Trastuzumab and RAD001 in Patients With Human Epidermal Growth Receptor 2 (HER-2) Overexpressing Breast Cancer

This study has been completed.
Information provided by (Responsible Party):
M.D. Anderson Cancer Center Identifier:
First received: April 21, 2006
Last updated: April 1, 2013
Last verified: April 2013

Primary Objectives:

  1. To identify the optimal dose and pharmacokinetics of RAD001 in combination with trastuzumab in a Phase I trial
  2. 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.

    1. 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.
    2. 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).

Secondary objectives:

  1. To determine the pharmacokinetics of RAD001 in combination with trastuzumab. In the phase II portion of the study, pharmacokinetic studies will be optional.
  2. To determine the nature and degree of toxicity of RAD001 in combination with trastuzumab in this cohort of patients
  3. 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.
  4. To correlate biomarker expression with response to therapy.

Condition Intervention Phase
Breast Cancer
Neoplasm Metastasis
Drug: Trastuzumab
Drug: RAD001
Phase 1
Phase 2

Study Type: Interventional
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

Resource links provided by NLM:

Further study details as provided by M.D. Anderson Cancer Center:

Primary Outcome Measures:
  • Optimal Dose of RAD001 in combination with Trastuzumab [ Time Frame: 3 week cycle ] [ Designated as safety issue: Yes ]
    Dose evaluated after cycle 1 for each dose level; Dose-limiting toxicity is defined as any grade 3 or 4 toxicity (based on Common Terminology Criteria (CTC) version 3) except fatigue.

  • 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 CR plus PR at any time plus persistent SD (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.

Enrollment: 40
Study Start Date: April 2006
Study Completion Date: February 2013
Primary Completion Date: February 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Trastuzumab + RAD001
Trastuzumab loading dose is 8 mg/kg daily; maintenance dose = 6 mg/kg once per 21 day cycle. RAD001 10 mg PO (by mouth) daily.
Drug: Trastuzumab
Loading dose is 8 mg/kg daily; maintenance dose = 6 mg/kg once per 21 day cycle.
Other Name: Herceptin
Drug: RAD001
10 mg PO (by mouth) daily

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Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. History of biopsy-proven HER-2-overexpressing breast cancer and radiographic evidence of metastatic disease. The HER-2 status can be determined either by immunohistochemistry (score, 3+) or by fluorescence in situ hybridization.
  2. History of trastuzumab resistance, defined as the development of progressive disease after trastuzumab-based therapy for metastatic breast cancer. Patient may not have received more than 2 prior trastuzumab-based regimens and one lapatinib-based regimen (either as single agent or in combination with chemotherapy)for metastatic breast cancer. Patients who develop metastatic disease during or after adjuvant or neoadjuvant trastuzumab are eligible.
  3. Performance status 0-2 (by Eastern Cooperative Oncology Group (ECOG)scale).
  4. Absolute neutrophil count (ANC) 1500/µl or higher; Platelets 100,000/µl or higher; Hemoglobin 9.0 gm/dL or higher; Serum creatinine 2.0 mg/dL or lower; Total bilirubin 1.5 mg/dL or lower; Serum glutamic pyruvic transaminase (SGPT) up to 3* upper limit of normal; Alkaline phosphatase up to 3* upper limit of normal; Calcium 11.0 mg/dL or lower.
  5. Age 18 years or older.
  6. Patients must not be pregnant. A pregnancy test will be obtained if the patient is a woman of child-bearing potential, defined as a sexually mature woman who has not undergone a hysterectomy or who has not been naturally postmenopausal for at least 24 consecutive months (i.e., who has had menses at any time in the preceding 24 consecutive months).
  7. Patients must have signed an informed consent document stating that they understand the investigational nature of the proposed treatment.
  8. Patients must have measurable disease using Response Evaluation Criteria in Solid Tumors (RECIST). Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension with longest diameter >/= 20 mm using conventional techniques or >/= 10 mm with spiral computed tomography (CT) scan.
  9. Patients may not be receiving any other investigational agents, and must not have received investigational agents within 15 days of enrollment.
  10. Left ventricular ejection fraction determined by echocardiogram or multigated acquisition (MUGA) (cardiac scan) must be 50% or higher.

Exclusion Criteria:

  1. 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
  2. Prior treatment with any investigational drug within the preceding 15 days
  3. Chronic treatment with systemic steroids or another immunosuppressive agent
  4. Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases, and patients diagnosed with brain mets or leptomeningeal disease (LMD) within 3 months.
  5. Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin.
  6. A known history of HIV seropositivity
  7. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RAD001 (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)
  8. Patients with an active, bleeding diathesis or on oral anti-vitamin K medication (except low dose coumadin)
  9. Patients who have received prior treatment with an mTor inhibitor.
  10. History of noncompliance to medical regimens.
  11. Patients unwilling to or unable to comply with the protocol.
  12. Patients who are receiving any other investigational agents
  13. Patients exhibiting confusion, disorientation, or having a history of major psychiatric illness that may impair the understanding of the informed consent.
  Contacts and Locations
Please refer to this study by its identifier: NCT00317720

United States, Texas
UT MD Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Principal Investigator: Francisco Esteva, MD M.D. Anderson Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: M.D. Anderson Cancer Center Identifier: NCT00317720     History of Changes
Other Study ID Numbers: 2005-0471
Study First Received: April 21, 2006
Last Updated: April 1, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by M.D. Anderson Cancer Center:
Breast Cancer
Metastatic Breast Cancer

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasm Metastasis
Neoplasms by Site
Breast Diseases
Skin Diseases
Neoplastic Processes
Pathologic Processes
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Antifungal Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
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