Vorinostat and Trastuzumab in Treating Patients With Metastatic or Locally Recurrent Breast Cancer

Phase 1

Completed

Conditions: Breast Cancer
Male Breast Cancer
Recurrent Breast Cancer
Stage IIIB Breast Cancer
Stage IIIC Breast Cancer
Stage IV Breast Cancer

Interventions: Drug: vorinostat
Drug: trastuzumab

Registration Number: NCT00258349

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This phase I/II trial is studying the side effects and best dose of vorinostat when given together with trastuzumab and to see how well they work in treating patients with metastatic breast canceror breast cancer that has recurred in the chest wall. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some find tumor cells and kill them or carry tumor-killing substances to them. Others interfere with the ability of tumor cells to grow and spread. Vorinostat and trastuzumab also may stop the growth of tumor cells by blocking blood flow to the tumor. Giving vorinostat together with trastuzumab may be a better way to block tumor growth.

Detailed Description: PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose of vorinostat in combination with trastuzumab (Herceptin) in patients with metastatic or local chest wall recurrent HER-2-amplified breast cancer. (Phase I) II. To determine the toxic effects of this regimen in these patients. (Phase I) III. To determine the response rate in patients treated with this regimen. (Phase II)

SECONDARY OBJECTIVE:

I. To determine the time to progression in patients treated with this regimen. (Phase II)

OUTLINE: This is an open-label, multicenter, dose-escalation study of vorinostat.

PHASE I: Patients receive oral vorinostat twice daily on days 1-14 and trastuzumab (Herceptin®) IV over 90 minutes 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 vorinostat 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. At least 6 patients are treated at the MTD.

PHASE II: Patients receive vorinostat at the MTD and trastuzumab as in phase I.

After completion of study treatment, patients are followed periodically for 3 years.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 16

Inclusion Criteria

Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
No active or ongoing infection
No history of allergic reaction to compounds of similar chemical or biologic composition to vorinostat or other agents used in study
No psychiatric illness or social situation that would preclude study compliance
No other uncontrolled illness
More than 3 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin; 1 week for capecitabine) and recovered
More than 3 weeks since prior radiotherapy and recovered
Recovered from prior therapy
At least 2 weeks since prior valproic acid
More than 4 weeks since prior investigational agents
More than 4 weeks since prior lapatinib ditosylate
No concurrent combination antiretroviral therapy for HIV-positive patients
Measurable disease, defined as >= 1 unidimensionally measurable lesion > 20 mm by conventional techniques or > 10 mm by spiral CT scan
No other concurrent investigational agents
Concurrent bisphosphonates allowed provided therapy was initiated prior to study treatment
No other concurrent anticancer therapy
Recurrent or progressive disease while receiving prior trastuzumab (Herceptin) (with or without chemotherapy) OR relapsed within 3 months of last dose of prior adjuvant trastuzumab for metastatic disease
Histologically confirmed breast cancer
Must overexpress HER-2 gene
Metastatic or chest wall recurrent disease
Site of measurable disease must not have been irradiated (except chest wall recurrence treated with adjuvant radiation therapy)
No untreated brain metastases
Previously treated brain metastasis responsive to radiotherapy and/or surgery allowed provided the brain is not the sole site of measurable disease
ECOG 0-2
Absolute neutrophil count >= 1,500/mm^3
Platelet count >= 100,000/mm^3
Hemoglobin >= 9 g/dL
AST and ALT =< 2 times upper limit of normal
Bilirubin =< 1.5 mg/dL (3 mg/dL in the presence of Gilbert's disease provided direct bilirubin is normal)
Creatinine =< 1.5 mg/dL
LVEF normal by nuclear scan or echocardiogram
No evidence of PR prolongation or AV block by EKG
No symptomatic congestive heart failure
No unstable angina pectoris
No cardiac arrhythmia

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Arm I	vorinostat	Patients will receive vorinostat by mouth twice a day for 2 weeks. They will also receive a 90-minute infusion of trastuzumab in week 1.
Arm I	trastuzumab	Patients will receive vorinostat by mouth twice a day for 2 weeks. They will also receive a 90-minute infusion of trastuzumab in week 1.

Primary Outcome Measures

Name	Time	Method
Response Rate	Tumor assessment was obtained at baseline, after 6 weeks (week 6 = last week of Cycle 2), and after every 4 cycles of therapy	Tumor response is assessed by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0. Response included complete response (CR) and partial response (PR). CR is defined as the disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of the longest diameters of target lesions, taking as reference the baseline sum longest diameter.

Secondary Outcome Measures

Name	Time	Method
Time to Progression	Tumor assessment was obtained at baseline, after 6 weeks (week 6 = last week of Cycle 2), and after every 4 cycles of therapy	Tumor response is assessed by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0. Disease progression is defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, or the appearance of one or more new lesion(s). Time to progression is defined as time from registration to disease progression.
Overall Survival	Survival was assessed every 3 months for first 2 years from protocol entry, then every 6 months until 3 years from study entry	Overall survival is defined as time from registration to death from any cause. Patients who were alive were censored as the last date of known alive.

Trial Locations

Locations (25): Siouxland Hematology Oncology Associates
🇺🇸
Sioux City, Iowa, United States
Iowa Methodist Medical Center
🇺🇸
Des Moines, Iowa, United States
Woodwinds Health Campus
🇺🇸
Woodbury, Minnesota, United States
Mercy Capitol
🇺🇸
Des Moines, Iowa, United States
Mercy Medical Center-Sioux City
🇺🇸
Sioux City, Iowa, United States
Meeker County Memorial Hospital
🇺🇸
Litchfield, Minnesota, United States
Iowa Lutheran Hospital
🇺🇸
Des Moines, Iowa, United States
Hutchinson Area Health Care
🇺🇸
Hutchinson, Minnesota, United States
Saint Vincent's Hospital and Medical Center of New York
🇺🇸
New York, New York, United States
Regions Hospital
🇺🇸
Saint Paul, Minnesota, United States
Mercy Medical Center - Des Moines
🇺🇸
Des Moines, Iowa, United States
Eastern Cooperative Oncology Group
🇺🇸
Boston, Massachusetts, United States
Saint John's Hospital - Healtheast
🇺🇸
Maplewood, Minnesota, United States
Saint Francis Regional Medical Center
🇺🇸
Shakopee, Minnesota, United States
Saint Luke's Regional Medical Center
🇺🇸
Sioux City, Iowa, United States
Johns Hopkins University
🇺🇸
Baltimore, Maryland, United States
University of Alabama at Birmingham
🇺🇸
Birmingham, Alabama, United States
Medical Oncology and Hematology Associates-Des Moines
🇺🇸
Des Moines, Iowa, United States
Saint Joseph's Hospital - Healtheast
🇺🇸
Saint Paul, Minnesota, United States
Hennepin County Medical Center
🇺🇸
Minneapolis, Minnesota, United States
Iowa Oncology Research Association CCOP
🇺🇸
Des Moines, Iowa, United States
Medical Oncology and Hematology Associates
🇺🇸
Des Moines, Iowa, United States
Virginia Piper Cancer Institute
🇺🇸
Minneapolis, Minnesota, United States
Albert Einstein College of Medicine
🇺🇸
Bronx, New York, United States
Montefiore Medical Center
🇺🇸
Bronx, New York, United States