Patient case: 64-year-old male with gastric cancer; genetic feature: ERBB2 amplification

Clinical trial: BMS-599626 in Treating Patients With Metastatic Solid Tumors

Summary: RATIONALE: BMS-599626 may stop the growth of tumor cells by blocking the enzymes necessary for their growth.
  PURPOSE: This phase I trial is studying the side effects and best dose of BMS-599626 in treating patients with metastatic solid tumors.

Detailed description: OBJECTIVES:
  Primary
  -  Determine the maximum tolerated dose, biologically active dose, and recommended phase II dose(s) of BMS-599626 in patients with metastatic HER2/neu-overexpressing primary solid tumors.
  Secondary
  -  Determine the safety and tolerability of this drug in these patients.
  -  Determine the pharmacokinetics of this drug in these patients.
  -  Determine the effect of this drug on biomarkers and predictive markers of HER1 and HER2 in skin and tumor in these patients.
  -  Evaluate tumor metabolic activity in response to this drug in these patients.
  -  Determine, preliminarily, evidence of anti-tumor activity of this drug in these patients.
  OUTLINE: This is an open-label, dose-escalation, multicenter study.
  Patients receive oral BMS-599626 once daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  Cohorts of 3-6 patients receive escalating doses of BMS-599626 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. Once the MTD is determined, 20 patients are treated at that dose level.
  PROJECTED ACCRUAL: Approximately 3-60 patients will be accrued for this study within 1 year.

Eligibility: DISEASE CHARACTERISTICS:
  -  Histologically or cytologically confirmed primary solid (i.e., non-hematologic) tumor
  -  Radiographic or tissue confirmation of metastatic disease
  -  Locally advanced disease allowed if no surgical or local therapeutic treatment exists
  -  HER2/neu overexpression (1+, 2+, or 3 +) by immunohistochemistry
  -  Tumors with HER2 gene amplification by fluorescence in situ hybridization analysis allowed
  -  Tumor paraffin tissue block OR 20-30 unstained slides from tumor tissue block must be available for biomarker and predictive marker analyses
  -  Disease progression during or after standard therapy OR no standard therapy exists
  -  Measurable or non-measurable disease
  -  Measurable disease is required for the expanded cohort treated at the maximum tolerated dose of the study drug
  -  No known brain metastasis
  -  Patients with controlled brain metastasis with no disease progression 60 days after prior therapy and no neurologic signs or symptoms are allowed
  -  Patients with signs or symptoms suggestive of brain metastasis are eligible provided that brain metastasis is ruled out by CT scan or MRI
  PATIENT CHARACTERISTICS:
  Age
  -  18 and over
  Performance status
  -  ECOG 0-1
  Life expectancy
  -  At least 3 months
  Hematopoietic
  -  Absolute neutrophil count ≥ 1,500/mm^3
  -  Platelet count ≥ 100,000/mm^3
  -  Hemoglobin ≥ 9.0 g/dL
  Hepatic
  -  Bilirubin ≤ 1.5 times upper limit of normal (ULN)
  -  ALT and AST ≤ 2.5 times ULN
  -  PT/PTT ≤ 1.5 times ULN
  -  INR ≤ 1.5 times ULN
  Renal
  -  Creatinine ≤ 1.5 times ULN
  -  Calcium normal
  Cardiovascular
  -  LVEF ≥ 45%
  -  Heart rate ≥ 50 beats/min on electrocardiogram
  -  No uncontrolled cardiovascular disease
  -  No myocardial infarction within the past 12 months
  -  No uncontrolled angina within the past 6 months
  -  No congestive heart failure within the past 6 months
  -  No prolonged QTc (> 450 msec) on electrocardiogram
  -  No diagnosed or suspected congenital long QT syndrome
  -  No history of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, or torsades de pointes)
  -  No history of second- or third-degree heart block
  -  Patients with pacemakers may be eligible
  -  No uncontrolled hypertension
  Other
  -  Not pregnant or nursing
  -  Negative pregnancy test
  -  Fertile patients must use effective contraception during and for at least 3 months after study participation
  -  Potassium normal
  -  Magnesium normal
  -  No medical condition that has a risk of causing torsades de pointes
  -  No active infection
  -  No serious uncontrolled medical disorder that would preclude study participation
  -  No dementia or altered mental status that would preclude giving informed consent
  -  No known allergy to BMS-599626 or related compound
  -  No prisoners or patients involuntarily incarcerated for treatment of either a psychiatric or physical (e.g., infectious disease) illness
  PRIOR CONCURRENT THERAPY:
  Biologic therapy
  -  At least 4 weeks since prior immunotherapy
  -  At least 2 weeks since prior targeted kinase inhibitor (e.g., trastuzumab [Herceptin^®])
  Chemotherapy
  -  At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas, mitomycin, or doxorubicin HCl liposome)
  Endocrine therapy
  -  At least 2 weeks since prior anticancer hormonal therapy
  Radiotherapy
  -  At least 4 weeks since prior radiotherapy
  Surgery
  -  Not specified
  Other
  -  Recovered from prior therapy
  -  Prior adjuvant or neoadjuvant therapy allowed
  -  No short-acting antacids (e.g., Maalox^® or TUMS^®) 8 hours before or 4 hours after study drug administration
  -  No recent anticancer therapy
  -  More than 4 weeks since prior investigational agents
  -  At least 5 days (or 5 half-lives) since prior drugs that cause torsades de pointes
  -  At least 48 hours since prior proton pump inhibitors (e.g., omeprazole or lansoprazole) or histamine H_2 antagonists (e.g., ranitidine, famotidine, or cimetidine)
  -  Concurrent low-dose coumadin allowed
  -  No other concurrent investigational agents
  -  No concurrent drugs that may cause torsades de pointes or QTc prolongation

Relevance to patient case: possibly relevant