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


Phase 1
18 Years
N/A
Not Enrolling
Both
Breast Cancer

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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 (HerceptinĀ®) 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 (HerceptinĀ®) 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 (HerceptinĀ®) 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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