RAD001 in Patients With Metastatic, Hormone-Refractory Prostate Cancer

• Sponsor: Daniel George, MD (Other)
• Overall Status: Completed
• CT.gov ID: NCT00629525
• Collaborator: Novartis Pharmaceuticals (Industry)
• Enrollment: 35
• Location: 1
• Arm: 1
• Duration (Months): 53
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the biochemical response rate (PSA) to single agent RAD001 in patients with metastatic hormone-refractory prostate cancer (HRPC).

Condition or Disease	Intervention/Treatment	Phase
Hormone Refractory Prostate Cancer	Drug: RAD001	Phase 2

Detailed Description

This is a single center, Phase II study of RAD001 in men with HRPC. The study design is a straight forward, two-stage design with tumor biopsies scheduled at screening and again at 4 weeks. FLT-PET scans are performed at screening and again at day 28, following initiation of treatment in the first 10 patients. Patients are assessed for adverse events every two weeks for the first month and monthly thereafter. Patients are assessed for response by PSA every 4 weeks and when applicable, for objective response every 2 months. If 4 or more responses are seen in the first 39 patients then the study will expand to 60 patients.

Study Design

• Study Type: Interventional
• Actual Enrollment: 35 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Single Arm, Two Center, Phase II Study of RAD001 in Patients With Metastatic, Hormone-Refractory Prostate Cancer
• Study Start Date: Aug 1, 2005
• Actual Primary Completion Date: Dec 1, 2009
• Actual Study Completion Date: Jan 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: RAD001 RAD001 at a dose of 10 mg PO daily	Drug: RAD001; RAD001 at a dose of 10 mg PO daily; Other Names: Everolimus

Outcome Measures

Primary Outcome Measures

1. Biochemical Response Rate [Patients were followed for a median of 315 days]

   Number of participants with 50% decline in serum PSA from baseline was pre-set as the primary measure of disease response.

Secondary Outcome Measures

1. Pathologic Response [Patients were followed for a median of 315 days]

   Number of participants with either a 50% or greater decrease in proliferation index or a 50% or greater increase in apoptotic index

2. Progression Free Survival [Patients were followed for a median of 315 days, with the last patient censored at 1309 days.]

   Time in months from the start of study treatment to the date of first progression according to RECIST 1.0, or to death due to any cause. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median PFS was estimated using a Kaplan-Meier curve.

3. Molecular Response [Patients were followed for a median of 315 days]

   Functional extent of mTOR inhibition by changes in the phosphorylation status of pS6 in prostate tumors.

4. Clinical Response [Patients were followed for a median of 315 days]

   The percentage of participants with a complete or partial response as defined by RECIST 1.0. Response Criteria are defined below: Complete Response: Disappearance of all target lesions Partial Response: At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD Progressive Disease: At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions Stable Disease: Neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum LD

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically confirmed diagnosis of adenocarcinoma of the prostate

• Clinical or radiographic evidence of metastatic disease

• ADT using LHRH agonist (eg leuprolide, goserelin) must continue on therapy. However, ketoconazole, estrogens, and all other forms of hormonal manipulation are not permitted on study.

• Evidence of disease progression on ADT as evidenced by:

• 2 consecutive PSA levels 50% or greater above the PSA nadir achieved on ADT and separated at least 1 week apart, or

• Radiographic evidence of disease progression defined by RECIST criteria and compared to prior studies on ADT.

• A minimum of 6 weeks has elapsed off of anti-androgen therapy without withdrawal response.

• A minimum of 4 weeks from any prior radiation therapy, surgery, chemotherapy or other investigational agent

• Biopsies will not be performed if platelet counts < 75,000/ ul, PTT, PT or INR > 1.4 times control

• Patients must have normal organ and marrow function as defined below:

• hemoglobin > 9.0g/dL

• absolute neutrophil count > 1,500/μl

• platelets > 100,000/μl

• total bilirubin < 1.5 X upper limit of normal (ULN)

• AST(SGOT)/ALT(SGPT) < 2.5 X ULN

• creatinine < 1.5 X ULN

• total fasting cholesterol < 350

• total triglycerides < 300

• Patients on antilipid therapy may participate in this study.

• Age > 18 years

• ECOG performance status 0 or 1

• Ability to swallow and retain oral medication

• Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• History of solid organ or stem cell transplantation

• Also, no current use of chronic immunosuppressive therapy is allowed

• Patients with known brain metastases (or history of brain metastases)

• History of HIV, hepatitis B, or hepatitis C infection

• Patients who have received investigational, biologic, hormonal (other than ADT), immunotherapy, or chemotherapy less than 4 weeks prior to entry on this study or have not recovered from the toxic effects of such therapy

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (requiring antifungal, antibiotic or antiviral therapy), symptomatic congestive heart failure (NYHC III or greater), unstable angina pectoris, cardiac arrhythmia (uncontrolled SVT or any VT), or psychiatric illness/social situations that would limit compliance with study requirements

• History of malabsorption syndrome, disease significantly affecting gastrointestinal function or major resection of the stomach or small bowel that could affect absorption, distribution, metabolism or excretion of study drugs.

• Any unresolved bowel obstruction or diarrhea

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Duke University MEdical Center	Durham	North Carolina	United States	27710

Sponsors and Collaborators

• Daniel George, MD
• Novartis Pharmaceuticals

Investigators

• Principal Investigator: Daniel J George, MD, Duke Health

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Daniel George, MD, Associate Professor of Medicine, Duke University
• ClinicalTrials.gov Identifier: NCT00629525
• Other Study ID Numbers: Pro00009495; 7521
• First Posted: Mar 6, 2008
• Last Update Posted: Mar 3, 2015
• Last Verified: Feb 1, 2015

• Additional relevant MeSH terms: Prostatic Neoplasms; Everolimus

Study Results

Participant Flow

Arm/Group Title	RAD001
Arm/Group Description	RAD001 at a dose of 10 mg PO daily
Period Title: Overall Study
STARTED	35
COMPLETED	32
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	RAD001
Arm/Group Description	RAD001 at a dose of 10 mg PO daily
Overall Participants	35
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	71
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	35 100%

Outcome Measures

1. Primary Outcome

Title	Biochemical Response Rate
Description	Number of participants with 50% decline in serum PSA from baseline was pre-set as the primary measure of disease response.
Time Frame	Patients were followed for a median of 315 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RAD001
Arm/Group Description	RAD001 at a dose of 10 mg PO daily
Measure Participants	35
Number [participants]	0 0%

2. Secondary Outcome

Title	Pathologic Response
Description	Number of participants with either a 50% or greater decrease in proliferation index or a 50% or greater increase in apoptotic index
Time Frame	Patients were followed for a median of 315 days

Outcome Measure Data

Analysis Population Description

Only subjects with paired samples were included in this analysis

Arm/Group Title	RAD001
Arm/Group Description	RAD001 at a dose of 10 mg PO daily
Measure Participants	4
Number [participants]	0 0%

3. Secondary Outcome

Title	Progression Free Survival
Description	Time in months from the start of study treatment to the date of first progression according to RECIST 1.0, or to death due to any cause. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median PFS was estimated using a Kaplan-Meier curve.
Time Frame	Patients were followed for a median of 315 days, with the last patient censored at 1309 days.

Outcome Measure Data

Analysis Population Description

Intent to treat

Arm/Group Title	RAD001
Arm/Group Description	RAD001 at a dose of 10 mg PO daily
Measure Participants	35
Median (95% Confidence Interval) [months]	3.58

4. Secondary Outcome

Title	Molecular Response
Description	Functional extent of mTOR inhibition by changes in the phosphorylation status of pS6 in prostate tumors.
Time Frame	Patients were followed for a median of 315 days

Outcome Measure Data

Analysis Population Description

Immunohistochemistry (IHC) for pS6 was compared for 9 pairs of samples for which paraffin embedded tissue was available.

Arm/Group Title	RAD001
Arm/Group Description	RAD001 at a dose of 10 mg PO daily
Measure Participants	9
Mean (Full Range) [percentage of decrease]	60.11

5. Secondary Outcome

Title	Clinical Response
Description	The percentage of participants with a complete or partial response as defined by RECIST 1.0. Response Criteria are defined below: Complete Response: Disappearance of all target lesions Partial Response: At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD Progressive Disease: At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions Stable Disease: Neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum LD
Time Frame	Patients were followed for a median of 315 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RAD001
Arm/Group Description	RAD001 at a dose of 10 mg PO daily
Measure Participants	35
Number [participants]	0 0%

Adverse Events

Time Frame	3 years
Adverse Event Reporting Description	data were collected in Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 and converted to version 4.0 for Clinicaltrials.gov entry
Arm/Group Title	RAD001
Arm/Group Description	RAD001 at a dose of 10 mg PO daily
All Cause Mortality
	RAD001
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	RAD001
	Affected / at Risk (%)	# Events
Total	8/35 (22.9%)
Cardiac disorders
Myocardial infarction	1/35 (2.9%)
General disorders
Death NOS	2/35 (5.7%)
Infections and infestations
Sepsis	1/35 (2.9%)
Investigations
INR increased	1/35 (2.9%)
Metabolism and nutrition disorders
Dehydration	1/35 (2.9%)
Nervous system disorders
Nervous system disorders - spinal cord compression	1/35 (2.9%)
Renal and urinary disorders
Hematuria	1/35 (2.9%)
Other (Not Including Serious) Adverse Events
	RAD001
	Affected / at Risk (%)	# Events
Total	35/35 (100%)
Blood and lymphatic system disorders
Anemia	14/35 (40%)
Gastrointestinal disorders
Constipation	6/35 (17.1%)
Diarrhea	11/35 (31.4%)
Dry Mouth	5/35 (14.3%)
Gastrointestinal disorders - Other, specify: Mucositis	19/35 (54.3%)
Mocositis oral	2/35 (5.7%)
Nausea	12/35 (34.3%)
Vomiting	10/35 (28.6%)
General disorders
Chills	2/35 (5.7%)
Edema Limbs	2/35 (5.7%)
Fatigue	18/35 (51.4%)
Facial Pain	5/35 (14.3%)
Fever	5/35 (14.3%)
Non-cardiac chest pain	2/35 (5.7%)
Investigations
Alanine aminotransferase increased	6/35 (17.1%)
Aspartate aminotransferase increased	15/35 (42.9%)
Cholesterol high	11/35 (31.4%)
Creatinine increased	2/35 (5.7%)
Lymphocyte count decreased	3/35 (8.6%)
Neutrophil count decreased	12/35 (34.3%)
Platelet count decreased	17/35 (48.6%)
Weight loss	11/35 (31.4%)
White blood cell decreased	8/35 (22.9%)
Metabolism and nutrition disorders
Anorexia	17/35 (48.6%)
Dehydration	2/35 (5.7%)
Hyperglycemia	3/35 (8.6%)
Hypertriglyceridemia	17/35 (48.6%)
Hypoalbuminemia	6/35 (17.1%)
Hypocalcemia	2/35 (5.7%)
Hypokalemia	3/35 (8.6%)
Hypophosphatemia	2/35 (5.7%)
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	2/35 (5.7%)
Myalgia	2/35 (5.7%)
Pain in extremity	5/35 (14.3%)
Nervous system disorders
Dizziness	3/35 (8.6%)
Dysgeusia	9/35 (25.7%)
Headache	4/35 (11.4%)
Respiratory, thoracic and mediastinal disorders
Cough	2/35 (5.7%)
Dyspnea	7/35 (20%)
Epistaxis	3/35 (8.6%)
Pneumonitis	3/35 (8.6%)
Sinus disorder	2/35 (5.7%)
Skin and subcutaneous tissue disorders
Dry skin	7/35 (20%)
Hyperhidrosis	2/35 (5.7%)
Rash maculo-papular	13/35 (37.1%)
Vascular disorders
Hypotension	2/35 (5.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.