Phase I Study of Intermittent High-Dose Lapatinib in Tandem With Capecitabine for HER2 Overexpressed/Amplified Metastatic Breast Cancer With Central Nervous System (CNS) Metastases
Overview
- Phase
- Phase 1
- Intervention
- Lapatinib in Tandem With Capecitabine
- Conditions
- Metastatic Breast Cancer
- Sponsor
- Memorial Sloan Kettering Cancer Center
- Enrollment
- 11
- Locations
- 9
- Primary Endpoint
- maximum tolerated dose (MTD)
- Status
- Completed
- Last Updated
- 5 years ago
Overview
Brief Summary
The purpose of this study is to see if capecitabine can be taken safely with different doses of lapatinib in patients with HER-2 positive breast cancer involving brain (brain metastases) and/or in spinal fluid (leptomeningeal disease).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Age ≥18 years
- •Histologically-confirmed metastatic adenocarcinoma of the breast with either invasive primary tumor or metastatic tissue confirmation of HER2+ status as defined by immunohistochemistry (IHC) with score of 3+, or, if 2+ with confirmatory fluorescence in situ hybridization (FISH) ratio of ≥ 2.0
- •Received prior trastuzumab or chemotherapy for metastatic breast cancer except if patient has CNS as only site of metastatic disease.
- •Radiologic evidence of new and/or progressive parenchymal brain metastasis, spinal cord metastases ( intramedullary) or leptomeningeal disease (LMD) by magnetic resonance (MR) imaging of the brain and/or spine, or CSF cytology evidence of new LMD.
- •Life expectancy of \>12 weeks.
- •ECOG Performance of 0 to 2
- •Non-escalating corticosteroid dose (not exceeding more than 16 mg daily of dexamethasone oral) for ≥ 5 days.
- •Prior therapy:
- •No limit to prior therapies with last anti-cancer treatment ≥ 2 weeks from initiation of protocol-based therapy provided all toxicities (other than alopecia) have resolved to ≤Grade 1 or baseline. For lapatinib and IV trastuzumab and/or pertuzumab, no washout is required.
- •Patients with prior whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS) are eligible, provided that there are new lesions not previously treated by SRS and ≥4 weeks have passed since radiation
Exclusion Criteria
- •Contraindications or history of allergic reaction to lapatinib or to capecitabine, known dihydropyrimidine dehydrogenase deficiency, or known hypersensitivity of 5-fluorouracil.
- •Craniotomy or any other major surgery, open biopsy, or significant traumatic injury within 4 weeks of enrollment.
- •Serious, non-healing wound, infection, ulcer, bone fracture, or uncontrolled seizures
- •Significant gastrointestinal disorder with diarrhea as a major symptom (example Crohn's disease, ulcerative colitis) or Grade ≥ 2 diarrhea of any etiology at baseline. Active hepatobiliary disease with the exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases, or stable chronic liver disease as determined by investigator's assessment.
- •Significant medical co-morbidities as described below:
- •Cardiac disease:
- •Congestive heart failure \>class II New York Heart Association (NYHA) or
- •Unstable angina (anginal symptoms at rest), or new-onset angina (begun within the last 3 months), or myocardial infarction within the 6 months prior to enrollment, or
- •Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.
- •Known history of QTc prolongation or Torsades de Pointes
Arms & Interventions
Lapatinib in Tandem With Capecitabine
A minimum of one patient at each dose level will be enrolled. Patients will receive a 4 week treatment cycle consisting of lapatinib 3 day on/11 day off in tandem with capecitabine 7 day on/7 day off with lapatinib. Both drugs will be administered orally as outpatient. Safety, toxicity, and DLT will be assessed weekly during the cycle 1 (first 4 weeks). Each patient will be monitored during cycle 1 prior to enrolling the next patient to the next higher dose level. Dose escalation will take place if no DLT or less than two occurrences of grade 2 toxicity (except those listed below) is observed within a given patient. In the event that a second instance of separate grade 2 toxicity (except those listed below) is noted, the cohort will be expanded to 3 patients at the same dose level and the study will revert to the standard 3+3 design with 3 patients per cohort. There will be no intra-patient dose escalation.
Intervention: Lapatinib in Tandem With Capecitabine
Outcomes
Primary Outcomes
maximum tolerated dose (MTD)
Time Frame: first 28-day cycle
During the standard 3+3, the probability that dose escalation will occur at any stage during MTD determination is a function of the underlying DLT rate at the current dose level. This probability can be calculated as the sum of the binomial probabilities of the following two outcomes that would permit escalation to occur: 1. No DLT observed in the first three patients. 2. One DLT is observed in the first three patients followed by no DLT observed in three additional patients at the same dose level.