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

Phase 1

Completed

• Conditions: Metastatic, Androgen Independent Prostate Cancer; Prostate Cancer
• Interventions: Drug: RAD001; Drug: Docetaxel; Drug: Prednisone

• Registration Number: NCT00459186
• Lead Sponsor: Dana-Farber Cancer Institute

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.

Study Timeline

• Study Start: 2005-11
• Study First Submitted: 2006-01-23
• Study First Submitted QC: 2007-04-10
• Study First Posted: 2007-04-11
• Primary Completion: 2012-12
• Study Completion: 2012-12
• Results First Submitted: 2013-12-13
• Results First Submitted QC: 2014-01-20
• Results First Posted: 2014-03-03
• Status Verified: 2016-04
• Last Update Submitted: 2016-04-13
• Last Update Posted: 2016-05-16

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 19

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
RAD001 Followed by RAD001 + Docetaxel	RAD001	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.
RAD001 Followed by RAD001 + Docetaxel	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.
RAD001 Followed by RAD001 + Docetaxel	Prednisone	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.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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%.

Trial Locations

Locations (5)

Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States

Dana-Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

Beth Israel Deaconess Medical Center; 🇺🇸 Boston, Massachusetts, United States

Brigham and Women's Hospital; 🇺🇸 Boston, Massachusetts, United States

Oregon Health Science University; 🇺🇸 Portland, Oregon, United States