Clinical trial NCT00317720
Conditions: Breast Cancer Neoplasm Metastasis
Keywords: Breast Cancer Metastatic Breast Cancer Trastuzumab RAD001 Herceptin
Sponsor: M.D. Anderson Cancer Center
Start date: 2006-04-01; Completion date: 2013-02-01
Enrollment: 40 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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.

Detailed description:
RAD001 is a new drug that was designed to block proteins that are important in the development and growth of cancer. It may also stop the growth of new blood vessels that help tumor growth, resulting in cell death.

Trastuzumab is a monoclonal antibody that binds to the HER-2 molecule on the surface of cancer cells. It does not bind to cells that do not have the HER-2 molecule. Trastuzumab slows the growth of cancer cells and also makes them more able to be treated with other chemotherapy drugs.

Before you begin to receive the study drug, you will have what are called "screening tests." These tests will help the doctor decide if you are eligible to take part in this study. You will have your complete medical history recorded, and a physical exam, including measurement of vital signs (blood pressure, heart rate, temperature, and breathing rate) will be performed. Routine blood tests (about 2 teaspoons) will be collected within 1 week before therapy. Cancer tissue taken at the time of your initial diagnosis or surgery will be collected. Special stains will be done that will help find ways in which researchers can predict the response of your cancer to trastuzumab plus RAD001. Women who are able to have children must have a negative urine pregnancy test. Some participants may need x-rays and/or positron emission tomography (PET) scans before receiving study drug and again within 3 weeks after the start of therapy.

If you are found to be eligible to take part in this study, you will receive RAD001 tablets by mouth once a day. Every 3 weeks (21 days) is considered 1 course of the study. The dose of trastuzumab you receive on this study will not be different from what you were receiving before this study started.

If you are participating in the Phase I portion of the study, you will have about 4 teaspoons of blood drawn before you start the study on Day 1. Blood samples will be drawn prior to initiation of treatment and at 0.5, 1, 2, 5, 8, 24 hours. You will also have around 4 teaspoons of blood drawn on Day 15 (before the start of treatment and at 0.5, 1, 2, 5, 8, and 24 hours).

While on study, you will have weekly blood tests (about 2 teaspoons) for the first 3 weeks. After 3 weeks, if you tolerate the study drug well, your blood tests (about 2 teaspoons each time) will be drawn once every 3 weeks, or as often as your physicians feel that they are necessary. Six (6) weeks after your first cycle of study drug, you will undergo x-rays, computed tomography (CT) scans, magnetic resonance imaging (MRI), or PET scans to see how you are responding to the study drug. If the disease shows a response to the study drug or is stable, then future x-rays, CT scans, MRI or PET scans will be performed every 6 weeks, or as often as the physician feels it is necessary. After that, the scans will be performed every 9 weeks, or as often as the physician feels it is necessary. A physical exam, including vital signs (blood pressure, heart rate, temperature, and breathing rate), will be done every 3 weeks and any time the physician feels it is necessary.

You will continue to take the study drug as long as you continue to benefit from it. You may be removed from this study if you do not respond after 2 courses of the study drug, intolerable side effects occur, or the disease gets worse. Your dose may be lowered if certain side effects occur.

Once you come off study, a physical exam, measurement of vital signs (blood pressure, heart rate, temperature, and breathing rate), a blood test (about 2 teaspoons), x-rays, and/or scans will be done.

This is an investigational study. Trastuzumab is commercially available for use as a single therapy or in combination with paclitaxel. However, the combination of trastuzumab and RAD001 is experimental. The FDA has authorized RAD001 for use in research only. Up to 47 patients will take part in this multicenter study. Up to 36 will be enrolled at UT MD Anderson.

Arms: arm 1: 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.
Interventions: intervention 1: Trastuzumab intervention 2: RAD001
Intervention descriptions: intervention 1: 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. intervention 2: Starting dose 10 mg by mouth daily. Phase I dose finding from two dose levels of daily RAD001 (5 and 10 mg).

Protocol documents: