A Multicentric, Randomized, Phase II Study Evaluating the Combination of METFORMIN With TAXOTERE®+Metformine Placebo Versus TAXOTERE®+Metformin for the Treatment of Metastatic Hormone-refractory Prostate Cancer.
Trial Snapshot
- Phase
- Phase 2
- Status
- Completed
- Sponsor
- Centre Antoine Lacassagne
- Enrollment
- 100
- Locations
- 1
- Primary Endpoint
- PSA response rate
Study Overview
Brief Summary
Prostate cancer is the second leading cause of mortality in men, representing 10 deaths about of 100 cancers (INVS 2009). Treatment for metastatic prostate cancer, when becoming resistant to hormone-treatment, is mostly resumed to a relatively ineffective chemotherapy (Docetaxel/TAXOTERE®) (1). Recently, numerous clinical and preclinical works showed that Metformin could represent an excellent candidate for treatment of advanced prostate cancer. This is a widely prescribed drug, for type 2 diabetes, with clinical advantage of exhibiting very rare serious side effects. On the other hand, the use of this molecule in patients was associated with a decrease of tumors incidence, in particular prostate cancer (2). Numerous in vitro and in vivo studies support its role as an anti-cancer drug, in several cell lines (3). These experimental results are consistent with a clinical trial pilot study, performed in colorectal cancer, showing anti proliferative effect of Metformin (4). In the field of prostate, F. Bost in J.F. Tanti's team (INSERM U895, Nice) demonstrated that Metformin inhibits cell viability of human prostate cancer cells, via mTOR downregulation and decrease tumor growth in a xenograft model (5). Furthermore, preclinical data performed by this team showed that Metformin increased significantly apoptosis induced by TAXOTERE®. Therefore, by targeting specifically cancer cell metabolism, Metformin offers new promising therapeutic strategy.
The primary objective of this randomized study is to evaluate the biological efficacy of Metformin combination with TAXOTERE® in patients with metastatic hormone-refractory prostate cancer. To achieve this purpose, PSA response rate will be evaluated according to ASTRO definitions (Bubley, Carducci et al. 1999). Concurrently, secondary endpoints will be under investigation in order to evaluate the clinical response according to RECIST criteria, the overall and free-progression survival and the quality of life. Toxicity assessment will also be performed regarding to this drug combination.
Considering the well tolerability of Metformin and the first clinical and pre-clinical data reports of it use in cancer treatment, combining Docetaxel (TAXOTERE®) with Metformin may represent a promising strategy for treatment of hormone-refractory prostate cancer.
Detailed Description
Prostate cancer: the current issues In developed countries, prostate cancer represents a major health issue and its incidence is rising globally, due to an aging society (Ferlay, Autier et al. 2007; Damber and Aus 2008). Indeed, over 70% of patients with prostate cancer are over the age of 65 years (Quinn and Babb 2002). In France, prostate cancer is the second most common cause of death from cancer in men and represents 10 deaths about of 100 by cancer (INVS 2009).
Although the screening and early detection have improved, a significant percentage of men diagnosed with prostate cancer will develop metastasis, reducing dramatically the 5-year relative survival (Jemal, Thun et al. 2008).
For patients with metastatic prostate cancer, the first-line treatment relies on androgen suppression following medical therapy or surgical orchiectomy. In about 80 percent of men, androgen ablation leads to symptomatic improvement; however, despite this treatment, the risk of relapse is at a median period of 24 months following hormone manipulation and the survival median is at about 3 years (1995; Sharifi, Dahut et al. 2005).
Clinical management of Castration-Resistant Prostate Cancer:
Currently, treatment for metastatic prostate cancer, when becoming unresponsiveness to androgen deprivation therapy, is mostly resumed to a relatively ineffective chemotherapy. Indeed, this disease state is considered the final stage of the disease in which the morbidity and mortality outlook is extremely bleak, and therapeutic options remain only palliative.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- Male
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •- Age > 18 years
- •Histologically confirmed prostate adenocarcinoma.
- •Karnofsky Performance Score > 50%
- •Evidence of metastatic disease by the presence of documented locoregional or distant metastases on CT scan of the abdomen and/or pelvis, or bone scintigraphy
- •Hormone Resistance Prostate Cancer defined as an increase in PSA level (3 consecutive measurements) after hormonal treatment (surgical castration or androgen blockade)
- •No prior chemotherapy (excepted phosphate estramustine or Estracyt®)
- •At least one month had to have elapsed between the withdrawal of antiandrogens and enrolment, except LH-RH agonist therapy that must be continued throughout this study.
- •Hormonal castration confirmed biologically (testosterone < 0.5 ng/ml)
- •Patient with adequate organ function:
- •Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
- •Haemoglobin ≥ 9 g/dL
- •Platelets (PTL) ≥ 100 x 109/L
- •AST - ALAT ≤ 2.5x ULN
- •Bilirubin ≤ 1.5 x ULN
- •Creatinine < 150 µmol/l
- •Alkaline phosphatases ≤ 2,5 x ULN
- •Patient with life expectancy > 3 months
- •Information delivered to patient and informed consent signed by the patient or legal representative
- •Patient affiliated with a health insurance system
Exclusion Criteria
- •The patient with at least one of the following criteria could not be included:
- •Age < 18 years
- •Patient with type II or type I diabetes
- •Excessive alcohol intake, acute or chronic.
- •Patients already treated with Metformin or an analog
- •Known hypersensitivity or allergy to Metformin HCl or any of the excipients.
- •Patients with a history of lactic acidosis
- •PSA increasement without lesions confirmed by radiography and/or bone scan.
- •Testosteronemia > 0.5 ng/ml
- •Any radiation within 4 weeks prior to study entry
- •Strontium 89 administration within 3 month before inclusion
- •Patient with active central nervous system (CNS) metastasis or with history of CNS metastasis
- •Peripheral neuropathy with grade > 3 (NCI), unrelated to cancer.
- •Patient treated for a cancer other than prostate cancer, with the exception of basal cell carcinoma
- •Treatment with any investigational agent
- •Treatment on another therapeutic clinical trial within 30 days before enrolment
- •Acute or chronic metabolic acidosis
- •Patients suffering from severe dehydration
- •Permanent contraindication to corticosteroids
- •Patient with history of poor compliance or current or past psychiatric conditions or severe acute or chronic medical conditions that would interfere with the ability to comply with the study protocol, such as completion of QoL questionnaire.
- •Patient enable to give informed consent
Arms & Interventions
Arm A : TAXOTERE® + Metformin placebo
Docetaxel (TAXOTERE®) will be administered at 75 mg/m2. Metformin (or placebo) is formulated into 850 mg tablets for oral administration and is to be dispensed twice a day on a continuous daily dosing schedule
Intervention: Placebo (Drug)
Arm A : TAXOTERE® + Metformin placebo
Docetaxel (TAXOTERE®) will be administered at 75 mg/m2. Metformin (or placebo) is formulated into 850 mg tablets for oral administration and is to be dispensed twice a day on a continuous daily dosing schedule
Intervention: TAXOTERE® (Drug)
Arm B : TAXOTERE® + Metformin
Docetaxel (TAXOTERE®) will be administered at 75 mg/m2. Metformin is formulated into 850 mg tablets for oral administration and is to be dispensed twice a day on a continuous daily dosing schedule
Intervention: METFORMIN (Drug)
Arm B : TAXOTERE® + Metformin
Docetaxel (TAXOTERE®) will be administered at 75 mg/m2. Metformin is formulated into 850 mg tablets for oral administration and is to be dispensed twice a day on a continuous daily dosing schedule
Intervention: TAXOTERE® (Drug)
Outcomes
Primary Outcomes
PSA response rate
Time Frame: Time until main objective analysis is 5 years
Secondary Outcomes
- Biochemical and clinical progression-free survival(5 years)