Carboplatin-Etoposide Combination in Hormone-Resistant Prostate Cancers

Study Overview
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Brief Summary
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The aim of our study is to assess the efficacy and toxicity of a chemotherapy regimen combining carboplatin and etoposide in patients with metastatic hormone-resistant prostate cancer and neuro-endocrine differentiation. Eligible patients are treated with the combination of carboplatin AUC4 on day 1 and etoposide 100 mg/m2 on day 1, day 2 and day 3 repeated every 3 weeks for a maximum of 6 cycles. Efficacy endpoints include Prostate Specific Antigen (PSA) and neuro-endocrine marker response (defined as a 50% or greater decrease from baseline serum values), objective response rate (according to RECIST criteria), and toxicity.

Detailed Description
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Neuro-endocrine differentiation is observed in the evolution of hormone-resistant prostate cancer. The aim of our study is to assess the efficacy and toxicity of a chemotherapy regimen combining carboplatin and etoposide in patients with metastatic hormone-resistant prostate cancer and neuro-endocrine differentiation. To be eligible, patients must have either circulating neuro-endocrine markers (Chromogranin A: CgA, Neuron Specific Enolase: NSE)and/or visceral metastases. Eligible patients are treated with the combination of carboplatin AUC4 administered on day 1 and etoposide 100 mg/m2 given on day 1, day 2 and day 3 and repeated every 3 weeks for a maximum of 6 cycles. The primary objective of the study is to assess objective response to the carboplatin - etoposide combination (according to RECIST criteria for lesions and defined as a 50% or greater decrease from baseline serum values for PSA and neuro-endocrine markers). Secondary objectives include evaluation of toxicity, duration of response, progression-free-survival and overall survival.

Official Title
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Phase II Multicenter Study Evaluating the Efficacy of Carboplatin-Etoposide Combination in Hormone-resistant Prostate Cancers With Neuroendocrine Differentiation.

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Carboplatin
* Drug: Etoposide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological evidence of prostate adenocarcinoma Metastatic disease, either measurable (lymph nodes, hepatic lesion, pulmonary lesions with longest diameter > or = 1 cm on spiral scan), or non measurable (bone metastasis) Patients must: Have received hormonal therapy via surgical or chemical castration (LH-RH agonist) with or without anti-androgens. Anti-androgen withdrawal is recommended before inclusion, with an off-treatment period of at least 4 weeks. LH-RH agonist treatment must be continued. Have a relapse or disease refractory to hormonal treatment (defined by a testosterone level < 0.5 µg/ml) Have neuroendocrine progression defined, whatever the PSA level, as: NSE and/or Chromogranin A > 1.5 x upper limit of normal (ULN) with or without visceral metastases (liver, lung, lymph node) No increase of NSE or Chromogranin A, but visceral metastases (either hepatic, pleuro-pulmonary, or nodal) with cytological or histological confirmation of the presence of an undifferentiated or neuro-endocrine component of prostatic origin Prior treatment by radiotherapy is allowed but radiation therapy must have been completed for at least 4 weeks before inclusion and irradiated areas must not represent more than 25% of marrow reserves Prior treatment by estramustine is allowed but must have been stopped at least 4 weeks before inclusion Age> or = 18 years Life expectancy> or = 3 months Karnofsky index> or = 50% Adequate haematological function: neutrophils> or = 1.5 G/l, platelets> or = 100 G/l, haemoglobin> or = 8 g/dl. Use of erythropoietin is allowed. Adequate liver function: bilirubin level within the institution's normal range, AST and ALT< or = 1.5 ULN Adequate renal function: creatinine clearance> or = 40 ml/min (Gault and Cockroft method) Signed written informed consent. Exclusion Criteria: Patients having no> 1.5 x ULN increase of at least one neuro-endocrine marker (NSE or chromogranin A) and no cytological or histological (undifferentiated or neuro-endocrine type) evidence of visceral metastasis (hepatic, pleuro-pulmonary, or nodal) History of other malignancies, other than curatively treated basal cell skin carcinoma or any other curatively treated cancer with no sign of recurrence within 5 years Symptomatically uncontrolled brain metastasis Interstitial radiation therapy (using strontium or samarium) within the previous 3 months Prior treatment with platinum salts or etoposide. Other chemotherapy regimens are allowed provided that the last dose has been administered> or = 4 weeks prior to inclusion. Concomitant treatment with other anti-cancer drugs, except corticoid or LH-RH agonist injections Peripheral neuropathy> or = 2 (NCI-CTCAE) Uncontrolled progressive thrombo-embolic disease Uncontrolled infection Medical history of acute myocardial infection or uncontrolled angina pectoris, or hypertension or uncontrolled arrythmia Inclusion in another clinical trial Impaired follow-up for social, geographical, familial or psychological reasons Any other unstable disease.

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carboplatin-Etoposide<br> | Drug: Carboplatin<br>* Carboplatin AUC4 on day 1 repeated every 3 weeks for a maximum of 6 cycles<br>Drug: Etoposide<br>* Etoposide 100 mg/m2 on day 1, day 2 and day 3 repeated every 3 weeks for a maximum of 6 cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (clinical and/or biological): Clinical: objective response of target lesions according to RECIST criteria Biological: greater than 50% decrease of PSA, NSE and Chromogranin A levels |  | Every 6 weeks during treatment (6 cycles of carboplatin-etoposide) and 3 to 4 weeks after the end of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response (clinical and/or biological) |  | Every three months until progression | 
| Toxicity |  | Every 3 weeks during treatment | 
| Progression-free survival and overall survival |  | Every three months until progression | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hormone resistant prostate cancer, Neuro-endocrine marker, Carboplatin-Etoposide combination, Neuro-endocrine differentiation