A Phase II Study of Rapamycin and Trastuzumab for Patients With HER-2 Receptor Positive Metastatic Breast Cancer
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Rapamycin; Trastuzumab
Intervention description: oral rapamycin 6 mg daily; 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.
Intervention MeSH terms: Sirolimus; Trastuzumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 11.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: HER-2 positive; breast cancer; HER-2 positive breast cancer

Summary:

      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.
    

Eligibility criteria:

        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