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

Prostate Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02945813
• Other study ID #: SAKK 08/15 - PROMET
• Secondary ID: 2016-003599-39
• Status: Terminated
• Phase: Phase 2
• Start date: October 24, 2017
• Est. completion date: February 28, 2022

Study information

• Verified date: April 2022
• Source: Swiss Group for Clinical Cancer Research
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 112
• Est. completion date: February 28, 2022
• Est. primary completion date: February 28, 2022
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Prostate Cancer
• Prostatic Neoplasms

Intervention

Drug:
• Metformin
850mg PO BID; 48 weeks

Radiation:
• Salvage Radiotherapy SRT
SRT 35 x 2Gy; 7 weeks

Locations

Country	Name	City	State
France	Centre Hospitalier Régional Universitaire (CHRU) Jean Minjoz	Besançon
France	Clinique Pasteur - Centre finistérien de radiothérapie et d'oncologie	Brest
France	Centre de lutte contre le cancer Léon Bérard	Lyon
France	Hôpital Saint-Louis	Paris
France	CHU de Poitiers - La Miletrie	Poitiers Cedex
France	Institut de Cancérologie de L'Ouest René Gauducheau	Saint Herblain cedex
France	Institut de Cancérologie de la Loire Lucien Neuwirth	Saint Priest en Jarez
France	Clinique Pasteur - Oncorad	Toulouse Cedex 3
Germany	Universitätsmedizin Berlin	Berlin
Germany	Klinikum der Universität München	München
Germany	Universitätsklinikum Rostock	Rostock
Germany	Universitätsklinik Tübingen	Tübingen
Germany	Universitätsklinikum Würzburg	Würzburg
Switzerland	Universitätsspital Basel	Basel
Switzerland	EOC-Istituto Oncologico della Svizzera Italiana	Bellinzona
Switzerland	Inselspital Bern	Bern
Switzerland	Kantonsspital Graubuenden	Chur
Switzerland	HFR - Hôpital cantonal	Fribourg
Switzerland	Hôpitaux Universitaires Genève HUG	Geneva
Switzerland	Clinique de Genolier	Genolier
Switzerland	Spital Thurgau	Münsterlingen
Switzerland	Hopital de Sion	Sion
Switzerland	Kantonsspital St. Gallen	St. Gallen
Switzerland	Kantonsspital Winterthur	Winterthur
Switzerland	Klinik Hirslanden	Zurich
Switzerland	Stadtspital Triemli	Zurich
Switzerland	UniversitätsSpital Zürich	Zurich

Sponsors (1)

Lead Sponsor	Collaborator
Swiss Group for Clinical Cancer Research

Countries where clinical trial is conducted

France,  Germany,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	Adverse Events (AE)	AEs will be assessed according to NCI CTCAE v4.03.	until 56 weeks (specific RT-related AEs : until 10 years)