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RAD001 and Bicalutamide for Androgen Independent Prostate Cancer

Primary Purpose

Prostate Cancer

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
RAD001
Bicalutamide
Sponsored by
Dana-Farber Cancer Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Prostate Cancer focused on measuring RAD001, bicalutamide, androgen independent prostate cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)MaleDoes not accept healthy volunteers

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

Sites / Locations

  • Beth Israel Deaconess Medical Center
  • Dana-Farber Cancer Institute

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

RAD001 + Bicalutamide

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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.
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.

Full Information

First Posted
February 28, 2008
Last Updated
November 6, 2017
Sponsor
Dana-Farber Cancer Institute
Collaborators
Beth Israel Deaconess Medical Center, Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT00630344
Brief Title
RAD001 and Bicalutamide for Androgen Independent Prostate Cancer
Official Title
A Phase II Trial of RAD001 and Bicalutamide for Androgen Independent Prostate Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
November 2017
Overall Recruitment Status
Completed
Study Start Date
February 2008 (undefined)
Primary Completion Date
May 2012 (Actual)
Study Completion Date
May 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Dana-Farber Cancer Institute
Collaborators
Beth Israel Deaconess Medical Center, Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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%.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Prostate Cancer
Keywords
RAD001, bicalutamide, androgen independent prostate cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
36 (Actual)

8. Arms, Groups, and Interventions

Arm Title
RAD001 + Bicalutamide
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
RAD001
Other Intervention Name(s)
everolimus
Intervention Type
Drug
Intervention Name(s)
Bicalutamide
Other Intervention Name(s)
Casodex
Primary Outcome Measure Information:
Title
Overall Response Rate
Description
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.
Time Frame
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 Measure Information:
Title
Incidence of Grade 4 Treatment-Related Toxicity
Description
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.
Time Frame
Assessed each cycle during therapy and up to 30 days post-therapy completion which is approximately 1 year for patients in this study cohort.
Title
Incidence of Grade 1-3 Treatment-Related Mucositis Toxicity
Description
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.
Time Frame
Assessed each cycle during therapy and up to 30 days post-therapy completion which is approximately 1 year for patients in this study cohort.
Title
Incidence of Grade 1-3 Treatment-Related Rash Toxicity
Description
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.
Time Frame
Assessed each cycle during therapy and up to 30 days post-therapy completion which is approximately 1 year for patients in this study cohort.
Title
Incidence of Grade 1-3 Treatment-Related Fatigue Toxicity
Description
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.
Time Frame
Assessed each cycle during therapy and up to 30 days post-therapy completion which is approximately 1 year for patients in this study cohort.
Title
Time to Progression (TTP)
Description
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.
Time Frame
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.

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mary-Ellen Taplin, MD
Organizational Affiliation
Dana-Farber Cancer Institute
Official's Role
Study Chair
Facility Information:
Facility Name
Beth Israel Deaconess Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
22928480
Citation
Nakabayashi M, Werner L, Courtney KD, Buckle G, Oh WK, Bubley GJ, Hayes JH, Weckstein D, Elfiky A, Sims DM, Kantoff PW, Taplin ME. Phase II trial of RAD001 and bicalutamide for castration-resistant prostate cancer. BJU Int. 2012 Dec;110(11):1729-35. doi: 10.1111/j.1464-410X.2012.11456.x. Epub 2012 Aug 29.
Results Reference
result

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RAD001 and Bicalutamide for Androgen Independent Prostate Cancer

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