Metformin-Docetaxel Association in Metastatic Hormone-refractory Prostate Cancer

NCT01796028 | Completed Phase 2 DMC

• 2 other identifiers: 2012-000530-192010/35
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

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.

Conditions

Prostatic Neoplasms

Keywords

Prostate Cancer

Outcome Measures

Primary Outcomes (1)

• PSA response rate

  Time until main objective analysis is 5 years

Secondary Outcomes (1)

• Biochemical and clinical progression-free survival

  5 years

Other Outcomes (2)

• Overall survival: Overall survival will be calculated from the date of randomization to the date of death from any causes.

  5 years

• Tolerance of the association: Tolerance will be assessed according to the NCI-CTCAE scale, version 4.0.

  5 YEARS

Study Arms (2)

Arm A : TAXOTERE® + Metformin placebo

PLACEBO COMPARATOR

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

Drug: Placebo; Drug: TAXOTERE®

Arm B : TAXOTERE® + Metformin

EXPERIMENTAL

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

Drug: METFORMIN; Drug: TAXOTERE®

Interventions

METFORMIN DRUG

Also known as: GLUCOPHAGE

Arm B : TAXOTERE® + Metformin

Placebo DRUG

Arm A : TAXOTERE® + Metformin placebo

TAXOTERE® DRUG

Arm A : TAXOTERE® + Metformin placebo; Arm B : TAXOTERE® + Metformin

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \- 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Centre Antoine Lacassagne: lead

Study Sites (1)

Centre ANTOINE LACASSAGNE

Nice, 06189, France

Location

Related Publications (1)

• Pujalte Martin M, Borchiellini D, Thamphya B, Guillot A, Paoli JB, Besson D, Hilgers W, Priou F, El Kouri C, Hoch B, Deville JL, Schiappa R, Cheli S, Milano G, Tanti JF, Bost F, Ferrero JM. TAXOMET: A French Prospective Multicentric Randomized Phase II Study of Docetaxel Plus Metformin Versus Docetaxel Plus Placebo in Metastatic Castration-Resistant Prostate Cancer. Clin Genitourin Cancer. 2021 Dec;19(6):501-509. doi: 10.1016/j.clgc.2021.08.008. Epub 2021 Sep 17.

  PMID: 34629300 DERIVED

Related Links

• Related Info

MeSH Terms

Conditions

Prostatic Neoplasms

Interventions

Metformin; Docetaxel

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Diterpenes; Terpenes

Study Officials

• Jean-Marc FERRERO, PhD

  Centre Antoine Lacassagne

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 12, 2012
• First Posted: February 21, 2013
• Study Start: January 1, 2013
• Primary Completion: December 1, 2015
• Study Completion: May 31, 2018
• Last Updated: June 6, 2018

Record last verified: 2018-01

Locations

FR (1)