Clinical trial NCT00541281: Safety and Efficacy Study of of Docetaxel vs Docetaxel Estramustine in Hormone Refractory Prostatic Cancer
Official title: Randomized Phase Ii Trial Of Weekly Docetaxel, Estramustine And Prednisone Versus Docetaxel And Prednisone In Patient With Hormone-Resistant Prostate Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hormone Resistant Prostate Cancer
Metastatic Prostate Cancer
Keywords: prostate cancer
hormone resistant
metastatic
estramustine combine to docetaxel
randomized study
Lead sponsor: Cliniques universitaires Saint-Luc- Université Catholique de Louvain
Sponsor class: OTHER
Collaborators: name: Sanofi
First posted: 2007-10-10
Enrollment: 150
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: we propose to randomize patients with hormone resistant prostate cancer between docetaxel/estramustine/prednisone and docetaxel/prednisone in a phase II study. The principal endpoint will be the efficacy in term of PSA response.

Detailed description: The addition of estramustine to other chemotherapeutic agents that affect microtubule function may improve their efficacy15, 16, 17, 18. A phase III trial compared vinblastine versus the combination of vinblastine plus estramustine as treatment for patients with hormone-refractory prostate cancer. They showed that the association of estramustine and vinblastine was superior to vinblastine alone for time to progression, PSA response and survival (Hudes et al., ASCO 2002). In addition, Berry et al. found that estramustine/paclitaxel improved PSA response rate but not overall survival compared with paclitaxel alone (Berry et al. ASCO2001).

Similar association has been studied with docetaxel. In a phase I trial combining docetaxel and estramustine19, 53% of patients reported a decrease in narcotic use and 63% experienced a PSA response. In another phase I trial, a reduction in PSA of 50% or more was observed in 14 of 17 patients (82%)20. In a phase II trial involving 35 patients, a PSA response was reported in 74% of the patients and objective response in 4 out of 7 patients with measurable disease21. Median survival 22 months in this last study. These studies as well as other support the combination of estramustine and docetaxel in the treatment of HRPC22, 23.

Recently, Oudard et al. competed a phase II randomized study comparing mitoxantrone/prednisone versus docetaxel/estramustine prednisone24. Docetaxel was given either weekly or every 3 weeks. Association of docetaxel/estramustine was found superior to mitoxantrone in term of PSA response, (67-63% versus 18%), clinical benefit (79-56% versus 41%) and survival (19.2 months versus 11.6 months). In addition, toxicities of these regimens were manageable and predictable. In this study, patients received 2 mgr of coumadin to prevent thromboembolic event due to estramustine and only 7 % of the patients had thrombosis. Other grade III \& IV toxicities of the estramustine/docetaxel combination included neutropenia (37% in the 3-week regimen and 0 % in the weekly regimen) nausea/vomiting (2% in the 3-week regimen and 0 % in the weekly regimen), diarrhea (7% in the 3-week regimen and 0 % in the weekly regimen). No febrile neutropenia was observed.

Although these data support a role for chemotherapy combinations, such as estramustine and docetaxel, in the treatment of HRPC, further studies are needed to determine the relative contribution of estramustine to the efficacy of docetaxel/estramustine regimen. In this context, we propose to randomize patients with hormone resistant prostate cancer between docetaxel/estramustine/prednisone and docetaxel/prednisone in a phase II study. The principal endpoint will be the efficacy in term of PSA response. We chose to use the weekly regimen as described by Oudard since the toxicity of this regimen is well described and is easily manageable in our experience.

Eligibility criteria: Inclusion Criteria:

* Signed informed consent prior to beginning protocol specific procedures.
* 18 years
* Histologically/cytologically proven prostate adenocarcinoma.
* Documented metastatic prostate adenocarcinoma
* Patients must have received prior hormonal therapy as defined below:
* Castration by orchiectomy and/or LHRH agonists with or without
* Antiandrogens
* Other hormonal agents (e.g., ketoconazole, ...)
* Testosterone level should be \< 50 ng/dl in all patients (castrated level).
* Respect of antiandrogen withdrawal period
* No prior chemotherapy regimen at the exception of estramustine phosphate.
* documented disease progression defined either (i) by PSA increase and/or (ii) imaging:
* Prior radiation therapy (to less or equal than 25% of the bone marrow only) is allowed. At least 4 weeks must have elapsed since the completion of radiation therapy and the patient must have recovered from side effects.
* Prior surgery is allowed. At least 4 weeks must have elapsed since the completion of surgery.
* Life expectancy \> 3 months.
* ECOG performance status 0-2.
* Normal cardiac function.

Exclusion Criteria:

* Prior chemotherapy except estramustine phosphate.(2)
* Prior isotope therapy
* Prior radiotherapy to \>25% of bone marrow
* Prior malignancy except the following: adequately treated basal cell or squamous cell skin cancer, or any other cancer from which the patient has been disease-free for \>5 years.
* Known brain or leptomeningeal involvement.
* Symptomatic peripheral neuropathy \> grade 2
* Other serious illness or medical condition
* Concurrent treatment with other experimental drugs.
* Treatment with any other anti-cancer therapy (except LHRH agonists)
* Treatment with systemic corticosteroids used for reasons other than specified by the protocol must be stopped prior to the administration of docetaxel.

Primary outcomes:
measure: To compare the efficacy of the association of Docetaxel and Estramustineand Prednisone versus Docetaxel and Prednisone in the treatment of hormone refractory prostate cancer in terms o PSA response
timeFrame: within 30 days after end of treatment
Secondary outcomes:
measure: PSA response Time to PSA progression PSA response duration Event Progression-Free Survival Overall survival Palliative response (Pain) Safety Objective response measurable disease (RECIST)
timeFrame: untill death occurs
Other outcomes:
Locations:
city: Ottignies
country: Belgium
facility: St Pierre
state: Brabant Wallon
city: Charleroi
country: Belgium
facility: Notre Dame et Reine Fabiola
state: Hainaut
city: Baudour
country: Belgium
facility: RHMS louis caty
city: Bouge
country: Belgium
facility: Clinique Saint Luc
city: Boussu
country: Belgium
facility: CHR Warquignies
city: Brasschaat
country: Belgium
facility: Az klina
city: Brussels
country: Belgium
facility: Parc Léopold
city: Bruxelles
country: Belgium
facility: Hôpitaux IRIS Sud
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires St luc
city: Eupen
country: Belgium
facility: Sint Nilolaus
city: Gilly
country: Belgium
facility: Clinique St Joseph
city: Gosselies
country: Belgium
facility: Notre Dame de Grâce
city: La-Louvière
country: Belgium
facility: CH Jolimont Lobbes
city: Liège
country: Belgium
facility: St Joseph
city: Mons
country: Belgium
facility: CHU Ambroise paré
city: Namur
country: Belgium
facility: clinique Sainte Elisabeth
city: Tournai
country: Belgium
facility: Notre Dame
city: Yvoir
country: Belgium
facility: Clinique Universitaire de Mt Godinne
city: Luxembourg
country: Luxembourg
facility: CHR Luxembourg
Study officials:
affiliation: Cliniques Universitaires St Luc
name: Jean-Pascal Machiels, MD PHD
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinqiue Universitaire de Mont Godinne
name: Joseph Kerger, MD
role: PRINCIPAL_INVESTIGATOR
References: