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

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

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.

Study Overview

• Status: Completed
• Conditions: Prostate Cancer
• Intervention / Treatment: Drug: Metformin

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.

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Phase 2

Contacts and Locations

Study Locations

• Switzerland
  • Aarau, Switzerland, CH-5001
    • Kantonsspital Aarau
  • Basel, Switzerland, CH-4031
    • Universitaetsspital-Basel
  • Bern, Switzerland, CH-3010
    • Inselspital Bern
  • Chur, Switzerland, CH-7000
    • Kantonsspital Graubuenden
  • Luzerne, Switzerland, CH-6000
    • Kantonsspital Luzern
  • St. Gallen, Switzerland, CH-9007
    • Kantonsspital - St. Gallen
  • Winterthur, Switzerland, CH-8401
    • Kantonsspital Winterthur
  • Zurich, Switzerland, 8038
    • Onkozentrum
  • Zurich, Switzerland, CH-8091
    • Universitaetsspital Zuerich

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Swiss Group for Clinical Cancer Research
• Investigators: Study Chair: Richard Cathomas, MD, Kantonsspital Graubuenden; Study Chair: Christian Rothermundt, MD, Cantonal Hospital of St. Gallen; Study Chair: Silke Gillessen, MD, Cantonal Hospital of St. Gallen

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 23, 2010
• Primary Completion (Actual): April 17, 2012
• Study Completion (Actual): August 9, 2019

Study Registration Dates

• First Submitted: November 17, 2010
• First Submitted That Met QC Criteria: November 17, 2010
• First Posted (Estimate): November 18, 2010

Study Record Updates

• Last Update Posted (Actual): August 13, 2019
• Last Update Submitted That Met QC Criteria: August 12, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: stage III prostate cancer; stage IV prostate cancer; recurrent prostate cancer; adenocarcinoma of the prostate; hormone-resistant prostate cancer
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: SAKK 08/09; SWS-SAKK-08/09; CDR0000688789 (Other Identifier: CDR0000688789)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No