Metformin Hydrochloride as First-Line Therapy in Treating Patients With Locally Advanced or Metastatic Prostate Cancer

Study Overview
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Brief Summary
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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
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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.

Official Title
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Metformin in Castration Resistant Prostate Cancer. A Multicenter Phase II Trial.

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Metformin<br>Metformin at a target dose of 2 x 1000 mg daily Until progression, unacceptable toxicity or refusal | Drug: Metformin<br>* Metformin Lifelong follow-up at a target dose of 2 x 1000 mg daily Until progression, unacceptable toxicity or refusal<br>* Other names: Metformin-Mepha;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) at 12 weeks | PFS is defined as the absence of disease progression or death at 12 weeks after start of treatment. | at 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS at 24 weeks | PFS is defined as the absence of any disease progression or death at 24 weeks after start of treatment | at 24 weeks | 
| Clinical benefit rate | Clinical benefit is defined as SD by imaging and symptoms - with or without PSA progression | at 12 weeks and 24 weeks | 
| Adverse events | All AEs will be assessed according to NCI CTCAE v4.0 | from start of treatment until progression or death of any cause | 
| Prostate-specific antigen (PSA) response | 50 % PSA response is defined as a decrease in PSA level of at least 50 % (compared to baseline PSA). 30 % PSA response is defined as a decrease in PSA level of at least 30 % (compared to baseline PSA). Best response is defined as the percentage of change in PSA from baseline to the maximum decline in PSA at any point under treatment at 12 weeks or later. If there is a steady increase after baseline, the best response is defined as the percentage of change in PSA from baseline to the minimum increase in PSA at any point under treatment at 12 weeks or later. | (50% and 30%, best and at 12 weeks) | 
| Changes in PSA doubling time | PSA-DT is calculated from the natural log of 2 divided by the slope of the relationship between the log of PSA and the time of PSA measurement for each patient. | after 12 weeks, after 24 weeks and at best PSA response | 
| Tumor response of measurable disease according to RECIST v 1.1 criteria | For patients with measurable disease at baseline RECIST v1.1 will be used to define CR, PR, SD and PD. | after 12 weeks of treatment | 
| Tumor assessment of bone lesions | Bone metastases can be assessed by radionuclide bone scan. | at 12 weeks | 
| Overall survival | OS will be calculated from registration until death | from registration until death | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adenocarcinoma of the prostate, hormone-resistant prostate cancer, stage III prostate cancer, stage IV prostate cancer, recurrent prostate cancer