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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
European Organisation for Research and Treatment of Cancer - EORTC
ClinicalTrials.gov Identifier:
NCT00068757
First received: September 10, 2003
Last updated: September 11, 2012
Last verified: September 2012
  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
Other: pharmacological study
Phase 1

Study Type: Interventional
Study Design: Masking: 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

Resource links provided by NLM:


Further study details as provided by European Organisation for Research and Treatment of Cancer - EORTC:

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 ]

Enrollment: 23
Study Start Date: August 2003
Primary Completion Date: November 2007 (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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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

Locations
Belgium
Institut Jules Bordet
Brussels, Belgium, 1000
France
Institut Curie Hopital
Paris, France, 75248
Netherlands
Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital
Amsterdam, Netherlands, 1066 CX
Sponsors and Collaborators
European Organisation for Research and Treatment of Cancer - EORTC
Investigators
Study Chair: Jan H. M. Schellens, MD, PhD The Netherlands Cancer Institute
  More Information

Additional Information:
No publications provided

Responsible Party: European Organisation for Research and Treatment of Cancer - EORTC
ClinicalTrials.gov Identifier: NCT00068757     History of Changes
Other Study ID Numbers: EORTC-16023-10051, EORTC-16023-10051, SPRI-P01900
Study First Received: September 10, 2003
Last Updated: September 11, 2012
Health Authority: United States: Federal Government

Keywords provided by European Organisation for Research and Treatment of Cancer - EORTC:
recurrent breast cancer
stage IIIB breast cancer
stage IIIC breast cancer
stage IV breast cancer
male breast cancer
HER2-positive breast cancer

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Paclitaxel
Trastuzumab
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 29, 2014