RAD001 and Bicalutamide for Androgen Independent Prostate Cancer

Study Overview
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Brief Summary
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In the treatment of castration-resistant prostate cancer (CRPC), therapies will long response durations remain elusive as a result of the inherent ability of prostate cancer cells to develop iterative resistance. The goal of this study is to learn if the study drug RAD001 together with Bicalutamide can slow the growth of prostate cancer. The safety of the combination will also be studied.

Detailed Description
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Bicalutamide, an androgen receptor (AR) antagonist, is frequently used as the first 'secondary hormonal therapy' in combination with another established agent (LHRH: luteinizing hormone-releasing hormone agonist/antagonist) to treat CRPC. A series of studies have shown that RAD001 through inhibition of mammalian target of rapamycin (mTOR) pathway has antitumor and anti-angiogenic activities. The hypothesis is that the combination of an antiandrogen and mTOR inhibitor would have additive and clinically significant effects in CRPC. STATISTICAL CONSIDERATIONS: The regimen will be considered promising if the rate of response/favorable outcome is 40% or greater. A rate of 20% (similar to that observed for bicalutamide alone) will not be considered worthy of further study. 38 patients (of whom 36 are assumed to be eligible) will be accrued to the study. If 11 or more patients have a favorable outcome (stable disease > 6 months or response), the combination will be considered worthy of further study. Given this design, there is a 9% probability of declaring the combination effective if the true favorable outcome rate is 20% and a 91% probability of declaring the combination effective if the true favorable outcome rate is 40%.

Official Title
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A Phase II Trial of RAD001 and Bicalutamide for Androgen Independent Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: RAD001
* Drug: Bicalutamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years of age or older Histologically documented prostate cancer Castration resistant prostate cancer defined as two rising PSAs on castration therapy Baseline PSA of 2ns/mL or greater Testosterone of 50ng/mL or less Patients on LHRH agonist/antagonist must continue therapy at the recommended dosing intervals Prior bicalutamide is allowed as long as treatment was for 6 months or longer Metastatic disease is not required Minimum of four weeks since any major surgery, completion of radiation, or completion of all prior systemic anticancer therapy ECOG Performance Status equal to or less than 2 Adequate bone marrow and liver function as outlined by parameters in the protocol Exclusion Criteria: Prior treatment with any investigational drug within the preceding 4 weeks Prior treatment with an mTOR inhibitor Fasting lipids over the parameters outlined in the protocol Chronic treatment with systemic steroids or another immunosuppressive agent Patients should not receive immunization with attenuated live vaccines during study period or within one week of study entry Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases Other malignancies within the past 3 years except for adequately treated or basal squamous cell carcinomas of the skin Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study Known history of HIV seropositivity Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RAD001 Patients with an active, bleeding diathesis or on oral anti-vitamin K medication (except low dose coumarin) Men able to conceive and unwilling to practice an effective method of birth control Known hypersensitivity to RAD001 or other rapamycins or to its excipients History of noncompliance to medical regimens

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: RAD001 + Bicalutamide<br>RAD001: once daily dose of 10 mg (5 mg tablets) Bicalutamide: once daily dose of 50 mg (50 mg tablets) 1 cycle=28 days Both agents are administered continuously until progression of disease or unacceptable toxicity. | Drug: RAD001<br> <br> * Other names: everolimus;Drug: Bicalutamide<br> <br> * Other names: Casodex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Overall response rate is the percentage of patients achieving response taking into consideration measurable disease, bone metastases, and PSA. PSA declines in the absence of both measurable disease and the appearance of new bone lesions or a response in measurable disease without an increase in PSA or the appearance of new bone lesions. Patients with stable disease (SD) lasting at least 6 months will also be considered responders. Per RECIST guidelines, for target lesions, complete response (CR) is complete disappearance of all target lesions and partial response (PR) is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. CR or PR confirmation is required within 4 weeks. Per modified PSAWG2 criteria (Scher H, Halabi S, Tannock I et al. JCO 2008) PSA response is defined as PSA decline ≥ 50% from baseline confirmed by a second measurement at least 4 weeks later. | PSA was measured monthly and measurable disease on imaging assessed every 2 cycles in first 8 weeks and every 3 cycles thereafter. In this study cohort, patients were followed on treatment up to approximately 1 year. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Grade 4 Treatment-Related Toxicity | All grade 4 adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv3 as reported on case report forms were counted. Incidence is the number of patients experiencing at least one treatment-related grade 4 AE of any type during the time of observation. | Assessed each cycle during therapy and up to 30 days post-therapy completion which is approximately 1 year for patients in this study cohort. | 
| Incidence of Grade 1-3 Treatment-Related Mucositis Toxicity | All grade 1-3 mucositis adverse events (AE) with treatment attribution of possible, probable or definite based on CTCAEv3 as reported on case report forms were counted. Incidence is the number of patients experiencing at least one treatment-related grade 1-3 mucositis AE during the time of observation. | Assessed each cycle during therapy and up to 30 days post-therapy completion which is approximately 1 year for patients in this study cohort. | 
| Incidence of Grade 1-3 Treatment-Related Rash Toxicity | All grade 1-3 rash adverse events (AE) with treatment attribution of possible, probable or definite based on CTCAEv3 as reported on case report forms were counted. Incidence is the number of patients experiencing at least one treatment-related grade 1-3 rash AE during the time of observation. | Assessed each cycle during therapy and up to 30 days post-therapy completion which is approximately 1 year for patients in this study cohort. | 
| Incidence of Grade 1-3 Treatment-Related Fatigue Toxicity | All grade 1-3 fatigue adverse events (AE) with treatment attribution of possible, probable or definite based on CTCAEv3 as reported on case report forms were counted. Incidence is the number of patients experiencing at least one treatment-related grade 1-3 fatigue AE during the time of observation. | Assessed each cycle during therapy and up to 30 days post-therapy completion which is approximately 1 year for patients in this study cohort. | 
| Time to Progression (TTP) | TTP estimated with Kaplan-Meier methods is defined as the time from treatment start to when PSA progression criteria is first met, or the date of measurable or non-measurable disease progression (PD). Absent progression, patients are censored at the date of the last PSA measurement. PSA progression is a ≥25% increase over baseline or nadir PSA, whichever is lowest with a minimum increase of 5 ng/mL. If PSA declines ≥50%, PSA progression is a ≥50% PSA increase above nadir with a minimum increase of 5 ng/mL or back to pretreatment baseline, whichever is lowest. PSA progression requires 2 week confirmation. Per RECIST, PD is at least a 20% increase in sum LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or appearance of new lesions. Non-measurable PD is defined as a worsening bone scan, as indicated by the appearance of two or more new lesions, the appearance of new non-bony metastases or a requirement for radiation therapy. | PSA was measured monthly and measurable disease on imaging assessed every 2 cycles in first 8 weeks and every 3 cycles thereafter. In this study cohort, patients were followed on treatment up to approximately 1 year. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RAD001, bicalutamide, androgen independent prostate cancer