Lonafarnib, Trastuzumab, and Paclitaxel in Treating Patients With HER2/Neu-Overexpressing Stage IIIB, Stage IIIC, or Stage IV Breast Cancer

Sponsor

European Organisation for Research and Treatment of Cancer - EORTC (Other)

Overall Status

Completed

CT.gov ID

NCT00068757

Collaborator

(none)

Enrollment

Locations

7.7

Patients Per Site

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop tumor cells from dividing so they stop growing or die. Lonafarnib may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Monoclonal antibodies, such as trastuzumab, can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Combining lonafarnib and trastuzumab with paclitaxel may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of lonafarnib when given together with trastuzumab and paclitaxel in treating patients with HER2/neu-overexpressing stage IIIB, stage IIIC, or stage IV breast cancer.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Biological: trastuzumab Drug: lonafarnib Drug: paclitaxel Other: pharmacological study	Phase 1

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

23 participants

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase I Study of Lonafarnib (SCH66336) in Combination With Herceptin Plus Paclitaxel in HER 2 NEU Overexpressing Breast Cancer

Study Start Date :

Aug 1, 2003

Actual Primary Completion Date :

Nov 1, 2007

Outcome Measures

Primary Outcome Measures

Dose-limiting toxicity and maximum tolerated dose as measured by CTC v 2.0 []

Secondary Outcome Measures

Translational research []
Pharmacokinetics (PK) and pharmacodynamics (PD) []
Clinical response as measured by RECIST criteria []

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Institut Jules Bordet	Brussels	Belgium	1000
2	Institut Curie Hopital	Paris	France	75248
3	Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital	Amsterdam	Netherlands	1066 CX