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

Condition(s) targeted: Breast Cancer

Intervention: trastuzumab (Drug); vorinostat (Drug); antiangiogenesis therapy (Procedure); enzyme inhibitor therapy (Procedure); monoclonal antibody therapy (Procedure)

Phase: Phase 1/Phase 2

Status: Suspended

Sponsored by: Eastern Cooperative Oncology Group

Official(s) and/or principal investigator(s):
Ramona Swaby, MD, Study Chair, Affiliation: Fox Chase Cancer Center
Joseph A. Sparano, MD, Affiliation: Albert Einstein College of Medicine of Yeshiva University
Lori J. Goldstein, MD, Affiliation: Fox Chase Cancer Center

RATIONALE: 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.

PURPOSE: 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.

Official title: A Phase I/II Suberoylanilide Hydroxamic Acid (SAHA) in Combination With Trastuzumab (Herceptin) in Patients With Advanced Metastatic and/or Local Chest Wall Recurrent Her-2 Amplified Breast Cancer

Study design: Treatment, Open Label

Primary outcome:

Time to progression

Toxicity

Detailed description: OBJECTIVES:

Phase I

- 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.

- Determine the toxic effects of this regimen in these patients.

Phase II

- Determine the response rate in patients treated with this regimen.

- Determine the time to progression in patients treated with this regimen.

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.

PROJECTED ACCRUAL: A total of 53 patients (18 for phase I, 35 for phase II) will be accrued for this study.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

DISEASE CHARACTERISTICS:

- Histologically confirmed breast cancer

- Must overexpress HER-2 gene

- Metastatic or chest wall recurrent disease

- 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

- Measurable disease, defined as ≥ 1 unidimensionally measurable lesion > 20 mm by

conventional techniques or > 10 mm by spiral CT scan

- 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

- Hormone receptor status:

- Not specified

PATIENT CHARACTERISTICS:

Sex

- Male or female

Menopausal status

- Not specified

Performance status

- ECOG 0-2

Life expectancy

- Not specified

Hematopoietic

- Absolute neutrophil count ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3

- Hemoglobin ≥ 9 g/dL

Hepatic

- 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)

Renal

- Creatinine ≤ 1. 5 mg/dL

Cardiovascular

- 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

Other

- 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

PRIOR CONCURRENT THERAPY:

Biologic therapy

- See Disease Characteristics

Chemotherapy

- See Disease Characteristics

- More than 3 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin; 1

week for capecitabine) and recovered

Radiotherapy

- See Disease Characteristics

- More than 3 weeks since prior radiotherapy and recovered

- No concurrent radiotherapy for brain metastases

Surgery

- See Disease Characteristics

Other

- 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

- No other concurrent investigational agents

- Concurrent bisphosphonates allowed provided therapy was initiated prior to study

treatment

- No other concurrent anticancer therapy

Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham, Birmingham, Alabama 35294, United States

MBCCOP - Medical College of Georgia Cancer Center, Augusta, Georgia 30912, United States

Swedish-American Regional Cancer Center, Rockford, Illinois 61104-2315, United States

CCOP - Iowa Oncology Research Association, Des Moines, Iowa 50309, United States

John Stoddard Cancer Center at Iowa Lutheran Hospital, Des Moines, Iowa 50316, United States

John Stoddard Cancer Center at Iowa Methodist Medical Center, Des Moines, Iowa 50309, United States

Medical Oncology and Hematology Associates at John Stoddard Cancer Center, Des Moines, Iowa 50309, United States

Medical Oncology and Hematology Associates at Mercy Cancer Center, Des Moines, Iowa 50314, United States

Mercy Cancer Center at Mercy Medical Center - Des Moines, Des Moines, Iowa 50314, United States

Mercy Capitol Hospital, Des Moines, Iowa 50307, United States

Mercy Medical Center - Sioux City, Sioux City, Iowa 51104, United States

Siouxland Hematology-Oncology Associates, LLP, Sioux City, Iowa 51101, United States

St. Luke's Regional Medical Center, Sioux City, Iowa 51104, United States

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231-2410, United States

Borgess Medical Center, Kalamazoo, Michigan 49001, United States

Bronson Methodist Hospital, Kalamazoo, Michigan 49007, United States

West Michigan Cancer Center, Kalamazoo, Michigan 49007-3731, United States

CCOP - Metro-Minnesota, Saint Louis Park, Minnesota 55416, United States

Fairview Ridges Hospital, Burnsville, Minnesota 55337, United States

Fairview Southdale Hospital, Edina, Minnesota 55435, United States

HealthEast Cancer Care at St. John's Hospital, Maplewood, Minnesota 55109, United States

HealthEast Cancer Care at St. Joseph's Hospital, St Paul, Minnesota 55102, United States

HealthEast Cancer Care at Woodwinds Health Campus, Woodbury, Minnesota 55125, United States

Hennepin County Medical Center - Minneapolis, Minneapolis, Minnesota 55415, United States

Hubert H. Humphrey Cancer Center at North Memorial Outpatient Center, Robbinsdale, Minnesota 55422-2900, United States

Hutchinson Area Health Care, Hutchinson, Minnesota 55350, United States

Meeker County Memorial Hospital, Lichfield, Minnesota 55355, United States

Mercy and Unity Cancer Center at Mercy Hospital, Coon Rapids, Minnesota 55433, United States

Mercy and Unity Cancer Center at Unity Hospital, Fridley, Minnesota 55432, United States

Minnesota Oncology Hematology, PA - Maplewood, Maplewood, Minnesota 55109, United States

Minnesota Oncology Hematology, PA - Woodbury, Woodbury, Minnesota 55125, United States

Park Nicollet Cancer Center, St. Louis Park, Minnesota 55416, United States

Regions Hospital Cancer Care Center, St. Paul, Minnesota 55101, United States

Ridgeview Medical Center, Waconia, Minnesota 55387, United States

St. Francis Cancer Center at St. Francis Medical Center, Shakopee, Minnesota 55379, United States

United Hospital, St. Paul, Minnesota 55102, United States

Virginia Piper Cancer Institute at Abbott - Northwestern Hospital, Minneapolis, Minnesota 55407, United States

Albert Einstein Cancer Center at Albert Einstein College of Medicine, Bronx, New York 10461, United States

Our Lady of Mercy Medical Center Comprehensive Cancer Center, Bronx, New York 10466, United States

St. Vincent's Comprehensive Cancer Center - Manhattan, New York, New York 10011, United States

St. Rita's Medical Center, Lima, Ohio 45801, United States

Fox Chase Cancer Center - Philadelphia, Philadelphia, Pennsylvania 19111-2497, United States

Lewistown Hospital, Lewistown, Pennsylvania 17044, United States

Mount Nittany Medical Center, State College, Pennsylvania 16803, United States

Penn State Cancer Institute at Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033-0850, United States

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: August 2006
Last updated: December 25, 2007