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Phase I Study Of BMS-599626 In Patients With Advanced Solid Malignancies That Express Her2

Phase 1
18 Years
Not Enrolling
Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

Phase I Study Of BMS-599626 In Patients With Advanced Solid Malignancies That Express Her2



- 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.


- 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

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.

Inclusion Criteria


- 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



- 18 and over

Performance status

- ECOG 0-1

Life expectancy

- At least 3 months


- Absolute neutrophil count ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3

- Hemoglobin ≥ 9.0 g/dL


- 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


- Creatinine ≤ 1.5 times ULN

- Calcium normal


- 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


- 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


Biologic therapy

- At least 4 weeks since prior immunotherapy

- At least 2 weeks since prior targeted kinase inhibitor (e.g., trastuzumab


- 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


- At least 4 weeks since prior radiotherapy


- Not specified


- 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

- Concurrent low-dose coumadin allowed

- No other concurrent investigational agents

- No concurrent drugs that may cause torsades de pointes or QTc prolongation

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

maximum tolerated dose of BMS-599626

Outcome Time Frame:

28 days

Safety Issue:


Principal Investigator

Mark D. Pegram, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Jonsson Comprehensive Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

August 2004

Completion Date:

Related Keywords:

  • Unspecified Adult Solid Tumor, Protocol Specific
  • unspecified adult solid tumor, protocol specific
  • Neoplasms



Jonsson Comprehensive Cancer Center at UCLA Los Angeles, California  90095-1781