Vorinostat, Paclitaxel, and Bevacizumab in Treating Patients With Metastatic Breast Cancer and/or Breast Cancer That Has Recurred in the Chest Wall and Cannot be Removed by Surgery

Condition(s) targeted: Breast Cancer

Intervention: bevacizumab (Drug); paclitaxel (Drug); vorinostat (Drug)

Phase: Phase 1/Phase 2

Status: Recruiting

Sponsored by: Albert Einstein College of Medicine of Yeshiva University

Official(s) and/or principal investigator(s):
Joseph A. Sparano, MD, Study Chair, Affiliation: Albert Einstein College of Medicine of Yeshiva University

RATIONALE: Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, 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. Bevacizumab may also may stop the growth of tumor cells by blocking blood flow to the tumor. Giving vorinostat together with paclitaxel and bevacizumab may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of vorinostat when given together with paclitaxel and bevacizumab and to see how well they work in treating patients with metastatic breast cancer and/or breast cancer that has recurred in the chest wall and cannot be removed by surgery.

Official title: A Phase I/II Study of a Combination of Suberoylanilide Hydroxamic Acid (Vorinostat) Plus Paclitaxel and Bevacizumab in Patients With Advanced Metastatic and/or Local Chest Wall Recurrent Breast Cancer

Study design: Treatment, Open Label

Primary outcome:

Maximum tolerated dose of vorinostat in combination with paclitaxel and bevacizumab

Recommended phase II dose

Objective response rate (complete and partial)

Overall-survival by Kaplan-Meier survival analysis

Secondary outcome:

Time to treatment failure by Kaplan-Meier survival analysis

Progression-free survival by Kaplan-Meier survival analysis

Toxicity according to CTCAE v. 3.0

Detailed description: OBJECTIVES:

- Determine the maximum tolerated dose and recommended phase II dose of vorinostat (SAHA)

in combination with paclitaxel and bevacizumab in patients with metastatic and/or locally recurrent inoperable chest wall breast cancer. (Phase I)

- Determine the efficacy (i. e., response rate, response duration, time to disease

progression, time to treatment failure, and overall survival) of this regimen in these patients. (Phase II)

- Determine the toxicity of this regimen in these patients. (Phase II)

OUTLINE: This is a phase I, multicenter, dose-escalation study of vorinostat (SAHA) followed by a phase II, open-label study.

- Phase I: Patients receive oral SAHA twice daily on days 1-3, 8-10, and 15-17, paclitaxel

IV over 1 hour on days 2, 9, and 16, and bevacizumab IV over 30-90 minutes on days 2 and 16. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of SAHA 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. The recommended phase II dose is defined as one dose level below the MTD.

- Phase II: Patients receive SAHA at the recommended phase II dose and paclitaxel and

bevacizumab as in phase I.

PROJECTED ACCRUAL: Approximately 45 patients will be accrued for this study.

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

Criteria:

DISEASE CHARACTERISTICS:

- Histologically or cytologically confirmed adenocarcinoma of the breast, meeting ≥ 1 of

the following criteria:

- Stage IV disease

- Locally recurrent inoperable chest wall disease

- At least 1 unidimensionally or bidimesionally measurable indicator lesion

- Nonmeasurable disease allowed (phase I only)

- No CNS metastases by CT scan or MRI

- Hormone receptor status not specified

PATIENT CHARACTERISTICS:

- Female or male

- Menopausal status not specified

- ECOG performance status (PS) 0-1 or Karnofsky PS 70-100%

- Absolute neutrophil count ≥ 1,500/mm³

- Platelet count ≥ 100,000/mm³

- Bilirubin normal

- AST and ALT ≤ 2. 5 times upper limit of normal (ULN)

- PTT < 1. 5 times normal

- INR or PT < 1. 5 times normal (unless patient is on full-dose anticoagulants)

- Creatinine normal OR creatinine clearance ≥ 60 mL/min

- Urine: protein creatinine ratio ≤ 0. 5 OR urine protein < 1,000 mg by 24-hour urine

collection

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for ≥ 6 months after

completion of study therapy

- Must be able to take oral medications on a continuous basis

- No history of allergic reactions attributed to compounds of similar chemical or

biologic composition to study drugs

- No ongoing or active infection

- No psychiatric illness or social situation that would limit study compliance

- No serious or nonhealing wound, ulcer, or bone fracture

- No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within

the past 4 weeks

- No significant traumatic injury within the past 4 weeks

- No clinically significant cardiovascular disease, including any of the following:

- Cerebrovascular accident within the past 6 months

- Unstable angina pectoris

- Uncontrolled hypertension

- Myocardial infarction or unstable angina within the past 6 months

- New York Heart Association class II-IV congestive heart failure

- Serious cardiac arrhythmia requiring medication

- Symptomatic congestive heart failure

- Clinically significant peripheral vascular disease

- No bleeding diathesis or coagulopathy

- No known hypersensitivity to Chinese hamster ovary cell products or other recombinant

human antibodies

- No other uncontrolled illness

PRIOR CONCURRENT THERAPY:

- At least 1 week since prior hormonal therapy

- Any number of prior hormonal therapies allowed

- At least 1 week since prior core biopsy

- At least 10 days since prior acetylsalicylic acid (aspirin > 325 mg/day) or other

nonsteroidal anti-inflammatory drugs known to inhibit platelet function, including any of the following:

- Dipyridamole

- Ticlopidine

- Clopidogrel

- Cilostazol

- At least 4 weeks since prior major surgical procedure or open biopsy

- At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) or

radiotherapy and recovered

- At least 4 weeks since prior trastuzumab (Herceptin®)

- No prior chemotherapy for metastatic disease

- Patients previously treated with a taxane (e. g., docetaxel or paclitaxel) are

eligible provided both of the following are true:

- Received taxane as a component of adjuvant and/or neoadjuvant therapy

- Relapsed ≥ 12 months after completion of taxane-based therapy

- No prior histone deacetylase inhibitors (e. g., valproic acid, PXD101, FR901228,

MS-275, or LAQ-824)

- Patients who have received such agents for other indications (e. g., epilepsy) may

enroll in this trial after a 30-day washout period

- No prior bevacizumab

- No prior gastrointestinal surgery or other procedures that may interfere with

absorption or swallowing of study drug

- No other prior invasive procedures

- No concurrent combination antiretroviral therapy for HIV-positive patients

- No other concurrent investigational agents

- No other concurrent anticancer agents or therapies

- No other concurrent investigational agents

- No concurrent major surgical procedures

- Concurrent full-dose anticoagulants (e. g., warfarin) with PT INR > 1. 5 allowed

provided both of the following criteria are met:

- In-range INR (usually between 2 and 3) on a stable dose of oral anticoagulant or

on a stable dose of low molecular weight heparin

- No active bleeding or pathological condition that carries a high risk of bleeding

(e. g., tumor involving major vessels or known varices)

Prince of Wales Hospital, Shatin, New Territories, Hong Kong; Recruiting
Winnie Yeo, Phone: 852-2632-2118

Yonsei Cancer Center at Yonsei University Medical Center, Seoul 120-752, Korea, Republic of; Recruiting
Hyun C. Chung, MD, PhD, Phone: 82-2-2228-8132, Email: unchung8@yumc.yonsei.ac.kr

National Cancer Centre - Singapore, Singapore 169610, Singapore; Recruiting
Soo Chin Lee, MD, Phone: 65-6772-4629

Mayo Clinic Scottsdale, Scottsdale, Arizona 85259-5499, United States; Recruiting
Tom R. Fitch, MD, Phone: 507-538-7623, Email: cancerclinicaltrials@mayo.edu

City of Hope Comprehensive Cancer Center, Duarte, California 91010-3000, United States; Recruiting
Clinical Trials Office - City of Hope Comprehensive Cancer Cen, Phone: 800-826-4673, Email: becomingapatient@coh.org

UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California 94115, United States; Recruiting
Clinical Trials Office - UCSF Helen Diller Family Comprehensi, Phone: 877-827-3222

Howard University Cancer Center, Washington, District of Columbia 20060, United States; Recruiting
Clinical Trials Office - Howard University Cancer Center, Phone: 202-806-9122

H. Lee Moffitt Cancer Center and Research Institute at University of South Florida, Tampa, Florida 33612-9497, United States; Recruiting
Clinical Trials Office - H. Lee Moffitt Cancer Center and Rese, Phone: 800-456-7121, Email: canceranswers@moffitt.usf.edu

Mayo Clinic - Jacksonville, Jacksonville, Florida 32224, United States; Recruiting
Edith A. Perez, MD, Phone: 507-538-7623, Email: cancerclinicaltrials@mayo.edu

Medical College of Georgia Cancer Center, Augusta, Georgia 30912, United States; Recruiting
Kapil N. Bhalla, MD, Phone: 706-721-0463

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231-2410, United States; Recruiting
Clinical Trials Office - Sidney Kimmel Comprehensive Cancer Ce, Phone: 410-955-8804, Email: jhcccro@jhmi.edu

Mayo Clinic Cancer Center, Rochester, Minnesota 55905, United States; Recruiting
Matthew P. Goetz, MD, Phone: 507-538-7623, Email: cancerclinicaltrials@mayo.edu

Park Nicollet Cancer Center, St. Louis Park, Minnesota 55416, United States; Recruiting
Bronagh Murphy, MD, Phone: 952-993-1517

Center for Cancer Care and Research, Saint Louis, Missouri 63141, United States; Recruiting
Alfred O. Greco, MD, Phone: 314-628-1210, Email: AGreco@tcccr.com

Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis, Saint Louis, Missouri 63110, United States; Recruiting
Matthew J. Ellis, MD, PhD, FRCP, Phone: 314-362-8903, Email: mellis@im.wustl.edu

Albert Einstein Cancer Center at Albert Einstein College of Medicine, Bronx, New York 10461, United States; Recruiting
Clinical Trials Office - Albert Einstein Cancer Center at Albe, Phone: 718-904-2730, Email: aecc@aecom.yu.edu

Eastchester Center for Cancer Care, Bronx, New York 10469, United States; Recruiting
Anthony D. Hoffman, MD, Phone: 718-732-4000, Email: anthony@eastchestercenter.com

Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center, New York, New York 10032, United States; Recruiting
Clinical Trials Office - Herbert Irving Comprehensive Cancer C, Phone: 212-305-8615

NYU Cancer Institute at New York University Medical Center, New York, New York 10016, United States; Recruiting
Amy D. Tiersten, MD, Phone: 212-652-1917

Weill Cornell Breast Center, New York, New York 10065, United States; Recruiting
Linda T. Vahdat, MD, Phone: 212-821-0644, Email: ltv2001@med.cornell.edu

Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center, Columbus, Ohio 43210-1240, United States; Recruiting
Clinical Trials Office - OSU Comprehensive Cancer Center, Phone: 614-293-4976, Email: osu@emergingmed.com

Fox Chase Cancer Center - Philadelphia, Philadelphia, Pennsylvania 19111-2497, United States; Recruiting
Clinical Trials Office - Fox Chase Cancer Center - Philadelphi, Phone: 215-728-4790

Sir Charles Gairdner Hospital - Nedlands, Nedlands, Western Australia 6009, Australia; Recruiting
Anna Nowak, MD, Phone: 61-8-9346-3841

University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, Wisconsin 53792-6164, United States; Recruiting
Clinical Trials Office - University of Wisconsin Paul P. Carbo, Phone: 608-262-5223

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

Starting date: July 2006
Last updated: July 23, 2008