Combination Treatment With Everolimus, Letrozole and Trastuzumab in Hormone Receptor and HER2/Neu-Positive Patients With Advanced Metastatic Breast Cancer and Other Solid Tumors: Evaluating Synergy and Overcoming Resistance
Overview
- Phase
- Phase 1
- Intervention
- Everolimus
- Conditions
- Advanced Malignant Solid Neoplasm
- Sponsor
- M.D. Anderson Cancer Center
- Enrollment
- 37
- Locations
- 5
- Primary Endpoint
- Maximum tolerated dose and/or recommended phase II dose
- Status
- Completed
- Last Updated
- 5 years ago
Overview
Brief Summary
This phase I trial studies the side effects and best dose of everolimus and trastuzumab when given together with letrozole in treating patients with hormone receptor-positive and human epidermal growth factor (EGF) receptor 2 (HER2)-positive breast cancer or other solid tumors that have spread to other places in the body. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Estrogen can cause the growth of breast cancer cells. Hormone therapy using letrozole may fight breast cancer by blocking the use of estrogen by tumor cells. Immunotherapy with monoclonal antibodies, such as trastuzumab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. Giving everolimus, letrozole, and trastuzumab together may be a better treatment for breast cancer and other solid tumors than everolimus alone.
Detailed Description
PRIMARY OBJECTIVES: I. Determine reasonable dose of drugs in treatment combination, including maximum tolerated dose (MTD) and toxicity profiles, via a brief initial "run-in"/dose escalation. II. Evaluate response, in patients with tumors that demonstrate hormone receptor (HR)-positivity (\> 1% on immunohistochemistry \[IHC\]) and human EGF receptor 2 (HER)-positivity (IHC 3 and/or IHC 2/3 and fluorescence in situ hybridization \[FISH\] amplification). SECONDARY OBJECTIVES: I. Correlate activity of combination with genomic and proteomic signatures. II. Evaluate 2 expanded cohorts of patients to include: 1) HR- and HER2-positive breast cancer (n=12) and 2) other HR- and HER2-positive tumors that have demonstrated activity in the dose escalation portion of the study (n=12). OUTLINE: This is a dose-escalation study of everolimus and trastuzumab. Patients receive everolimus orally (PO) once daily (QD) and letrozole PO QD. Patients also receive trastuzumab intravenously (IV) over 30-90 minutes once every 3 weeks. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for at least 30 days.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Signed informed consent obtained prior to any screening procedures
- •Performance status =\< 1
- •Absolute neutrophil count (ANC) \>= 1 x 10\^9/L
- •Platelets \>= 75 x 10\^9/L
- •Hemoglobin (Hb) \> 8 g/dL
- •Total serum bilirubin =\< 2.0 mg/dL
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\< 2.5 x upper limit of normal (ULN) (=\< 5 x ULN in patients with liver metastases)
- •International normalized ratio (INR) =\< 2
- •Serum creatinine =\< 1.5 x ULN
- •Fasting serum cholesterol =\< 300 mg/dL or =\< 7.75 mmol/L and fasting triglycerides =\< 2.5 x ULN; Note: in case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication
Exclusion Criteria
- •Patients currently receiving anticancer therapies or who have received anticancer therapies within 4 weeks of the start of everolimus (including chemotherapy, radiation therapy, antibody based therapy, etc.)
- •Known intolerance or hypersensitivity to everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus)
- •Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral everolimus
- •Uncontrolled diabetes mellitus as defined by glycated hemoglobin (HbA1c) \> 8% despite adequate therapy; patients with a known history of impaired fasting glucose or diabetes mellitus (DM) may be included, however blood glucose and antidiabetic treatment must be monitored closely throughout the trial and adjusted as necessary
- •Patients who have any severe and/or uncontrolled medical conditions such as:
- •Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction 6 months prior to start of everolimus, serious uncontrolled cardiac arrhythmia, or any other clinically significant cardiac disease
- •Symptomatic congestive heart failure of New York Heart Association class III or IV
- •Active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis (i.e. quantifiable hepatitis B virus \[HBV\]-deoxyribonucleic acid \[DNA\] and/or positive hepatitis B surface antigen \[HbsAg\], quantifiable hepatitis C virus \[HCV\]-ribonucleic acid \[RNA\])
- •Known severely impaired lung function (spirometry and diffusion capacity of the lungs for carbon monoxide \[DLCO\] 50% or less of normal and oxygen \[O2\] saturation 88% or less at rest on room air)
- •Active, bleeding diathesis
Arms & Interventions
Treatment (everolimus, letrozole, trastuzumab)
Patients receive everolimus PO QD and letrozole PO QD. Patients also receive trastuzumab IV over 30-90 minutes once every 3 weeks. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Everolimus
Treatment (everolimus, letrozole, trastuzumab)
Patients receive everolimus PO QD and letrozole PO QD. Patients also receive trastuzumab IV over 30-90 minutes once every 3 weeks. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Treatment (everolimus, letrozole, trastuzumab)
Patients receive everolimus PO QD and letrozole PO QD. Patients also receive trastuzumab IV over 30-90 minutes once every 3 weeks. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Letrozole
Treatment (everolimus, letrozole, trastuzumab)
Patients receive everolimus PO QD and letrozole PO QD. Patients also receive trastuzumab IV over 30-90 minutes once every 3 weeks. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Trastuzumab
Outcomes
Primary Outcomes
Maximum tolerated dose and/or recommended phase II dose
Time Frame: 21 days
Defined as the highest dose at which no more than 1 of 6 patients has had dose-limiting toxicity.
Clinical benefit rate
Time Frame: Up to 4 years
Defined as the percentage of patients with stable disease \>= 6 months/partial response/complete response. The point estimate and the 90% exact confidence interval for the clinical benefit rate will be calculated.