Clinical trial NCT02945813: SAKK 08/15 - PROMET - Salvage Radiotherapy +/- Metformin for Patients With Prostate Cancer After Prostatectomy
Official title: SAKK 08/15 - PROMET - Multicenter, Randomized Phase II Trial of Salvage Radiotherapy +/- Metformin for Patients With Prostate Cancer After Prostatectomy
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Prostate Cancer
Keywords: Prostate Cancer
Prostate Cancer after Prostatectomy
Phase II Trial
Salvage Radiotherapy
Metformin
Lead sponsor: Swiss Group for Clinical Cancer Research
Sponsor class: OTHER
First posted: 2016-10-26
Enrollment: 112
Sex: MALE
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Time to progression (TTP)
timeFrame: within 18 months after randomization
Secondary outcomes:
measure: Progression free survival (PFS)
timeFrame: within 18 months after randomization
measure: Undetectable Prostate Specific Antigen (PSA) under normal testosterone levels
timeFrame: up to 18 months after last radiotherapy fraction
measure: 50% PSA response
timeFrame: at randomization up to 18 months after last radiotherapy fraction.
measure: Clinical progression-free survival
timeFrame: week 64 then every 6 months for the first year and every 12 months thereafter up to 10 years from last RT fraction.
measure: Time to further anti-cancer systemic therapy
timeFrame: week 64 then every 6 months for the first year and every 12 months thereafter up to 10 years from last RT fraction.
measure: Prostate cancer-specific survival (PCSS)
timeFrame: at week 64 then every 6 months for the first year and every 12 months thereafter up to 10 years from last RT fraction.
measure: Overall survival (OS)
timeFrame: at week 64 then every 6 months for the first year and every 12 months thereafter up to 10 years from last RT fraction.
measure: Adverse Events (AE)
timeFrame: until 56 weeks (specific RT-related AEs : until 10 years)
Other outcomes:
Locations:
city: Besançon
country: France
facility: Centre Hospitalier Régional Universitaire (CHRU) Jean Minjoz
city: Brest
country: France
facility: Clinique Pasteur - Centre finistérien de radiothérapie et d'oncologie
city: Lyon
country: France
facility: Centre de lutte contre le cancer Léon Bérard
city: Paris
country: France
facility: Hôpital Saint-Louis
city: Poitiers Cedex
country: France
facility: CHU de Poitiers - La Miletrie
city: Saint Herblain cedex
country: France
facility: Institut de Cancérologie de L'Ouest René Gauducheau
city: Saint Priest en Jarez
country: France
facility: Institut de Cancérologie de la Loire Lucien Neuwirth
city: Toulouse Cedex 3
country: France
facility: Clinique Pasteur - Oncorad
city: Berlin
country: Germany
facility: Universitätsmedizin Berlin
city: München
country: Germany
facility: Klinikum der Universität München
city: Rostock
country: Germany
facility: Universitätsklinikum Rostock
city: Tübingen
country: Germany
facility: Universitätsklinik Tübingen
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg
city: Basel
country: Switzerland
facility: Universitätsspital Basel
city: Bellinzona
country: Switzerland
facility: EOC-Istituto Oncologico della Svizzera Italiana
city: Bern
country: Switzerland
facility: Inselspital Bern
city: Chur
country: Switzerland
facility: Kantonsspital Graubuenden
city: Fribourg
country: Switzerland
facility: HFR - Hôpital cantonal
city: Geneva
country: Switzerland
facility: Hôpitaux Universitaires Genève HUG
city: Genolier
country: Switzerland
facility: Clinique de Genolier
city: Münsterlingen
country: Switzerland
facility: Spital Thurgau
city: Sion
country: Switzerland
facility: Hopital de Sion
city: St. Gallen
country: Switzerland
facility: Kantonsspital St. Gallen
city: Winterthur
country: Switzerland
facility: Kantonsspital Winterthur
city: Zurich
country: Switzerland
facility: Klinik Hirslanden
city: Zurich
country: Switzerland
facility: Stadtspital Triemli
city: Zurich
country: Switzerland
facility: UniversitätsSpital Zürich
Study officials:
affiliation: Bern University Hospital - Radiation Oncology
name: Daniel M. Aebersold, Prof
role: STUDY_CHAIR
affiliation: Miller School of Medicine, University of Miami
name: Alan Dal Pra, MD
role: STUDY_CHAIR
References: