Trastuzumab and RAD001 in Patients With Human Epidermal Growth Receptor 2 (HER-2) Overexpressing Breast Cancer
- To identify the optimal dose and pharmacokinetics of RAD001 in combination with trastuzumab in a Phase I trial
To determine the efficacy of RAD001 plus trastuzumab in HER-2-overexpressing patients with resistance to trastuzumab-based therapy for metastatic breast cancer in a Phase II trial.
- Trastuzumab resistance will be defined as the development of progressive disease after trastuzumab-based therapy for metastatic breast cancer. Patients who develop metastases while receiving adjuvant or neoadjuvant trastuzumab will be eligible.
- Efficacy would be measured by the rate of objective response plus stable disease lasting 6 months (complete response (CR) + partial response (PR) + stable disease SD).
- To determine the pharmacokinetics of RAD001 in combination with trastuzumab. In the phase II portion of the study, pharmacokinetic studies will be optional.
- To determine the nature and degree of toxicity of RAD001 in combination with trastuzumab in this cohort of patients
- To determine expression levels of total and phosphorylated mTOR and p70S6K-T389-P as well as relevant downstream signaling components (e.g., S6, 4E-BP1) in pre- and post- treatment tumor samples.
- To correlate biomarker expression with response to therapy.
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I-II Study of Trastuzumab in Combination With RAD001 in Patients With HER-2 Overexpressing, PTEN-deficient Metastatic Breast Cancer Progressing on Trastuzumab-Based Therapy|
- Optimal Dose of RAD001 in Combination With Trastuzumab (Phase I) [ Time Frame: Following two 3 week cycles of therapy ] [ Designated as safety issue: Yes ]
In Phase I, two dose levels of RAD001 were studied: 10 mg (dose level 1) and 5 mg (dose level -1) where each dose was evaluated after cycle 1. At MDACC, the Continual Reassessment Method (CRM) for determining Maximum Tolerated Dose (MTD) was applied to the two predefined RAD001 dose levels; and at DFCI/BIDMC, a 3 x 3 study design was utilized.
Optimal dose defined as the dose most closely associated with a toxicity rate of 0.20, and toxicity defined as any grade 3 or 4 toxicity (based on Common Terminology Criteria (CTC) version 3.0 except fatigue. Participants underwent clinical evaluation every 3 weeks (one cycle) and radiologic evaluations every 6 weeks. After the second cycle, participants underwent a radiologic evaluation using the same imaging technique used at initial evaluation (ie, computed tomography or magnetic resonance imaging).
- Clinical Benefit Response Rate (CBR) [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]Efficacy measured by the clinical benefit response rate (CBR), defined as confirmed Complete Response (CR) plus Partial Response (PR) at any time plus Persistent Stable Disease (pSD). Confirmed CR is defined as disappearance of all target lesions at the time of radiographic evaluation; pSD was defined as SD lasting 24 weeks. Complete Response (CR): disappearance of all target lesions, and Partial Response (PR): at least a 30% decrease in the sum of longest diameter (LD) of target lesions taking as a reference the baseline sum LD. Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease taking as references the smallest sum LD since the treatment started.
|Study Start Date:||April 2006|
|Study Completion Date:||February 2013|
|Primary Completion Date:||February 2013 (Final data collection date for primary outcome measure)|
Experimental: Trastuzumab + RAD001
Trastuzumab loading dose is 8 mg/kg daily; maintenance dose = 6 mg/kg once per 21 day cycle. Starting RAD001 dose 10 mg by mouth daily.
Loading dose = 8 mg/kg daily; maintenance dose = 6 mg/kg once per 21 day cycle.
If participant on trastuzumab at time of registration, loading dose deferred and received maintenance dose (6 mg/kg every 3 weeks). If the last trastuzumab dose was given 1 week (for participants receiving 2 mg/kg/week), or 3 weeks before registration (for participants receiving 6 mg/kg every 3 weeks), a loading dose (8 mg/kg) was given followed by maintenance dose.
Other Name: HerceptinDrug: RAD001
Starting dose 10 mg by mouth daily. Phase I dose finding from two dose levels of daily RAD001 (5 and 10 mg).
Other Name: Everolimus
Show Detailed Description
Please refer to this study by its ClinicalTrials.gov identifier: NCT00317720
|United States, Texas|
|UT MD Anderson Cancer Center|
|Houston, Texas, United States, 77030|
|Principal Investigator:||Francisco Esteva, MD||M.D. Anderson Cancer Center|