Phase I Study of Lonafarnib (SCH66336) in Combination With Herceptin Plus Paclitaxel in HER 2 NEU Overexpressing Breast Cancer
18 Years
N/A
Both
Breast Cancer
Trial Information
Phase I Study of Lonafarnib (SCH66336) in Combination With Herceptin Plus Paclitaxel in HER 2 NEU Overexpressing Breast Cancer
OBJECTIVES:
Primary
- Determine the maximum tolerated dose and recommended phase II dose of lonafarnib in
combination with trastuzumab (Herceptin®) and paclitaxel in patients with
HER2/neu-overexpressing stage IIIB, IIIC, or IV breast cancer.
- Determine the qualitative and quantitative toxicity of this regimen in these patients.
Secondary
- Determine the pharmacokinetic profiles of these drugs in these patients.
- Correlate the pharmacodynamics with the pharmacokinetics of this regimen in these
patients.
- Correlate the pharmacokinetics and pharmacodynamics of this regimen with observed
toxicity in these patients.
- Determine the response to this regimen in patients with measurable disease.
OUTLINE: This is a nonrandomized, open-label, multicenter, dose-escalation study of
lonafarnib.
- Course 1: Patients receive a loading dose of trastuzumab (Herceptin®) IV over 90
minutes on day 1 and over 30 minutes on days 8 and 15. Patients also receive paclitaxel
IV over 3 hours on day 1.
- Course 2: Patients receive trastuzumab IV over 30 minutes on days 1, 8, and 15 and
paclitaxel IV over 3 hours on day 2. Patients also receive oral lonafarnib twice daily
on days 3-21.
- Course 3 and all subsequent courses: Patients receive oral lonafarnib twice daily on
days 1-21; trastuzumab IV over 30 minutes on days 1, 8, and 15; and paclitaxel IV over
3 hours on day 1.
Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Cohorts of 3-6 patients receive escalating doses of lonafarnib until the maximum tolerated
dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2
of 6 patients experience dose-limiting toxicity.
Patients are followed every 8 weeks until disease progression.
PROJECTED ACCRUAL: A total of 3-36 patients will be accrued for this study.
Inclusion Criteria
DISEASE CHARACTERISTICS:
- Histologically or cytologically confirmed breast cancer
- Stage IIIB, IIIC, or IV
- HER2/neu overexpression
- 3+ by immunohistochemistry
- 2+ allowed if positive fluorescent in situ hybridization
- Disease meets the following treatment criteria:
- Paclitaxel/trastuzumab (Herceptin®) may be appropriate therapy
- Anthracycline therapy is not a suitable approach
- No clinical signs of CNS involvement
- Hormone receptor status:
- Not specified
PATIENT CHARACTERISTICS:
Age
- 18 and over
Sex
- Male or female
Menopausal status
- Not specified
Performance status
- ECOG 0-2 OR
- WHO 0-2
Life expectancy
- Not specified
Hematopoietic
- Neutrophil count at least 1,500/mm^3
- Platelet count at least 100,000/mm^3
- Hemoglobin at least 10.0 g/dL (6.2 mmol/L)
Hepatic
- Bilirubin no greater than 1.5 times upper limit of normal (ULN)
- Alkaline phosphatase less than 2.5 times ULN (5 times ULN if liver metastases are
present)
- AST and ALT less than 2.5 times ULN (5 times ULN if liver metastases are present)
Renal
- Creatinine clearance at least 40 mL/min
Cardiovascular
- Cardiac ejection fraction normal by MUGA
- QTc interval no greater than 440 msec
- No cardiac dysfunction
Other
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception during and for up to 3 months after
study participation
- No concurrent severe/unstable systemic disease
- No infection
- No circumstances that would preclude study participation (e.g., alcoholism or
substance abuse)
- No psychological, familial, sociological, or geographical condition that would
preclude study compliance and follow-up
PRIOR CONCURRENT THERAPY:
Biologic therapy
- More than 1 year since prior trastuzumab
- No concurrent prophylactic growth factors
Chemotherapy
- More than 1 year since prior paclitaxel
- More than 4 weeks since other prior chemotherapy
Endocrine therapy
- More than 1 day since prior hormonal therapy
- More than 2 days since prior high-dose chronic steroids
- More than 2 days since prior ethinyl estradiol
- No concurrent high-dose chronic steroids
- No concurrent ethinyl estradiol
Radiotherapy
- More than 4 weeks since prior radiotherapy
Surgery
- Not specified
Other
- More than 2 days since prior administration of and no concurrent CYP3A4 inducers or
inhibitors, including any of the following:
- Gestodene
- Itraconazole
- Ketoconazole
- Cimetidine
- Erythromycin
- Carbamazepine
- Phenobarbital
- Phenytoin
- Rifampin
- Sulfinpyrazone
- No concurrent grapefruit juice
- No other concurrent anticancer agents
- No other concurrent investigational therapy
Type of Study:
Interventional
Study Design:
Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Dose-limiting toxicity and maximum tolerated dose as measured by CTC v 2.0
Safety Issue:
Yes
Principal Investigator
Jan H. M. Schellens, MD, PhD
Investigator Role:
Study Chair
Investigator Affiliation:
The Netherlands Cancer Institute
Authority:
United States: Federal Government
Study ID:
EORTC-16023-10051
NCT ID:
NCT00068757
Start Date:
August 2003
Completion Date:
Related Keywords:
- Breast Cancer
- recurrent breast cancer
- stage IIIB breast cancer
- stage IIIC breast cancer
- stage IV breast cancer
- male breast cancer
- HER2-positive breast cancer
- Breast Neoplasms
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