Feasibility of a Chemotherapy With Docetaxel-Prednisone for Castration-resistant Metastatic Prostate Cancer Elderly Patients

Study Overview
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Brief Summary
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The objective of this study is to evaluate the feasibility of two different chemotherapy protocols with adjusted doses for patients aged 75 and over who often have medical problems other than prostate cancer. Patient will receive Docetaxel either every 3 weeks or weekly. In both cases, chemotherapy is combined with prednisone. The protocol will be considered feasible when patient will receive 6 cycles of chemotherapy (1 cycle = 3 weeks). Additionally to this primary objective, efficacy will also be evaluated for both protocols as well as tolerance to treatment, quality of life and evolution of geriatric data.

Detailed Description
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Standard management of castration-resistant metastatic prostate cancer is represented by chemotherapy with Docetaxel 75 mg/m² every 3 weeks combined with Prednisone since a symptomatic and overall survival benefit was demonstrated. Although this benefit is independent of age in the study by Tannock (cut-off:69), it does not seem possible to extrapolate these results, obtained in a selected population, to the majority of patients we encounter in daily practice, >= 75 years old and / or unfit. Retrospective studies have shown that chemotherapy was feasible, at standard or adapted doses in an unselected elderly population with good results in terms of tolerance and efficacy over symptoms. Our study aims to evaluate prospectively the feasibility of a chemotherapy with Docetaxel/Prednisone administered every 3 weeks (60 mg / m² at D1C1 then 70 mg / m² at D1 for subsequent cycles if tolerance is good) or weekly (35mg / m² at D1 and D8 with Day 1 = Day 21) to patients >= 75 years old, evaluated by comprehensive geriatric assessment, belonging to group 2 vulnerable or to group 3 frail of the classification proposed by the International Society of Geriatric Oncology (SIOG). Feasibility is defined as the possibility for a patient to receive 6 cycles of chemotherapy without withdrawal. Reasons for study withdrawal were defined by the GERICO Group and are the followings: stop or delay of chemotherapy > 2 weeks Necessity to reduce the dose of chemotherapy > 25 % febrile neutropenia or non-haematological grade 3 toxicity (except alopecia) according to NCI-CTCAE V4.0. Geriatric criterion (Activity of Daily Living (ADL) decrease >= 2 points) The statistical methodology used is a double randomized phase II after stratification according to the SIOG criteria, based on a Simon Optimum plan. A pharmacokinetic / pharmacodynamic study is associated to our project, based on a method of population pharmacokinetic. The aim is to highlight predictors of the haematological tolerance of this chemotherapy by evaluating clinical, geriatric and biological parameters. The results of this study will support the terms of prescription of chemotherapy, in patients aged 75 and over, classified as vulnerable or frail regarding SIOG criteria, with defined geriatric assessment.

Official Title
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Randomized Phase II Study Evaluating the Feasibility of a Chemotherapy With Docetaxel-Prednisone in a Weekly Schedule or Every 3 Weeks, for Castration-resistant Metastatic Prostate Cancer Elderly Patients (>=75), Vulnerable or Frail , as Defined by the Criteria of the International Society of Geriatric Oncology (SIOG)

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Docetaxel every 3 weeks + Prednisone
* Drug: Docetaxel weekly+ Prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >= 75 Histologically proven prostate adenocarcinoma Metastatic disease, not pre-treated with chemotherapy refractory to castration Hormone refractory prostate cancer is defined as follows: Patients with documented testosterone castration (<0.50 ng / ml) Patient who received prior hormonal therapy (either orchidectomy or Luteinizing hormone-releasing hormone (LHRH) agonist alone or combined with an anti-androgen) Patients should continue primary androgen suppression by LHRH agonist (in case of non-surgical castration) For patients treated with anti-androgens prior to inclusion, a wash-out period is required (4 weeks for flutamide and nilutamide, 6 weeks for other products) as well as measured progression after anti-androgen discontinuation. Progressive disease under hormonotherapy, with progression defined by Increase of PSA level (two consecutive increases of PSA compared to baseline with a minimum of one week between both measurements) OR emergence of a new lesion OR measurable progressive disease (increase of a previous measurable lesion >= 25% in cross section) OR progressive bone metastases (defined only by the appearance of a new lesion on bone scan) OR progressive symptoms (defined as cancer pain Grade 2 according to the NCI-CTC V4.0, despite level 2 analgesics intake). Patients of Groups 2 and 3 [ vulnerable and frail] of SIOG classification WHO Performance Status (PS) >= 3 PSA >= 5 ng / ml Neutrophils >= 2.109 /L Platelets >= 100.109/L Haemoglobin ≥ 9 g/dl Bilirubin and SGOT / SGPT <1.5 x ULN (<= 2.5 x ULN if hepatic metastasis) creatinine <= 2.5 x ULN In case of previous palliative or analgesic radiotherapy, a minimum of 14 days must have elapsed between end of radiotherapy and inclusion into the study Previous treatment with bisphosphonates should be continued without change during the study treatment and can not be initiated either within 28 days prior to study entry or during the study Signed informed consent by patients, according to local regulations Exclusion Criteria: healthy or terminal illness Groups according to the recommendations of International Society of Geriatric Oncology (SIOG) Concomitant or previous malignancy within 5 years prior the study (except basal or squamous in situ cell skin carcinoma) Presence of brain metastasis symptoms Prior treatment by intravenous radiopharmaceutical agent (e.g. Strontium 89, Samarium lexidronam) within 2 months before study entry Initiation of a bisphosphonate therapy within 28 days prior to randomisation Any concomitant anticancer treatment (radiotherapy, radiopharmaceutical agent, chemotherapy) Patients with uncontrolled infection Patients with peripheral neuropathy of grade> 1 Patients medically unstable (e.g. unstable diabetes, uncontrolled hypertension or decompensated heart failure or myocardial infarct within 3 months) Gastro duodenal active ulcer Hypersensitivity to study drugs Treatment with any experimental drug within 30 days prior to or during the study Psychological, familial, sociological or geographical location conditions which do not allow medical monitoring and compliance with study protocol. Patients protected by the law or patients placed under protective supervision of adults

Ages Eligible for Study
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Minimum Age: 75 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A - Docetaxel every 3 weeks + Prednisone<br>Docetaxel: 60 mg/m²/day at C1 then 70 mg/m²/day for subsequent cycles every 3 weeks Prednisone 10 mg/day continuously | Drug: Docetaxel every 3 weeks + Prednisone<br>* Docetaxel IV 60 mg/m²/d then IV 70 mg/m²/d for subsequent cycles every 3 weeks Prednisone 10 mg/day continuously<br>* Other names: TAXOTERE;Drug: Docetaxel weekly+ Prednisone<br>* Docetaxel weekly 35 mg/m²/day at day 1 and day 8 of each cycle (J1 = J21) Prednisone 10 mg/day continuously<br>* Other names: TAXOTERE;|
| Experimental: Arm B - Docetaxel weekly + Prednisone<br>Docetaxel weekly 35 mg/m²/day on day 1 and day 8 of each cycle (J1 = J21) Prednisone 10 mg/day continuously | Drug: Docetaxel weekly+ Prednisone<br>* Docetaxel weekly 35 mg/m²/day at day 1 and day 8 of each cycle (J1 = J21) Prednisone 10 mg/day continuously<br>* Other names: TAXOTERE;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of 2 different protocols of Docetaxel chemotherapy | Main criteria is the rate of patients receiving 6 cycles of treatment without experiencing any of the following criteria: Stop or delay of chemotherapy > 2 weeks Necessity to reduce the dose of chemotherapy > 25 % Febrile neutropenia or non-haematological grade 3 toxicity (except alopecia)according to NCI-CTCAE V4.0 Geriatric criterion ( ADL decrease >= 2 points) | Up to 18 weeks (6 cycles of chemotherapy) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall Survival is defined as the time from randomization until death for any cause or last follow-up news (censored data). | From randomization until death for any cause or last follow-up news (censored data) | 
| Geriatric evaluation | The impact of the chemotherapy will be evaluated on Comprehensive Geriatric Assessment : Test de screening G8 Cumulative Illness Rating Scale(CIRSG) Folstein Mini Mental State (MMS) Activity of Daily Living (ADL) Instrumental Activity of Daily Living (IADL) Geriatric Depression Scale (GDS) Mini Nutritionnal Assessment (MNA) | At baseline, D1 of Cycle 1 and Cycle 4, at the end of treatment and at follow-up visits | 
| Number of patients with Adverse Events | Tolerance and safety will be assessed through recording of adverse events using NCI-CTCAE toxicity classification V4.0. | At baseline, D1 of each cycle , at the end of treatment and at the follow-up visits | 
| Quality of Life | The impact of the chemotherapy is evaluated on the European Organisation for Research and Treatment of Cancer (EORTC) Quality Of Life - Questionnaire - QLQ-C30 | At baseline, D1 of the Cycle 4, at the end of the treatment and at the follow-up visits | 
| Vital signs measurement | Tolerance and safety will be assessed through vital signs measurement. | At baseline, D1 of each cycle , at the end of treatment and at the follow-up visits | 
| Prostate-specific antigen (PSA) measurements | Efficacy will be assessed through monitoring PSA values | At baseline, D1 of each cycle , at the end of treatment and at the follow-up visits | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic Prostate cancer, Elderly patients, Vulnerable and Frail (SIOG classification), castration-resistant