Carboplatin, Everolimus, and Prednisone in Treating Patients With Metastatic Prostate Cancer That Progressed After Docetaxel

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as carboplatin and prednisone, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving carboplatin together with everolimus and prednisone may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving carboplatin together with everolimus and prednisone works in treating patients with metastatic prostate cancer that progressed after docetaxel.

Detailed Description
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OBJECTIVES: Primary To evaluate the time to progression (TTP) achieved with carboplatin and everolimus in patients with castrate resistant metastatic prostate cancer that progressed after docetaxel-based chemotherapy. Secondary To evaluate the safety of this regimen. To assess the PSA response rate in patients treated with this regimen. To evaluate the overall survival (OS) outcome in these patients. To investigate the association of TTP and PSA response rate with correlative markers, such as phospho mTOR, pAKT, and p70S6. To evaluate the pharmacokinetics of this regimen. To explore the association of TTP, OS, and circulating tumor tumor cell count. OUTLINE: Patients receive carboplatin IV over 30-60 minutes on day 1, oral prednisone twice daily on days on days 1-21, and oral everolimus once daily on days 2-21 of course 1 and on days 1-21 of subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Blood and tumor tissue samples are collected periodically for pharmacodynamic, pharmacokinetic, and biomarker analysis. After completion of study treatment, patients are followed up every 3 months.

Official Title
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Phase II Trial of Carboplatin and Everolimus (RAD001) in Metastatic Castrate Resistant Prostate Cancer (CRPC) Pretreated With Docetaxel Chemotherapy.

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: carboplatin
* Drug: RAD 001
* Drug: prednisone
* Other: laboratory biomarker analysis
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed metastatic adenocarcinoma of the prostate Objective disease progression or rising PSA despite androgen deprivation therapy and antiandrogen withdrawal (when applicable) Progressed after ≥ 1 prior docetaxel-based chemotherapy regimen for metastatic disease Patients with measurable disease* must have either rising PSA, increase in size of the lesion(s), or both Patients with rising PSA as the only evidence of disease progression must demonstrate a rising trend with 2 successive elevations ≥ 1 week apart Patients with no measurable disease must have a PSA ≥ 5 ng/mL or new areas of bony metastases on bone scan NOTE: *There is no minimum PSA requirement for patients with measurable disease Documented to be castrate with a testosterone level of ≤ 0.5 ng/mL Leuteinizing hormone-releasing hormone agonist therapy must be continued, if required to maintain castrate levels of testosterone No uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases PATIENT CHARACTERISTICS: Zubrod performance status 0-1 ANC ≥ 1,500/mm^3 Hemoglobin ≥ 9.0 g/dL Platelet count ≥ 100,000/mm^3 Total bilirubin ≤ 1.5 times upper limit of normal (ULN) Calculated creatinine clearance ≥ 50 mL/min OR serum creatinine ≤ 2 mg/dL AST and/or ALT ≤ 2.5 times ULN if alkaline phosphatase normal OR alkaline phosphatase ≤ 4 times ULN if AST and/or ALT normal (for patients without documented bone metastases or for patients with liver metastases) AST and/or ALT < 2.5 times ULN, without regard to alkaline phosphatase levels (for patients with documented bone metastases) Fasting serum cholesterol ≤ 300 mg/dL OR ≤ 7.75 mmol/L AND fasting triglycerides ≤ 2.5 times ULN (in the case that one or both of these thresholds are exceeded, the patient is eligible only after initiation of appropriate lipid-lowering medication) Fertile patients must use effective contraception during and for ≥ 6 months after completion of study treatment Willing and able to comply with this study Able to ingest oral medication No other malignancies except non-melanoma skin cancer or any other adequately treated cancer in complete remission for ≥ 2 years No significant traumatic injury within the past 4 weeks No active (acute or chronic) or uncontrolled severe infections No severe and/or uncontrolled medical conditions or other conditions that could affect study participation, including the following: NYHA class III-IV symptomatic congestive heart failure Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within the past 6 months, serious uncontrolled cardiac arrhythmia, or any other clinically significant cardiac disease Severely impaired lung function as defined by spirometry and DLCO that is 50% of the normal predicted value and/or oxygen saturation that is ≤ 88% at rest on room air Uncontrolled diabetes as defined by fasting serum glucose > 1.5 times ULN Liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent hepatitis Known history of HIV seropositivity, hepatitis B or C Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) Active, bleeding diathesis No known hypersensitivity to everolimus or other rapamycins (sirolimus, temsirolimus) or to their excipients No history of noncompliance to medical regimens No uncontrolled diabetes mellitus PRIOR CONCURRENT THERAPY: See Disease Characteristics At least 1 prior docetaxel based regimen for metastatic disease Docetaxel based combination therapy or docetaxel alone considered as 1 regimen No more than 2 prior chemotherapy regimens for metastatic disease No prior treatment with an mTOR inhibitor (sirolimus, temsirolimus, everolimus) At least 6 weeks since prior bicalutamide or nilutamide At least 4 weeks since prior flutamide More than 4 weeks since prior and no other concurrent investigational drugs More than 4 weeks since prior and no other concurrent anticancer therapies (including chemotherapy, radiotherapy, or antibody-based therapy) More than 4 weeks since prior and no concurrent major surgery (defined as requiring general anesthesia) and recovered More than 1 week since prior and no concurrent immunization with attenuated live vaccines No concurrent chronic, systemic treatment with corticosteroids or other immunosuppressive agents Topical or inhaled corticosteroids are allowed No concurrent prophylactic growth factors Concurrent bisphosphonate therapy allowed

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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, RAD 001 & Prednisone<br>Carboplatin: AUC=4 by Calvert's formula (max dose 600 mg)*IV over 30-60 min, Day 1 of a 21 day cycle RAD 001: 5 mg Orally daily, starting from Day 2 continuously Prednisone 5 mg Orally twice daily, continuously | Drug: carboplatin<br>* AUC = 5 by Calvert's formula, day 1 of each 21 day cycle<br>* Other names: Paraplatin®;Drug: RAD 001<br>* 5 mg orally starting on Day 2 then continuous<br>* Other names: Everolimus;Drug: prednisone<br>* 5 mg orally twice a day starting on Day 1 then continuous<br>* Other names: Sterapred DS;Other: laboratory biomarker analysis<br>* Samples will be collected from archival tissue.<br>Other: pharmacological study<br>* Samples will be collected Cycle 1, day 1, 2 & 8 and Cycle 2, Day 1 & 2<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression (TTP) | Progression defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions taking as references the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. | Up to 63 days while on treatment, then up 90 days thereafter. From date of registration to date of progressive disease. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Toxicity as Measured by NCI CTCAE v3.0 Criteria | Number of Participants with Grade 3/4 Toxicity as measured by NCI CTCAE v3.0 criteria | Day 1 of each cycle (every 21 days), through study completion, an average of 6 months | 
| PSA Response Rate | PSA response rate with response defined as => a 30% reduction in PSA | Day 1 of each cycle (every 21 days), through study completion, an average of 6 months | 
| Association of PSA Response Rate With Correlative Markers (Phospho mTOR, pAKT, and p70S6) | PSA response defined as a decrease of 30% or more will be tabled against mTOR, pAKT, and p70S6 (1+, 2+, 3+ vs ND) | Archival tissue will be collected if available. Optional biopsies pre-treatment and 24 hours after first everolimus and carboplatin dose | 
| Pharmacokinetics: Observed Carboplatin AUC Was Estimated Based on the Concentration in the 2.75-h Sample. | Using a limited sampling model (i.e., AUC = 0.52 × C2.75h + 0.92) (Sorensen et al., 1993), observed carboplatin AUC was estimated based on the concentration in the 2.75-h sample. | Samples were collected Cycle 2, Day 1 | 
| Overall Survival | Overall Survival as measured by the Kaplan-Meier method | After treatment, participants will be contacted every 3 months up to 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hormone-resistant prostate cancer, recurrent prostate cancer, stage IV prostate cancer, adenocarcinoma of the prostate