Metastatic, Androgen Independent Prostate Cancer, Prostate Cancer
Conditions
Keywords
prostate cancer, RAD001, mTOR inhibition, docetaxel
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).
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.
Interventions
DRUGRAD001
Daily for two weeks
DRUGDocetaxel
Infusion once per cycle
DRUGPrednisone
Prednisone 5 mg by mouth twice daily
Sponsors
Novartis
Massachusetts General Hospital
Beth Israel Deaconess Medical Center
Oregon Health and Science University
Dana-Farber Cancer Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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: 1. 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. 2. CTCAE grade 3 or 4 fever identified with a source (i.e. infection, tumor) 3. CTCAE grade 3 or 4 alkaline phosphatase. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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%. |
Countries
United States
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
Participants by arm
| Arm | Count |
|---|---|
| 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. | 18 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| PET Imaging and Assessment | Adverse Event | 3 |
| Single Agent RAD001 | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | RAD001 Followed by RAD001 + Docetaxel |
|---|---|
| Age, Continuous | 62 years |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 18 / 18 |
| serious Total, serious adverse events | 13 / 18 |
Outcome results
Primary
Number of Patients Free of Dose Limiting Toxicity
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: 1. 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. 2. CTCAE grade 3 or 4 fever identified with a source (i.e. infection, tumor) 3. CTCAE grade 3 or 4 alkaline phosphatase.
Time frame: 21 days
Population: Patients who received combination treatment with RAD001 + Docetaxel
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RAD001 Followed by RAD001 + Docetaxel | Number of Patients Free of Dose Limiting Toxicity | 14 participants |
Secondary
Response Based on PET Scan
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
Population: All patients receiving at least one dose of RAD001
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| RAD001 Followed by RAD001 + Docetaxel | Response Based on PET Scan | Stable Metabolic Disease | 67 percentage of participants |
| RAD001 Followed by RAD001 + Docetaxel | Response Based on PET Scan | Progressive Metabolic Disease | 11 percentage of participants |
| RAD001 Followed by RAD001 + Docetaxel | Response Based on PET Scan | Partial Metabolic Response | 22 percentage of participants |