A Phase II Study of Rapamycin and Trastuzumab for Patients With HER-2 Receptor Positive Metastatic Breast Cancer

The recruitment status of this study is unknown because the information has not been verified recently.
Verified June 2009 by Yale University.
Recruitment status was  Recruiting
Genentech, Inc.
Information provided by:
Yale University
ClinicalTrials.gov Identifier:
First received: December 14, 2006
Last updated: June 5, 2009
Last verified: June 2009

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.

Condition Intervention Phase
Breast Cancer
Drug: Rapamycin
Drug: Trastuzumab
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
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

Resource links provided by NLM:

Further study details as provided by Yale University:

Primary Outcome Measures:
  • To determine the clinical activity of oral daily rapamycin administered in combination with weekly intravenous trastuzumab in patients with HER2 overexpressing advanced breast cancer [ Time Frame: Determine the proportion of patients who are progression-free (CR, PR and stable disease) at 16 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • To determine the objective response rate according to RECIST criteria, duration of response, and time to progression in patients with HER2 overexpressing advanced breast cancer receiving trastuzumab and rapamycin [ Time Frame: upon completion of study ] [ Designated as safety issue: No ]
  • To determine the rate of cardiac dysfunction in patients treated with the combination of trastuzumab and rapamycin [ Time Frame: Upon completion of study ] [ Designated as safety issue: Yes ]
  • 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 ]
  • 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: Upon completion of study ] [ 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 ]

Estimated Enrollment: 30
Study Start Date: December 2006
Estimated Study Completion Date: May 2010
Estimated Primary Completion Date: May 2010 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Rapamycin
    oral rapamycin 6 mg daily
    Other Names:
    • Rapamune
    • Sirolimus
    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

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Histologically confirmed HER2 overexpressing (IHC 3+ and/or FISH +) metastatic breast cancer with measurable disease. Patients with either HER2 3+ positive tumors by immunohistochemistry (Dako Herceptest®) or gene amplification (> 2 copies) by fluorescence in-situ hybridation (FISH) are eligible.
  • Progression following at least 8 weeks of standard doses of Herceptin or a Herceptin containing regimen.
  • Off Herceptin for a minimum of 2 weeks.
  • Patients must have measurable disease as defined by RECIST guidelines (the lesion that will be biopsied on study cannot be the only measurable lesion).
  • Life expectancy > 3 months
  • Age ≥18 years
  • ECOG performance status ≤2
  • Adequate bone marrow function as indicated by the following:

    • ANC ≥1500/µL
    • Platelets ≥100,000/µL
    • Hemoglobin ≥9 g/dL
  • Adequate liver function, as indicated by bilirubin ≤1.5 x ULN, AST or ALT <2x ULN.
  • Adequate renal function, as indicated by creatinine <1.5 x upper limit of normal (ULN)
  • Ability to understand and the willingness to sign a written informed consent.
  • Adequate birth control: Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and must have a negative serum or urine pregnancy test within 1 week prior to beginning treatment on this trial. Pregnant and nursing patients are excluded because the effects of the combination of Rapamycin on a fetus or nursing child are unknown. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
  • Fasting serum cholesterol <350 mg/d L and triglycerides < 400 mg/ d L.
  • Biopsy is required but patients or physicians may opt out of this part of the trial if sufficient justification is provided. Justification must be provided to the PI in writing indicating excessive physical risk or psychological trauma if biopsy is undertaken.

Exclusion Criteria:

  • Active infection or treatment for systemic infections within 14 days of enrollment
  • Patients with active brain metastases requiring treatment, inclusive but not limited to surgery, radiation, and corticosteroids (patients with asymptomatic non- progressing brain metastasis who have completed treatment ≥30 days before enrollment and without evidence of progression on a post treatment MRI may be considered for the study).
  • Pregnant or lactating women
  • Prior chemotherapy within the last 4 weeks (last 6 weeks for nitrosureas/mitomycin)
  • Prior radiation therapy within the last 4 weeks; prior radiation therapy to indicator lesion (unless objective disease recurrence or progression within the radiation portal has been documented since completion of radiation).
  • Prior therapy with rapamycin, rapamycin analogs, or experimental agents targeting mTOR.
  • Concomitant malignancies or previous malignancies within the last 5 years, with the exception of adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix.
  • Ejection fraction <50% or below the lower limit of the institutional normal range, whichever is lower
  • Hypersensitivity to trial medications
  • Patients may not be receiving any other investigational agents within 30 days before enrollment.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Pregnant women are excluded from this study because the investigational agents may have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with these agents, breastfeeding should be discontinued if the mother is treated.
  • HIV-positive patients are ineligible because these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy and the potential pharmacokinetic interaction between antiretroviral therapy and the investigational agents.
  • Use of all herbal and alternative medications within 4 weeks. All herbal and alternative medications should be discontinued while on study, these include but not limited to: Hydrastis canadensis (goldenseal) - Uncaria tomentosa (cat's claw) - Echinacea angustifolia roots - trifolium pratense (wild cherry) - matricaria chamomila (chamomile) - Glycyrrhiza glabra (licorice) - dillapiol - naringenim.
  • Use of any of these medications within 4 weeks; cyclosporine, diltiazen, ketoconazole, rifampin, fluconazole, delavirdine, nicardipine, pioglitazone, and sulfonamides, erythromycin, clarithromycin, itraconazole, erythromycin, metoclopramide, nevirapine, phenobarbital, phenytoin, indinavir, fosamprenavir, nefazadone, St Johns Wort.
  • Consumption of grapefruit juice is prohibited during the study.
  • Use of warfarin (Coumadin), immunosuppressive agents or chronic oral, intravenous or topical steroid
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00411788

Contact: Jeannie Kluytenaar, RN 203-785-6523 jeannie.kluytenaar@yale.edu
Contact: Michele Alguard 203-737-5908 michele.alguard@yale.edu

United States, Connecticut
Bridgeport Hospital Recruiting
Bridgeport, Connecticut, United States, 06610
Contact: Diane Eannotti, RN    203-384-4547    ndeann@bphosp.org   
Yale Comprehensive Cancer Center at Yale University School of Medicine Recruiting
New Haven, Connecticut, United States, 06519
Sponsors and Collaborators
Yale University
Genentech, Inc.
Principal Investigator: Maysa Abu-Khalaf, MD Yale University
  More Information

Responsible Party: Maysa Abu-Khalaf, M.D. Principal Investigator, Yale University School of Medicine
ClinicalTrials.gov Identifier: NCT00411788     History of Changes
Other Study ID Numbers: 0605001396 
Study First Received: December 14, 2006
Last Updated: June 5, 2009
Health Authority: United States: Institutional Review Board

Keywords provided by Yale University:
HER-2 positive
breast cancer
HER-2 positive breast cancer

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Antineoplastic Agents
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on August 25, 2016