A Phase II Study of Rapamycin and Trastuzumab for Patients With HER-2 Receptor Positive Metastatic Breast Cancer
Rapamune (generic name: Sirolimus®) is a drug that has been approved by the Food and Drug Administration (government) for use in patients receiving a kidney transplant to prevent the patient's body from rejecting the transplanted kidney. It has shown antitumor effects in the laboratory, but has not been approved at this time for the treatment of cancer. Herceptin is a new form of chemotherapy that has been approved by the Food and Drug Administration for the treatment of breast cancer.
This study is designed to evaluate the effect and safety of combining Rapamune and Herceptin on breast cancer. Rapamune and Herceptin are being combined because results from our laboratory studies suggest that the combination of the two drugs is superior to either drug used alone. Results from laboratory studies performed at other institutions suggest that adding Rapamune to Herceptin may also reverse the resistance to Herceptin. Although there has been extensive experience using Herceptin alone and Rapamune alone in human subjects, the combination of Herceptin and Rapamune has not been previously evaluated. In addition, we hope to better understand how these treatments work against an individual woman's tumor by analyzing tissue samples before, and during treatment.
|Study Design:||Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase II Study of Rapamycin (Rapamune, Sirolimus) and Trastuzumab (Herceptin) for Patients With HER-2 Receptor Positive Metastatic Breast Cancer|
- Proportion of Patients Who Are Progression-free (CR, PR and Stable Disease) [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
To determine the clinical activity of oral daily rapamycin administered in combination with weekly intravenous trastuzumab in patients with HER2 overexpressing advanced breast cancer, the primary outcome is to determine the proportion of patients who are progression-free at 16 weeks, defined by complete response (CR), partial response (PR), or stable disease (SD).who are progression free at 16 weeks, defined by complete response (CR), partial response (PR), or stable disease (SD). Response objectives assessed using response evaluation criteria (RECIST) 1.0
This primary outcome was reworded from its original format when results were entered.
- Objective Response Rate (ORR) [ Time Frame: study completion up to 58 weeks ] [ Designated as safety issue: No ]
ORR was determined according to RECIST criteria, duration of response, and time to progression in patients with HER2 overexpressing advanced breast cancer receiving trastuzumab and rapamycin. The objective response rate (ORR) by response evaluation criteria (RECIST) 1.0, duration of response, safety, and pharmacodynamic endpoints.
This secondary outcome measure was reworded from its original submission when results were entered.
- Incidence of Cardiac Dysfunction [ Time Frame: study completion up to 58 weeks ] [ Designated as safety issue: Yes ]
This safety measure was used to determine the number of patients treated with the combination of trastuzumab and rapamycin with cardiac dysfunction.
This secondary outcome measure was reworded from its original version when results were entered.
- To Determine Pre and Post Therapy Changes in the Levels, Phosphorylation Status and/or Subcellular Localization of the Affected Signal Transduction Molecules HER2, Akt, S6K and 4EBP1 in Blood and Tumor Tissues [ Time Frame: Upon completion of study ] [ Designated as safety issue: No ]These data were not collected and analyzed as described here in the initial protocol submission.
- To Determine if Currently Available RNA Expression Profiles Associated With Response to Herceptin Will be Predictably Altered in Tumors Treated With Trastuzumab and Rapamycin, and Will Further Elucidate the Mechanism of Synergy of These Two Agents [ Time Frame: study completion ] [ Designated as safety issue: No ]
- To Evaluate the Use of FDG-PET as an Early Predictor of Response to the Combination of Rapamycin and Trastuzumab, be Assessing Changes in Glucose Metabolism and Cell Viability Between Pre- and Post-treatment [ Time Frame: Upon completion of study ] [ Designated as safety issue: No ]
|Study Start Date:||December 2006|
|Study Completion Date:||May 2010|
|Primary Completion Date:||May 2010 (Final data collection date for primary outcome measure)|
Experimental: sirolimus and trastuzumab
Patients received oral sirolimus 6 mg daily in combination with weekly trastuzumab administered intravenously with a loading dose of 4 mg/kg followed by 2 mg/kg weekly in a 28-day cycle. A subsequent amendment allowed trastuzumab to be administered every 3 weeks for patient convenience, with a loading dose of 8 mg/kg followed by a 6 mg/kg in a 21-day cycle. Sirolimus was administered at a 6 mg oral daily dose. Cycles were repeated on an every 21 or 28-day schedule until disease progression, unacceptable toxicity, or the development of any of the criteria for study removal. Doses were reduced or discontinued based on tolerability.
oral rapamycin 6 mg daily
Other Names:Drug: Trastuzumab
Trastuzumab 4 mg/kg will be administered (intravenous) on day 1, and this will be followed by weekly dose of 2 mg/kg starting day 8.
Other Name: Herceptin
Please refer to this study by its ClinicalTrials.gov identifier: NCT00411788
|United States, Connecticut|
|Bridgeport, Connecticut, United States, 06610|
|Yale Comprehensive Cancer Center at Yale University School of Medicine|
|New Haven, Connecticut, United States, 06519|
|Principal Investigator:||Maysa Abu-Khalaf, MD||Yale University|