de Cancerologie de L'Ouest; 🇫🇷 Saint Herblain, France

Centre OSCAR LAMBRET; 🇫🇷 Lille, France

Clinique Victor Hugo; 🇫🇷 Le Mans, France

ICANS - Institut de cancérologie Strasbourg Europe; 🇫🇷 Strasbourg, France

Chru Bretonneau; 🇫🇷 Tours, France

Centre LEON BERARD; 🇫🇷 Lyon, France

CHRU de BREST - HOPITAL MORVAN; 🇫🇷 Brest, France

Centre Eugene Marquis; 🇫🇷 Rennes, France

Centre Henri Becquerel; 🇫🇷 Rouen, France

Centre GEORGES FRANCOIS LECLERC; 🇫🇷 Dijon, France

Societe de Recherche Oncologique Clinique 37 (Roc 37); 🇫🇷 Chambray-lès-Tours, France