The Use of RAD001 With Docetaxel in the Treatment of Metastatic, Androgen Independent Prostate Cancer

• Sponsor: Dana-Farber Cancer Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT00459186
• Collaborator: Novartis (Industry), Massachusetts General Hospital (Other), Beth Israel Deaconess Medical Center (Other), Oregon Health and Science University (Other)
• Enrollment: 19
• Locations: 5
• Arm: 1
• Duration (Months): 85
• Patients Per Site: 3.8
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the safety and optimal dose of RAD001 and docetaxel plus prednisone in men with hormone refractory, metastatic prostate cancer (Phase I).

Once an appropriate dose is reached, the purpose then will be to determine the response rate of docetaxel plus RAD001 (Phase II).

Condition or Disease	Intervention/Treatment	Phase
Metastatic, Androgen Independent Prostate Cancer; Prostate Cancer	Drug: RAD001; Drug: Docetaxel; Drug: Prednisone	Phase 1/Phase 2

Detailed Description

• Patients will be designated into one of two groups based upon the results of a FDG-PET scan.

• A patient with a baseline positive scan will have serum drawn for baseline serum proteomics assessment then be treated with RAD001 daily for two weeks. On day 10-14, another FDG-PET scan and serum assessment will be performed. An optional bone marrow biopsy may also be done. On day 15, patients will enter the Phase I portion of the trial at the current enrolling dosage or if Phase I is completed patients will enter Phase II.

• A patient that does not have a positive scan will enter directly into the Phase I trial or Phase II depending on which trial is currently enrolling.

• Phase I trial patients will have weekly laboratory evaluations and clinical evaluation every three weeks.

• Phase II trial patients will have laboratory evaluations on day one and day eight and clinical evaluation every three weeks.

• The maximum duration of the trial is one year of therapy.

Study Design

• Study Type: Interventional
• Actual Enrollment: 19 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Study of RAD001 With Docetaxel in the Treatment of Metastatic, Androgen Independent Prostate Cancer
• Study Start Date: Nov 1, 2005
• Actual Primary Completion Date: Dec 1, 2012
• Actual Study Completion Date: Dec 1, 2012

Arms and Interventions

Arm

Intervention/Treatment

Experimental: RAD001 Followed by RAD001 + Docetaxel RAD001 10 mg daily for 2 weeks, followed by RAD001 + Docetaxel at one of three doses: 5 mg RAD001 and docetaxel at 60 mg/m2, 10 mg RAD001 and docetaxel at 60 mg/m2, and 10 mg RAD001 and docetaxel at 70 mg/m2. RAD001 was given daily. Docetaxel was given every 3 weeks by intravenous infusion. Patients also received prednisone 5 mg by mouth twice daily.

Drug: RAD001; Daily for two weeks; Drug: Docetaxel; Infusion once per cycle; Drug: Prednisone; Prednisone 5 mg by mouth twice daily

Outcome Measures

Primary Outcome Measures

1. Number of Patients Free of Dose Limiting Toxicity [21 days]

   A dose limiting toxicity was defined as an adverse event or laboratory abnormality that occurs to patients on the Phase I portion of the trial, during the first 21 days following the first dose of RAD001/docetaxel during cycle 1, judged to be related to RAD001/docetaxel and meeting any of the following criteria: Hematologic Toxicity: CTCAE grade 4 neutropenia > 7 days or any Grade 3 or 4 neutropenia with fever Or CTCAE grade 3 or 4 thrombocytopenia > 7 days Non-hematologic toxicity: The occurrence of non-hematologic CTCAE grade 3 or 4 adverse events will be considered dose limiting, except for the following: CTCAE grade 3 nausea or grade 3 or 4 vomiting CTCAE grade 3 or 4 vomiting will only be considered dose limiting if it occurs despite the use of standard anti-emetics. CTCAE grade 3 or 4 fever identified with a source (i.e. infection, tumor) CTCAE grade 3 or 4 alkaline phosphatase.

Secondary Outcome Measures

1. Response Based on PET Scan [10 to 14 days after study entry]

   Patients were scanned using Positron Emission Tomography (PET) before and after receiving single agent RAD001. Patients were classified as having partial metabolic response, stable metabolic disease, or progressive metabolic disease based on changes in PET imaging from baseline to post-treatment. A positive FDG-PET for the purposes of this study consisted of a visualized area of abnormal increased FDG uptake that matched the anatomic location of an abnormality seen on bone scan or CT. Metabolic response was assessed for percent change in SUVmax according to the criteria of the European Organization for Research and Treatment of Cancer (EORTC) : partial metabolic response (PMR) ≤ -25%; stable metabolic disease (SMD) -25% + 25%; progressive metabolic disease (PMD) > 25%.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Adenocarcinoma of the prostate with radiographic evidence of metastatic disease.

• Willingness to undergo a baseline tumor biopsy.

• Castrate levels of testosterone (testosterone < 50 ng/dL) on androgen deprivation therapy (ADT) with evidence of progression on ADT. GnRH therapy will be continued for those on it at baseline

• Patient must have suspected tumor in an area that is safe to biopsy.

• Other prior hormonal interventions or experimental approaches are allowed. These therapies must have been discontinued for a minimum of 28 days with cancer progression.

• Prior or concurrent use of bisphosphonates is allowed.

• One prior non-taxane chemotherapy allowed

• ≥ 3 weeks since major surgery; ≥ 4 weeks since radiotherapy; ≥ 8 weeks since prior strontium-89 or samarium 153

• Performance Status: ECOG 0 or 1

• ANC > 1,500/_l; platelets > 100,000/_l; total Bilirubin < upper limit of normal; AST and ALT < 3 x upper limits of normal; creatinine < 1.5 x upper limits of normal; total fasting cholesterol < 350 mg/dl; total triglycerides < 300 mg/dl

Exclusion Criteria:

• Ongoing oral steroid use. Patients with a history of oral steroid use are eligible as long as the steroids have been discontinued prior to study entry. Ongoing topical and/or inhaled steroid use is allowed.

• Prior taxane chemotherapy

• Prior mTOR inhibitors (RAD001, rapamycin, CCI-779)

• Currently active second malignancy other than non-melanoma skin cancer.

• Ongoing peripheral neuropathy of Grade 2

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
2	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
3	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
4	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
5	Oregon Health Science University	Portland	Oregon	United States

Sponsors and Collaborators

• Dana-Farber Cancer Institute
• Novartis
• Massachusetts General Hospital
• Beth Israel Deaconess Medical Center
• Oregon Health and Science University

Investigators

• Principal Investigator: Mary Ellen Taplin, MD, Dana-Farber Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mary-Ellen Taplin, MD, Associate Professor of Medicine, HMS, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT00459186
• Other Study ID Numbers: 05-184
• First Posted: Apr 11, 2007
• Last Update Posted: May 16, 2016
• Last Verified: Apr 1, 2016

• Keywords provided by Mary-Ellen Taplin, MD, Associate Professor of Medicine, HMS, Dana-Farber Cancer Institute: prostate cancer; RAD001; mTOR inhibition; docetaxel
• Additional relevant MeSH terms: Prostatic Neoplasms; Prednisone; Docetaxel; Everolimus

Study Results

Participant Flow

Recruitment Details	Patients were recruited from the Genitourinary Oncology clinics of Dana-Farber Cancer Institute and the Knight Cancer Institute at Oregon Health and Science University between November, 2005 and October, 2008

Arm/Group Title	RAD001 Followed by RAD001 + Docetaxel
Arm/Group Description	RAD001 10 mg daily for 2 weeks, followed by RAD001 + Docetaxel at one of three doses: 5 mg RAD001 and docetaxel at 60 mg/m2, 10 mg RAD001 and docetaxel at 60 mg/m2, and 10 mg RAD001 and docetaxel at 70 mg/m2. RAD001 was given daily. Docetaxel was given every 3 weeks by intravenous infusion. Patients also received prednisone 5 mg by mouth twice daily.
Period Title: Single Agent RAD001
STARTED	19
COMPLETED	18
NOT COMPLETED	1
Period Title: Single Agent RAD001
STARTED	18
COMPLETED	15
NOT COMPLETED	3
Period Title: Single Agent RAD001
STARTED	15
COMPLETED	15
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	RAD001 Followed by RAD001 + Docetaxel
Arm/Group Description	RAD001 10 mg daily for 2 weeks, followed by RAD001 + Docetaxel at one of three doses: 5 mg RAD001 and docetaxel at 60 mg/m2, 10 mg RAD001 and docetaxel at 60 mg/m2, and 10 mg RAD001 and docetaxel at 70 mg/m2. RAD001 was given daily. Docetaxel was given every 3 weeks by intravenous infusion. Patients also received prednisone 5 mg by mouth twice daily.
Overall Participants	18
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	62
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	18 100%

Outcome Measures

1. Primary Outcome

Title	Number of Patients Free of Dose Limiting Toxicity
Description	A dose limiting toxicity was defined as an adverse event or laboratory abnormality that occurs to patients on the Phase I portion of the trial, during the first 21 days following the first dose of RAD001/docetaxel during cycle 1, judged to be related to RAD001/docetaxel and meeting any of the following criteria: Hematologic Toxicity: CTCAE grade 4 neutropenia > 7 days or any Grade 3 or 4 neutropenia with fever Or CTCAE grade 3 or 4 thrombocytopenia > 7 days Non-hematologic toxicity: The occurrence of non-hematologic CTCAE grade 3 or 4 adverse events will be considered dose limiting, except for the following: CTCAE grade 3 nausea or grade 3 or 4 vomiting CTCAE grade 3 or 4 vomiting will only be considered dose limiting if it occurs despite the use of standard anti-emetics. CTCAE grade 3 or 4 fever identified with a source (i.e. infection, tumor) CTCAE grade 3 or 4 alkaline phosphatase.
Time Frame	21 days

Outcome Measure Data

Analysis Population Description

Patients who received combination treatment with RAD001 + Docetaxel

Arm/Group Title	RAD001 Followed by RAD001 + Docetaxel
Arm/Group Description	RAD001 10 mg daily for 2 weeks, followed by RAD001 + Docetaxel at one of three doses: 5 mg RAD001 and docetaxel at 60 mg/m2, 10 mg RAD001 and docetaxel at 60 mg/m2, and 10 mg RAD001 and docetaxel at 70 mg/m2. RAD001 was given daily. Docetaxel was given every 3 weeks by intravenous infusion. Patients also received prednisone 5 mg by mouth twice daily.
Measure Participants	15
Number [participants]	14 77.8%

2. Secondary Outcome

Title	Response Based on PET Scan
Description	Patients were scanned using Positron Emission Tomography (PET) before and after receiving single agent RAD001. Patients were classified as having partial metabolic response, stable metabolic disease, or progressive metabolic disease based on changes in PET imaging from baseline to post-treatment. A positive FDG-PET for the purposes of this study consisted of a visualized area of abnormal increased FDG uptake that matched the anatomic location of an abnormality seen on bone scan or CT. Metabolic response was assessed for percent change in SUVmax according to the criteria of the European Organization for Research and Treatment of Cancer (EORTC) : partial metabolic response (PMR) ≤ -25%; stable metabolic disease (SMD) -25% + 25%; progressive metabolic disease (PMD) > 25%.
Time Frame	10 to 14 days after study entry

Outcome Measure Data

Analysis Population Description

All patients receiving at least one dose of RAD001

Arm/Group Title	RAD001 Followed by RAD001 + Docetaxel
Arm/Group Description	RAD001 10 mg daily for 2 weeks, followed by RAD001 + Docetaxel at one of three doses: 5 mg RAD001 and docetaxel at 60 mg/m2, 10 mg RAD001 and docetaxel at 60 mg/m2, and 10 mg RAD001 and docetaxel at 70 mg/m2. RAD001 was given daily. Docetaxel was given every 3 weeks by intravenous infusion. Patients also received prednisone 5 mg by mouth twice daily.
Measure Participants	18
Partial Metabolic Response	22 122.2%
Stable Metabolic Disease	67 372.2%
Progressive Metabolic Disease	11 61.1%

Adverse Events

Arm/Group Title	RAD001 Followed by RAD001 + Docetaxel
Arm/Group Description	RAD001 10 mg daily for 2 weeks, followed by RAD001 + Docetaxel at one of three doses: 5 mg RAD001 and docetaxel at 60 mg/m2, 10 mg RAD001 and docetaxel at 60 mg/m2, and 10 mg RAD001 and docetaxel at 70 mg/m2. RAD001 was given daily. Docetaxel was given every 3 weeks by intravenous infusion. Patients also received prednisone 5 mg by mouth twice daily.
All Cause Mortality
	RAD001 Followed by RAD001 + Docetaxel
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	RAD001 Followed by RAD001 + Docetaxel
	Affected / at Risk (%)	# Events
Total	13/18 (72.2%)
Blood and lymphatic system disorders
Anemia	1/18 (5.6%)
Febrile neutropenia	3/18 (16.7%)
Hepatobiliary disorders
Cholecystitis	1/18 (5.6%)
Infections and infestations
Infection with Grade 3-4 neutrophils - lung	1/18 (5.6%)
Infection with Grade 0-2 neutrophils - lung	1/18 (5.6%)
Investigations
Leukopenia	6/18 (33.3%)
Neutropenia	8/18 (44.4%)
Thrombocytopenia	1/18 (5.6%)
Metabolism and nutrition disorders
Hyperglycemia	2/18 (11.1%)
Hypokalemia	1/18 (5.6%)
Vascular disorders
Hypertension	1/18 (5.6%)
Other (Not Including Serious) Adverse Events
	RAD001 Followed by RAD001 + Docetaxel
	Affected / at Risk (%)	# Events
Total	18/18 (100%)
Gastrointestinal disorders
Constipation	1/18 (5.6%)
Diarrhea w/o prior colostomy	8/18 (44.4%)
Hemorrhoids	1/18 (5.6%)
Muco/stomatitis by exam - oral cavity	4/18 (22.2%)
Muco/stomatitis (symptom) oral cavity	1/18 (5.6%)
Nausea	4/18 (22.2%)
GI-other	1/18 (5.6%)
Abdomen - pain	1/18 (5.6%)
General disorders
Fatigue	8/18 (44.4%)
Fever w/o neutropenia	2/18 (11.1%)
Rigors/chills	1/18 (5.6%)
Edema limb	2/18 (11.1%)
Infections and infestations
Infection with Grade 0-2 neutrophils - upper airway	2/18 (11.1%)
Investigations
Weight loss	1/18 (5.6%)
Elevated AST/SGOT	4/18 (22.2%)
Hypercholesterolemia	5/18 (27.8%)
Metabolism and nutrition disorders
Anorexia	2/18 (11.1%)
Hypernatremia	1/18 (5.6%)
Hyponatremia	1/18 (5.6%)
Hypertriglyceridemia	1/18 (5.6%)
Musculoskeletal and connective tissue disorders
Extremity-limb - pain	1/18 (5.6%)
Joint - pain	1/18 (5.6%)
Muscle - pain	1/18 (5.6%)
Nervous system disorders
Taste disturbance	2/18 (11.1%)
Dizziness	1/18 (5.6%)
Neuropathy-sensory	3/18 (16.7%)
Psychiatric disorders
Depression	1/18 (5.6%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	1/18 (5.6%)
Nose - hemorrhage	3/18 (16.7%)
Throat/pharynx/larynx - pain	1/18 (5.6%)
Cough	3/18 (16.7%)
Dyspnea	4/18 (22.2%)
Pneumonitis/pulmonary infiltrates	2/18 (11.1%)
Skin and subcutaneous tissue disorders
Alopecia	3/18 (16.7%)
Nail changes	1/18 (5.6%)
Rash/desquamation	2/18 (11.1%)
Hand-foot reaction	1/18 (5.6%)

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.