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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00317720
Recruitment Status : Completed
First Posted : April 25, 2006
Results First Posted : June 12, 2014
Last Update Posted : June 26, 2014
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:

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 or disease Intervention/treatment Phase
Breast Cancer Neoplasm Metastasis Drug: Trastuzumab Drug: RAD001 Phase 1 Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 40 participants
Intervention Model: Single Group Assignment
Masking: None (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
Study Start Date : April 2006
Actual Primary Completion Date : February 2013
Actual Study Completion Date : February 2013

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
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.
Drug: Trastuzumab

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: Herceptin

Drug: 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

Primary Outcome Measures :
  1. Optimal Dose of RAD001 in Combination With Trastuzumab (Phase I) [ Time Frame: Following two 3 week cycles of therapy ]

    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).

  2. Clinical Benefit Response Rate (CBR) [ Time Frame: 6 weeks ]
    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.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): 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

Additional Information:
Publications of Results:
Responsible Party: M.D. Anderson Cancer Center Identifier: NCT00317720     History of Changes
Other Study ID Numbers: 2005-0471
First Posted: April 25, 2006    Key Record Dates
Results First Posted: June 12, 2014
Last Update Posted: June 26, 2014
Last Verified: June 2014

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
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents