Neoadjuvant Tipifarnib, Docetaxel, and Capecitabine in Treating Patients With Locally Advanced or Metastatic Solid Tumors or Stage IIIA or Stage IIIB Breast Cancer

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Completed

CT.gov ID

NCT00070252

Collaborator

(none)

Enrollment

Locations

Arm

Duration (Months)

7.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Phase I/II trial to study the effectiveness of neoadjuvant tipifarnib combined with docetaxel and capecitabine in treating patients who have locally advanced or metastatic solid tumors or stage IIIA or stage IIIB breast cancer. Tipifarnib may stop the growth of tumor cells by blocking the enzymes necessary for cancer cell growth. Drugs used in chemotherapy, such as docetaxel and capecitabine, use different ways to stop tumor cells from dividing so they stop growing or die. Combining tipifarnib with docetaxel and capecitabine may kill more tumor cells.

Condition or Disease	Intervention/Treatment	Phase
Adult Solid Neoplasm Inflammatory Breast Carcinoma Male Breast Carcinoma Stage IIIA Breast Cancer Stage IIIB Breast Cancer	Drug: Capecitabine Drug: Docetaxel Other: Laboratory Biomarker Analysis Other: Pharmacological Study Drug: Tipifarnib	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

Determine the maximum tolerated dose and recommended dose of capecitabine in combination with docetaxel and tipifarnib in patients with locally advanced or metastatic solid tumors. (Phase Ib) II. Determine the complete pathological and clinical response rate in patients with stage IIIA or IIIB breast cancer treated with this regimen. (Phase II)

SECONDARY OBJECTIVES:

Determine the toxicity of this regimen in these patients. II. Determine disease-free and overall survival of patients treated with this regimen.

OUTLINE: This is a multicenter, dose-escalation study of capecitabine. Patients in phase II are stratified according to type of breast cancer (inflammatory vs noninflammatory).

Cohorts of 3-6 patients receive escalating doses of capecitabine 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.

Phase II: Patients receive oral tipifarnib twice daily for 6 days. Beginning at least 48 hours after completion of the initial dose of tipifarnib, patients receive treatment as in phase Ib for up to 6 courses at the MTD of capecitabine. Patients in phase Ib are followed at 3 months.

Patients in phase II are followed every 4 months for up to 5 years.

PROJECTED ACCRUAL: A total of 24-53 patients (9-18 for phase Ib and 15-35 for phase II) will be accrued for this study within 14-35 months.

Study Design

Study Type:

Interventional

Actual Enrollment :

53 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase Ib/II Neoadjuvant Trial of the Farnesyltransferase Inhibitor, R115777 With Docetaxel and Capecitabine for Patients With Stage IIIA or IIIB Breast Cancer

Study Start Date :

Sep 1, 2003

Actual Primary Completion Date :

Feb 1, 2006

Actual Study Completion Date :

Jun 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (tipifarnib, capecitabine, docetaxel) Phase Ib: Patients receive oral tipifarnib twice daily and oral capecitabine twice daily on days 1-14 and docetaxel IV over 30-60 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Phase II: Patients receive oral tipifarnib twice daily for 6 days. Beginning at least 48 hours after completion of the initial dose of tipifarnib, patients receive treatment as in phase Ib for up to 6 courses at the MTD of capecitabine.	Drug: Capecitabine Given PO Other Names: Ro 09-1978/000 Xeloda Drug: Docetaxel Given IV Other Names: RP56976 Taxotere Taxotere Injection Concentrate Other: Laboratory Biomarker Analysis Correlative studies Other: Pharmacological Study Correlative studies Drug: Tipifarnib Given orally (PO) Other Names: R115777 Zarnestra

Arm

Intervention/Treatment

Experimental: Treatment (tipifarnib, capecitabine, docetaxel)

Phase Ib: Patients receive oral tipifarnib twice daily and oral capecitabine twice daily on days 1-14 and docetaxel IV over 30-60 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Phase II: Patients receive oral tipifarnib twice daily for 6 days. Beginning at least 48 hours after completion of the initial dose of tipifarnib, patients receive treatment as in phase Ib for up to 6 courses at the MTD of capecitabine.

Drug: Capecitabine

Given PO

Other Names:

Ro 09-1978/000

Xeloda

Drug: Docetaxel

Given IV

Other Names:

RP56976

Taxotere

Taxotere Injection Concentrate

Other: Laboratory Biomarker Analysis

Correlative studies

Other: Pharmacological Study

Correlative studies

Drug: Tipifarnib

Given orally (PO)

Other Names:

R115777

Zarnestra

Outcome Measures

Primary Outcome Measures

Dose-limiting toxicity (DLT) as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 (Phase I) [21 days]
Pathologic complete response rate (Phase II) [Up to 5 years]
Estimated by the number of patients with a complete pathologic response divided by the total number of evaluable patients. Ninety-five percent confidence intervals for the true pathologic complete response probability will be calculated according to the approach of Duffy and Santner.

Secondary Outcome Measures

Clinical tumor response (complete response [CR] or partial response [PR]) (Phase I) [Up to 5 years]
Clinical responses will be summarized by simple descriptive summary statistics.
Overall survival [From registration to death due to any cause, assessed up to 5 years]
The distribution of survival time will be estimated using the method of Kaplan-Meier.
Toxicity as assessed by the National Cancer Institute (NCI) CTCAE version 3.0 [Up to 5 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically or cytologically confirmed solid tumor
Locally advanced or metastatic
No known standard therapy that is potentially curative or definitely capable of extending life expectancy
No history of metastatic brain disease within the past 6 months
Treated metastatic brain disease is allowed provided disease has been stable for more than 6 months and does not require concurrent steroids or anti-seizure medication
Histologically confirmed breast cancer
Stage IIIA or stage IIIB, including ipsilateral palpable supraclavicular lymph node(s) without other distant metastasis
Invasive disease confirmed by 1 of the following*:
Incisional biopsy
Punch biopsy (applicable for clinical T4b tumors)
Core needle (cutting needle) biopsies
No distant metastatic disease
Hormone receptor status:
Not specified
Male or female
Performance status - ECOG 0-1
Absolute neutrophil count at least 2,000/mm^3
Platelet count at least 100,000/mm^3
Hemoglobin at least 10.0 g/dL
Bilirubin no greater than upper limit of normal (ULN)
Alkaline phosphatase no greater than 2.5 times ULN
AST no greater than 2.5 times ULN
Creatinine no greater than 1.25 times ULN
Creatinine clearance at least 50 mL/min
No cardiac arrhythmia
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
No active infection requiring antibiotics
No diabetes
No symptomatic neurologic condition
No other uncontrolled serious medical condition
No other malignancy within the past 3 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
No history of hypersensitivity to intravenous paclitaxel or other medication containing Cremophor EL or polysorbate 80 as a carrier (phase Ib)
Phase Ib only:
More than 4 weeks since prior immunotherapy
More than 4 weeks since prior biologic therapy
No concurrent immunotherapy
Phase Ib and II:
No concurrent prophylactic filgrastim (G-CSF)
Phase Ib only:
More than 1 year since prior adjuvant docetaxel before metastatic relapse
More than 4 weeks since prior chemotherapy and recovered
No prior capecitabine AND docetaxel (in combination or as single agents)
Prior capecitabine OR docetaxel allowed
No other concurrent chemotherapy
Phase II only:
No prior cytotoxic chemotherapy for breast cancer
Phase Ib only:
More than 3 weeks since prior radiotherapy
No prior radiotherapy to more than 25% of bone marrow
No concurrent radiotherapy
Phase II only:
No prior radiotherapy for breast cancer
Phase Ib only:
More than 4 weeks since prior major surgery
Phase II only:
No prior surgery (other than core or incisional biopsy for diagnostic purposes) for breast cancer
Phase Ib only:
No other ancillary investigational therapy
Phase Ib and II:
No concurrent sorivudine or brivudine

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic in Arizona	Scottsdale	Arizona	United States	85259
2	Howard University Cancer Center CCOP	Washington	District of Columbia	United States	20060
3	Mayo Clinic in Florida	Jacksonville	Florida	United States	32224-9980
4	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan	United States	48201
5	Mayo Clinic	Rochester	Minnesota	United States	55905
6	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
7	University of Wisconsin Medical School	Milwaukee	Wisconsin	United States	53201