• Dose-limiting toxicity and maximum tolerated dose as measured by CTC v 2.0 [ Designated as safety issue: Yes ]
  

• Translational research [ Designated as safety issue: No ]
  
• Pharmacokinetics (PK) and pharmacodynamics (PD) [ Designated as safety issue: No ]
  
• Clinical response as measured by RECIST criteria [ Designated as safety issue: No ]
  

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.

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