Lapatinib and RAD-001 for HER2 Positive Metastatic Breast Cancer

INCLUSION CRITERIA

• Females > 18 years of age
• Histologically proven adenocarcinoma of breast in primary or metastatic setting. Stage: Locally advanced (inoperable) or metastatic
• HER2 positive breast cancer (IHC 3+ or FISH ratio of > 2.0)
• ECOG Performance status 0-2
• Up to four prior chemotherapy regimens and anti-HER2 agents in metastatic setting allowed. Must have progressed on at least one HER2 targeted therapy (lapatinib or Herceptin) for metastatic breast cancer.
• Women of childbearing potential must have negative urine or serum pregnancy test within 7 days prior to administration of Everolimus. If barrier contraceptives are used, they must be continued throughout trial by both sexes. Hormonal contraceptives not acceptable as a sole method of contraception.
• Adequate kidney function: serum creatinine of < 1.5 mg/dl and/or creatinine clearance of > 60 mL/min
• Adequate hepatic function: transaminases < 2.5 x upper limit of normal (up to 5 x ULN in patients with liver metastases) and total bilirubin < 1.5 mg/dL. Adequate coagulation: INR ≤ 2.0 and PTT < 1.5 X the upper limit of institution normal range. Oral anticoagulants, eg, warfarin are CYP2C9 substrates and, as such, no interaction with Everolimus is expected. Anticoagulation with Coumadin is allowed if target INR is ≤ 2.0 and stable for > 2weeks. Anticoagulation with LMW is allowed.
• Must be informed of investigational nature of study, and must sign an informed consent
• Pretreatment lab values (must be performed within 14 days of patient registration unless otherwise specified. Other baseline studies must be performed within 30 days of registration.
• Patients will have baseline CT chest, abdomen and pelvis within 30 days of registration.
• Adequate cardiac function (LVEF ≥ 50% as measured by echocardiogram or MUGA scan).
• 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, patient may be included after initiation of appropriate lipid lowering medication with approval from the principal investigator.

• Must have measurable or non-measurable disease by RECIST criteria (version 1.1), with radiologic scans performed within 30 days of registration. Baseline scans can include:

  • CT Scan or MRI and Bone Scan OR
  • PET/CT provided it is performed with both IV and oral contrast and the CT is acquired with 5mm or less slice thickness. If IV contrast administration is contraindicated, patients should have CT scan without contrast and bone scan or MRI and bone scan.
  • MRI of brain will be used for baseline assessment and tumor response assessment for CNS lesions.
  • Baseline imaging method(s) should be used to determine tumor response throughout course of study.

  • Measurable disease: lesions with clearly defined margins that can be accurately measured in at least one diameter (longest diameter to be recorded) with a minimum size of:

    • 10mm by CT scan (CT scan slice thickness no greater than 5mm)
    • 10mm caliper measurement by clinical exam (lesions which cannot be accurately measured with calipers should be recorded as non-measurable)
    • 20mm by chest xray
    • Malignant lymph nodes: to be considered pathologically enlarged and measurable. Lymph node must be > 15mm in short axis when assessed by CT scan. At baseline and in follow-up, only short axis will be measured and followed.

  • Non-measurable disease: all other lesions including small lesions (longest diameter < 10mm or pathological lymph nodes with > to <15 mm (short axis), and masses with margins not clearly defined. Lesions that are considered non-measurable include:

    • Bone lesions
    • Leptomeningeal disease
    • Ascites
    • Pleural/pericardial effusion
    • Inflammatory breast disease
    • Abdominal masses that are not confirmed and followed by imaging techniques
    • Cystic lesion
    • Lymphangitic involvement of skin or lung

• The following pre-study tests should be obtained within 14 days prior to registration in accordance with good medical practice. Results of these tests do not determine eligibility and minor deviations are acceptable if they do not impact patient safety in the judgment of the treating physician:

  • ANC > 1,000/mm3
  • platelet count > 100,000/mm3
  • hemoglobin > 9 g/dL

Exclusion Criteria:

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring parenteral antibiotics or psychiatric illness/social situations that would limit compliance with study requirements.
• GI tract disease resulting in an inability to take oral medication, malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (eg, Crohn's, ulcerative colitis).
• Current active hepatic or biliary disease (exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)
• Pregnant and lactating women. Women of reproductive potential not using or unwilling to use effective birth control methods throughout the trial.

• Severe and/or uncontrolled medical conditions or other conditions that could affect participation in the study such as:

  • Symptomatic congestive heart failure of NYHA Class III or IV
  • unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease
  • liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C). Note: A detailed assessment of Hepatitis B/C medical history and risk factors must be done at screening for all patients. HBV DNA and HCV RNA PCR testing required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior HBV/HCV infection.
• Patients with symptomatic brain metastases who have not completed radiation therapy and/or are receiving systemic steroid therapy. Patients with leptomeningeal disease will be excluded.
• Patients receiving chronic, systemic treatment with corticosteroids (of more than 4mg/day or equivalent of dexamethasone. Doses of dexamethasone of up to 8mg/day may be administered for less than 2 weeks) or another immunosuppressive agent. Topical or inhaled corticosteroids are allowed.
• Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period.
• Severely impaired lung function defined as spirometry and DLCO that is < 50% of the normal predicted value and/or 02 saturation that is 88% or less at rest on room air.
• Uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN.
• Active (acute or chronic) or uncontrolled severe infections.
• Known history of HIV seropositivity.
• Active, bleeding diathesis.
• Patients who have received prior treatment with an mTOR inhibitor (eg, sirolimus, temsirolimus, everolimus).
• Known hypersensitivity to Everolimus or other rapamycins (eg, sirolimus, temsirolimus) or to its excipients.
• Active Hepatitis B or C infection.
• Life expectancy of < 2 months.
• Prior anti-cancer therapy (eg, biologic or other targeted therapy, chemotherapy, hormonal therapy) within 2 weeks prior to Day 1 if the patient has recovered from all AEs to grade 1 except for alopecia.
• Prior investigational anti-cancer therapy within 4 weeks prior to Day 1.
• Patients who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, have not recovered from side effects of any major surgery (defined as requiring general anesthesia) or may require major surgery during the course of study.
• Other malignancies within past 3 years except for adequately treated carcinoma of cervix or basal or squamous cell carcinomas of the skin.