SAKK 08/15 - PROMET - Salvage Radiotherapy +/- Metformin for Patients With Prostate Cancer After Prostatectomy

Study Overview
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Brief Summary
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The main objective of the trial is to explore the efficacy of salvage radiotherapy (SRT) plus metformin compared to SRT in the endpoint of time to progression after prostatectomy failure.

Detailed Description
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Although the use of salvage radiotherapy (SRT) is the only potentially curative treatment after prostatectomy failure, it has provided suboptimal results over the years. Metformin may represent an effective and inexpensive means to improve SRT outcomes with a favorable therapeutic ratio. Taken pre-clinical and retrospective clinical data together, there is a compelling rationale for conducting a RCT with SRT and metformin. Herein we propose a multicenter, randomized, open-label, proof-of-concept phase II trial with the hypothesis that the addition of metformin to SRT can delay time to progression compared to the standard-of-care SRT. The study has 1:1 randomization and stratification variables include Gleason score, PSA at SRT, surgical margin status and ADT use.

Official Title
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SAKK 08/15 - PROMET - Multicenter, Randomized Phase II Trial of Salvage Radiotherapy +/- Metformin for Patients With Prostate Cancer After Prostatectomy

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Metformin
* Radiation: Salvage Radiotherapy SRT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent according to ICH/GCP regulations before registration and prior to any trial specific procedures Histologically confirmed adenocarcinoma of the prostate without small cell features Tumor stage pT2a-3b, pN0 or cN0, M0, R0-1 resection margins, according to UICC TNM 2009, Gleason score available Radical prostatectomy (RP) at least 12 weeks before registration PSA progression after RP defined as two consecutive rises with the final PSA > 0.1 ng/mL or three consecutive rises. The first value must be measured earliest 4 weeks after RP PSA ≤ 2 ng/mL within 14 days prior to registration Age ≥ 18 years at time of registration WHO performance status 0-1 Adequate hepatic function within 14 days prior to registration: bilirubin ≤ 1.5 x ULN (exception if Gilbert's syndrome ≤ 3 x ULN), AST and ALT ≤ 2.5 x ULN Adequate renal function within 14 days prior to registration: calculated corrected creatinine clearance ≥ 60 mL/min, according to the formula of corrected Cockcroft-Gault Patient agrees not to father a child and to use effective contraceptive methods during salvage radiotherapy and until 6 months after the last fraction of radiotherapy Exclusion Criteria: Persistent PSA (> 0.4 ng/mL) 4 to 20 weeks after RP Pelvic lymph node enlargement > 0.8 cm in short axis diameter (cN positive) assessed by mpMRI within 12 weeks prior to registration, unless the enlarged lymph node is sampled and negative Evidence of macroscopic local recurrence assessed by mpMRI within 12 weeks prior to registration Palpable prostatic fossa mass suggestive of recurrence, unless an ultrasound guided biopsy is negative for malignancy Presence or history of prostate cancer metastases. In case of clinical suspicion (e.g. bone pain), imaging (e.g. bone scan, Choline-PET, PSMA-PET, whole body MRI) must be performed. The imaging method is at the discretion of the investigator. If PET/CT scan was performed, any metabolic uptake considered clinically suspicious for malignancy, unless biopsy proves to be negative. History of hematologic or primary solid tumor malignancy, unless in remission for at least 3 years from registration with the exception of curatively treated localized non-melanoma skin cancer Patients diagnosed with diabetes mellitus Treatment with metformin within the last 3 months prior to registration Prior pelvic radiotherapy Hormonal treatment as bilateral orchiectomy prior or following RP Usage of products known to affect PSA levels within 4 weeks prior to start of trial treatment Bilateral hip prosthesis Severe or active co-morbidity likely to impact on the advisability of salvage RT, e.g.: History of inflammatory bowel disease or any malabsorption syndrome or conditions that would interfere with enteral absorption Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months Transmural myocardial infarction within the last 6 months Chronic Obstructive Pulmonary Disease (COPD) exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration Any condition associated with increased risk of lactic acidosis (e.g. alcohol abuse, congestive heart failure NYHA III or IV Clinically significant history of liver disease consistent with Child-Pugh Class B or C, including viral or other hepatitis, current alcohol abuse, or cirrhosis Severe or uncontrolled kidney disease resulted in impaired kidney function (GFR <60ml/min) Any acute or chronic condition that could cause tissue hypoxia (e.g. cardiac or respiratory insufficiency, recent myocardial infarction, shock) Treatment with any experimental drug or participation within a clinical trial within 30 days prior to registration (exception: concurrent participation in the biobank project SAKK 63/12 is allowed) Any concomitant drug contraindicated for use with metformin according to the approved product information Known hypersensitivity to metformin/placebo or to any of its components Hereditary intolerance to fructose; known galactose-1-phosphate uridyl transferase deficiency, UDP galactose 4 epimerase deficiency, galactokinase deficiency, Fanconi-Bickel syndrome, congenital lactase deficiency, or glucose-galactose malabsorption (due to the lactose-containing placebo) Inability or unwillingness to swallow oral medication Any other serious underlying medical, psychiatric, psychological, familial or geographical condition, which in the judgment of the investigator may interfere with the planned staging, treatment and follow-up, affect patient compliance or place the patient at high risk from treatment-related complications

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Metformin<br>Metformin - 850mg PO BID; 48 weeks Salvage radiotherapy SRT - 35 x 2Gy; 7 weeks | Drug: Metformin<br>* 850mg PO BID; 48 weeks<br>Radiation: Salvage Radiotherapy SRT<br>* SRT 35 x 2Gy; 7 weeks<br>|
| Active Comparator: Arm B: Salvage Radiotherapy<br>- Salvage radiotherapy SRT - 35 x 2Gy; 7 weeks | Radiation: Salvage Radiotherapy SRT<br>* SRT 35 x 2Gy; 7 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to progression (TTP) | The primary endpoint of the trial is time to progression (TTP), defined as time from randomization until one of the following events, whichever comes first: Biochemical progression Clinical progression Death due to clinical progression | within 18 months after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) | PFS is defined as time from randomization until one of the following events, whichever comes first: Biochemical progression Clinical progression Death from any cause | within 18 months after randomization | 
| Undetectable Prostate Specific Antigen (PSA) under normal testosterone levels | Undetectable PSA is defined as a serum PSA value of ≤0.05 ng/mL for at least two consecutive measurements after the last radiotherapy fraction and up to 18 months thereafter. To count as undetectable PSA under normal testosterone levels, the testosterone level has to be ≥50 ng/dL (i.e. a non-castrate testosterone level). | up to 18 months after last radiotherapy fraction | 
| 50% PSA response | 50% PSA response is defined as a ≥50% PSA decline after radiotherapy compared to the serum PSA level at randomization up to 18 months after last radiotherapy fraction. | at randomization up to 18 months after last radiotherapy fraction. | 
| Clinical progression-free survival | Clinical progression-free survival will be calculated as the time from randomization until clinical progression or death due to any cause. | week 64 then every 6 months for the first year and every 12 months thereafter up to 10 years from last RT fraction. | 
| Time to further anti-cancer systemic therapy | Time to further anti-cancer systemic therapy (e.g. hormonal treatment) is defined as the time from randomization to the start of any type of salvage systemic treatment. | week 64 then every 6 months for the first year and every 12 months thereafter up to 10 years from last RT fraction. | 
| Prostate cancer-specific survival (PCSS) | Prostate cancer-specific survival will be calculated as the time from randomization to the date of death due to prostate cancer. | at week 64 then every 6 months for the first year and every 12 months thereafter up to 10 years from last RT fraction. | 
| Overall survival (OS) | Overall survival will be calculated as the time from randomization to the date of death from any cause. | at week 64 then every 6 months for the first year and every 12 months thereafter up to 10 years from last RT fraction. | 
| Adverse Events (AE) | AEs will be assessed according to NCI CTCAE v4.03. | until 56 weeks (specific RT-related AEs : until 10 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prostate Cancer, Prostate Cancer after Prostatectomy, Phase II Trial, Salvage Radiotherapy, Metformin