Clinical trial NCT01243385: Metformin Hydrochloride as First-Line Therapy in Treating Patients With Locally Advanced or Metastatic Prostate Cancer
Official title: Metformin in Castration Resistant Prostate Cancer. A Multicenter Phase II Trial.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Prostate Cancer
Keywords: adenocarcinoma of the prostate
hormone-resistant prostate cancer
stage III prostate cancer
stage IV prostate cancer
recurrent prostate cancer
Lead sponsor: Swiss Group for Clinical Cancer Research
Sponsor class: OTHER
First posted: 2010-11-18
Enrollment: 44
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: Metformin hydrochloride may make some enzymes active. These enzymes may block other enzymes needed for cell growth and stop the growth of tumor cells.

PURPOSE: This phase II trial is studying the safety of giving metformin hydrochloride as first-line therapy in treating patients with locally advanced or metastatic prostate cancer.

Detailed description: OBJECTIVES:

* To determine the activity and safety of metformin hydrochloride as first-line therapy in patients with locally advanced or metastatic castration-resistant prostate cancer.

OUTLINE: This is a multicenter study.

Patients receive oral metformin hydrochloride twice daily on days 1-28. Treatment repeats every 4 weeks in the absence of disease progression or unacceptable toxicity.

Previously collected and post-treatment tumor tissue may be analyzed for PTEN status and PI3kinase-dependent pathway activation via immunohistochemistry. Blood samples may also be collected periodically and analyzed for biomarkers, pharmacogenetics, pharmacodynamics, pharmacokinetics.

After completion of study therapy, patients are followed up every 3 months.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically confirmed adenocarcinoma of the prostate

  * Locally advanced or metastatic disease with no curative therapy possible
* PSA progression defined as the following:

  * Increase in PSA of ≥ 25% (and an absolute increase of ≥ 2 ng/mL) over nadir value on hormonal therapy measured on 3 successive occasions at least 1 week apart

    * If the third measurement is not higher than the second, a fourth measurement will be taken and only if the fourth measurement is higher than the second, the patient may be enrolled
* PSA doubling time ≥ 55 days (if used to define progression, must not be older than 6 months)
* PSA \< 114 ng/mL
* Testosterone level ≤ 1.7 nmol/L (≤ 50 ng/dL) after at least 1 hormonal treatment (orchiectomy or luteinizing hormone-releasing hormone \[LHRH\] agonist)
* Patients who have not undergone surgical castration must continue LHRH agonist therapy during study treatment
* Oligosymptomatic or asymptomatic in relation to disease
* No known or suspected CNS metastases

PATIENT CHARACTERISTICS:

* WHO performance status 0-1
* Hemoglobin ≥ 90 g/L
* Neutrophil count ≥ 1.5 x 10\^9/L
* Platelet count ≥ 100 x 10\^9/L
* AST ≤ 2.5 times upper limit of normal (ULN)
* Bilirubin ≤ 1.5 times ULN
* Creatinine clearance ≥ 60 mL/min
* Compliant and geographically proximal for proper staging and follow-up
* No previous malignancy within the past 2 years except for localized nonmelanoma skin cancer or Ta or Tis bladder cancer
* No history of diabetic ketoacidosis, diabetic coma, or pre-coma
* No known history of HIV, hepatitis B, or hepatitis C positivity
* No known hypersensitivity to the trial drug or any of its components
* No serious underlying medical condition that, in the judgment of the investigator, would impair the ability of the patient to participate in the trial (e.g., uncontrolled or acute severe infection, uncontrolled diabetes, advanced chronic obstructive pulmonary disease \[COPD\], or heart failure)
* No psychiatric disorder precluding understanding of information on trial related topics, giving informed consent, or interfering with compliance for oral drug intake
* No known alcohol abuse

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* At least 6 weeks since prior antiandrogen therapy and without withdrawal response
* At least 30 days since prior treatment in another clinical trial
* At least 4 weeks since prior major surgery
* At least 4 weeks since prior products known to affect PSA levels
* At least 2 weeks since prior local radiation
* No prior chemotherapy, radioisotopes, small molecules, or immunotherapy for prostate cancer
* No prior metformin hydrochloride
* No concurrent pharmacotherapy for diabetes mellitus
* No concurrent finasteride, dutasteride, ketoconazole, or abiraterone acetate
* No concurrent corticosteroids with an equivalent dose of \> 7.5 mg of prednisolone
* No concurrent radiotherapy
* No bisphosphonates started after registration
* No concurrent drugs contraindicated for use with the trial drug according to the Swissmedic approved product information
* No other concurrent anticancer drugs
* No other concurrent experimental or investigational drugs

Primary outcomes:
measure: Progression-free survival (PFS) at 12 weeks
timeFrame: at 12 weeks
Secondary outcomes:
measure: PFS at 24 weeks
timeFrame: at 24 weeks
measure: Clinical benefit rate
timeFrame: at 12 weeks and 24 weeks
measure: Adverse events
timeFrame: from start of treatment until progression or death of any cause
measure: Prostate-specific antigen (PSA) response
timeFrame: (50% and 30%, best and at 12 weeks)
measure: Changes in PSA doubling time
timeFrame: after 12 weeks, after 24 weeks and at best PSA response
measure: Tumor response of measurable disease according to RECIST v 1.1 criteria
timeFrame: after 12 weeks of treatment
measure: Tumor assessment of bone lesions
timeFrame: at 12 weeks
measure: Overall survival
timeFrame: from registration until death
Other outcomes:
Locations:
city: Aarau
country: Switzerland
facility: Kantonsspital Aarau
city: Basel
country: Switzerland
facility: Universitaetsspital-Basel
city: Bern
country: Switzerland
facility: Inselspital Bern
city: Chur
country: Switzerland
facility: Kantonsspital Graubuenden
city: Luzerne
country: Switzerland
facility: Kantonsspital Luzern
city: St. Gallen
country: Switzerland
facility: Kantonsspital - St. Gallen
city: Winterthur
country: Switzerland
facility: Kantonsspital Winterthur
city: Zurich
country: Switzerland
facility: Onkozentrum
city: Zurich
country: Switzerland
facility: UniversitaetsSpital Zuerich
Study officials:
affiliation: Cantonal Hospital of St. Gallen
name: Christian Rothermundt, MD
role: STUDY_CHAIR
affiliation: Kantonsspital Graubuenden
name: Richard Cathomas, MD
role: STUDY_CHAIR
affiliation: Cantonal Hospital of St. Gallen
name: Silke Gillessen, MD
role: STUDY_CHAIR
References:
citation: Rothermundt C, Hayoz S, Templeton AJ, Winterhalder R, Strebel RT, Bartschi D, Pollak M, Lui L, Endt K, Schiess R, Ruschoff JH, Cathomas R, Gillessen S. Metformin in chemotherapy-naive castration-resistant prostate cancer: a multicenter phase 2 trial (SAKK 08/09). Eur Urol. 2014 Sep;66(3):468-74. doi: 10.1016/j.eururo.2013.12.057. Epub 2014 Jan 4.