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

Sponsor:	European Organization for Research and Treatment of Cancer
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00068757

Purpose

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	Intervention	Phase
Breast Cancer	Biological: trastuzumab Drug: lonafarnib Drug: paclitaxel	Phase I

Study Type:	Interventional
Study Design:	Treatment, Open Label
Official Title:	Phase I Study of Lonafarnib (SCH66336) in Combination With Herceptin Plus Paclitaxel in HER 2 NEU Overexpressing Breast Cancer

Resource links provided by NLM:

Genetics Home Reference related topics: breast cancer

MedlinePlus related topics: Breast Cancer Cancer

Drug Information available for: Paclitaxel Trastuzumab Lonafarnib

U.S. FDA Resources

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

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

Secondary Outcome Measures:

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 ]

Estimated Enrollment:	36
Study Start Date:	August 2003
Estimated Primary Completion Date:	June 2008 (Final data collection date for primary outcome measure)

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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00068757

Locations

Belgium
Institut Jules Bordet	Recruiting
Brussels, Belgium, 1000
Contact: Contact Person 32-2-541-3510
France
Institut Curie Hopital	Recruiting
Paris, France, 75248
Contact: Contact Person 33-1-4432-4100
Netherlands
Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital	Recruiting
Amsterdam, Netherlands, 1066 CX
Contact: Contact Person 31-20-512-2665

Sponsors and Collaborators

European Organization for Research and Treatment of Cancer

Investigators

Investigator:

Jan H. M. Schellens, MD, PhD

Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

No publications provided

Study ID Numbers:	CDR0000327986, EORTC-16023-10051, SPRI-P01900
Study First Received:	September 10, 2003
Last Updated:	June 16, 2009
ClinicalTrials.gov Identifier:	NCT00068757 History of Changes
Health Authority:	Unspecified

Keywords provided by National Cancer Institute (NCI):

recurrent breast cancer
stage IIIB breast cancer
stage IIIC breast cancer
stage IV breast cancer
male breast cancer

Additional relevant MeSH terms:

Skin Diseases
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Mitosis Modulators
Breast Neoplasms
Antimitotic Agents
Pharmacologic Actions
Neoplasms

Neoplasms by Site
Paclitaxel
Therapeutic Uses
Tubulin Modulators
Trastuzumab
Antineoplastic Agents, Phytogenic
Breast Diseases

ClinicalTrials.gov processed this record on November 09, 2009