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

A Phase I/II Study of 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

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.

Study Overview

• Status: Completed
• Conditions: Breast Cancer; Male Breast Cancer; Stage IV Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Recurrent Breast Cancer
• Intervention / Treatment: Drug: vorinostat; Drug: trastuzumab

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.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • Iowa
    • Des Moines, Iowa, United States, 50309
      • Iowa Methodist Medical Center
    • Des Moines, Iowa, United States, 50314
      • Mercy Medical Center - Des Moines
    • Des Moines, Iowa, United States, 50309
      • Medical Oncology and Hematology Associates-Des Moines
    • Des Moines, Iowa, United States, 50316
      • Iowa Lutheran Hospital
    • Des Moines, Iowa, United States, 50307
      • Mercy Capitol
    • Des Moines, Iowa, United States, 50309
      • Iowa Oncology Research Association CCOP
    • Des Moines, Iowa, United States, 50314
      • Medical Oncology and Hematology Associates
    • Sioux City, Iowa, United States, 51104
      • Saint Luke's Regional Medical Center
    • Sioux City, Iowa, United States, 51101
      • Siouxland Hematology Oncology Associates
    • Sioux City, Iowa, United States, 51104
      • Mercy Medical Center-Sioux City
  • Maryland
    • Baltimore, Maryland, United States, 21287-8936
      • Johns Hopkins University
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Eastern Cooperative Oncology Group
  • Minnesota
    • Hutchinson, Minnesota, United States, 55350
      • Hutchinson Area Health Care
    • Litchfield, Minnesota, United States, 55355
      • Meeker County Memorial Hospital
    • Maplewood, Minnesota, United States, 55109
      • Saint John's Hospital - Healtheast
    • Minneapolis, Minnesota, United States, 55415
      • Hennepin County Medical Center
    • Minneapolis, Minnesota, United States, 55407
      • Virginia Piper Cancer Institute
    • Saint Paul, Minnesota, United States, 55101
      • Regions Hospital
    • Saint Paul, Minnesota, United States, 55102
      • Saint Joseph's Hospital - Healtheast
    • Shakopee, Minnesota, United States, 55379
      • Saint Francis Regional Medical Center
    • Woodbury, Minnesota, United States, 55125
      • Woodwinds Health Campus
  • New York
    • Bronx, New York, United States, 10461
      • Albert Einstein College Of Medicine
    • Bronx, New York, United States, 10467-2490
      • Montefiore Medical Center
    • New York, New York, United States, 10011
      • Saint Vincent's Hospital and Medical Center of New York

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I; 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.	Drug: vorinostat; Given orally; Drug: trastuzumab; Given IV

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response Rate	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.	Tumor assessment was obtained at baseline, after 6 weeks (week 6 = last week of Cycle 2), and after every 4 cycles of therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Progression	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.	Tumor assessment was obtained at baseline, after 6 weeks (week 6 = last week of Cycle 2), and after every 4 cycles of therapy
Overall Survival	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.	Survival was assessed every 3 months for first 2 years from protocol entry, then every 6 months until 3 years from study entry

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Ramona Swaby, Eastern Cooperative Oncology Group

Study record dates

Study Major Dates

• Study Start: August 1, 2006
• Primary Completion (Actual): August 1, 2010
• Study Completion (Actual): September 1, 2010

Study Registration Dates

• First Submitted: November 22, 2005
• First Submitted That Met QC Criteria: November 22, 2005
• First Posted (Estimate): November 24, 2005

Study Record Updates

• Last Update Posted (Estimate): June 2, 2014
• Last Update Submitted That Met QC Criteria: May 29, 2014
• Last Verified: October 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; Neoplasms; Neoplasms by Site; Disease Attributes; Breast Diseases; Breast Neoplasms; Recurrence; Breast Neoplasms, Male; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Histone Deacetylase Inhibitors; Trastuzumab; Vorinostat
• Other Study ID Numbers: NCI-2009-00503 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U10CA021115 (U.S. NIH Grant/Contract); CDR0000449963; E1104 (Other Identifier: CTEP)