Phase I-II Study of Vorinostat, Paclitaxel, and Bevacizumab in Metastatic Breast Cancer

Phase 1

Completed

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

Interventions: Drug: vorinostat
Drug: paclitaxel
Biological: bevacizumab

Registration Number: NCT00368875

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 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. 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 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.

Detailed Description: PRiMARY OBJECTIVES:

I. To determine the recommended phase II dose of oral suberoylanilide hydroxamic acid (vorinostat) in combination with weekly paclitaxel and bevacizumab in patients with chest wall recurrent or metastatic breast cancer. (Phase I) II. To determine the efficacy (response rate, response duration, time to disease progression, time to treatment failure, and overall survival) and toxicity of oral suberoylanilide hydroxamic acid (vorinostat) in combination with weekly paclitaxel and bevacizumab in patients with chest wall recurrent or metastatic breast cancer. (Phase II)

SECONDARY OBJECTIVES:

I. To determine whether in vivo treatment with vorinostat induces a) acetylation of proteins including histone H3 and H4, b) ubiquitylation of proteins, and c) the levels of p21 and p27 levels in the peripheral blood mononuclear cells (pre treatment vs. cycle 1 day 2 after 3 VORINOSTAT doses but prior to paclitaxel.

II. To determine whether in vivo treatment with vorinostat induces a) acetylation of proteins including histone H3 and H4, ubiquitylation of proteins, and c) the levels of Bim, Bak, tBID, p21 and p27 levels, as well as down regulate Bcl-2, Bcl-xL and survivin in chest wall recurrent or metastatic breast cancer cells (pre treatment vs. cycle 1 day 2 after 3 vorinostat doses but prior to paclitaxel).

III. To determine whether in the primary breast cancer (and metastatic cancer if available) pretreatment levels of Her-2, Estrogen Receptor (ER)-alpha, Progesterone Receptor (PR), p21, p27, p-AKT, p-ERK1/2, HDAC1, 2, 3, 4, 6, 10 and SIRT2 levels predict for the response to treatment with VORINOSTAT plus paclitaxel.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 54

Inclusion Criteria

histologically or cytologically confirmed adenocarcinoma of the breast; effective with version 2.2 (1/26/09), only patients with disease that is accessible to biopsy and consent to serial biopsy are eligible
stage IV disease, locally recurrent inoperable chest wall disease; at least one bidimensional and/or unidimensional, measurable indicator lesion must be present (patients with only non-measurable disease are eligible for the phase I trial only); all sites of disease should be noted and followed
ECOG performance status =< 1 (Karnofsky >= 70%)
Absolute neutrophil count >= 1,500/ul
Platelets >= 100,000/ul
Total bilirubin within normal institutional limits
AST(SGOT)/ALT(SGPT) =< 2.5 x institutional upper limit of normal
PTT and either INR or PT < 1.5 x normal
Creatinine within normal institutional limits OR creatinine clearance >= mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
Urine protein should be screened by urine analysis for Urine Protein Creatinine (UPC) ratio; for UPC ratio > 0.5, 24-hour urine protein should be obtained and the level should be < 1000 mg for patient enrollment;
LVEF must be at or above the lower institutional limit of the normal range (on MUGA or Echo obtained within 12 weeks of registration, or within 4 weeks of prior Herceptin)
Not pregnant/lactating

Exclusion criteria:

chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
may not be receiving any other investigational agents.
history of allergic reactions attributed to compounds of similar chemical or biologic composition to vorinostat or other agents used in the study (e.g., paclitaxel, bevacizumab, quinolones)
uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
vorinostat, paclitaxel, bevacizumab	bevacizumab	Vorinostat BID on days 1-3, 8-10, and 15-17, paclitaxel IV over 1 hour on days 2, 9, and 16, bevacizumab IV over 30-90 minutes on days 2 and 16, repeat every 28 days.
vorinostat, paclitaxel, bevacizumab	vorinostat	Vorinostat BID on days 1-3, 8-10, and 15-17, paclitaxel IV over 1 hour on days 2, 9, and 16, bevacizumab IV over 30-90 minutes on days 2 and 16, repeat every 28 days.
vorinostat, paclitaxel, bevacizumab	paclitaxel	Vorinostat BID on days 1-3, 8-10, and 15-17, paclitaxel IV over 1 hour on days 2, 9, and 16, bevacizumab IV over 30-90 minutes on days 2 and 16, repeat every 28 days.

Primary Outcome Measures

Name	Time	Method
Recommended Phase II Dose as Assessed by NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (Phase I)	28 days	Dose-limiting toxcities (DLT) were defined as grade 3-4 febrile neutropenia, thrombocytopenia and non-hemtological toxicity attributed to therapy (nausea, vomiting and diarrhea would be considered dose limiting only if not adequately controlled with therapy). Any toxicity occurring during cycle 1 that resulted in dose reduction of vorinostat or paclitaxel or failure to complete all protocol specificed doses in the first cycle was also considered a DLT
Objective Response Rate (CR + PR)	Up to 12 months	Estimated and a 95% confidence interval will be estimated via binomial proportions. Per Response Evaluation Criteria in Solid Tumors (RECIST) for target lesions and assessed by CT scan: Complete response (CR): Disappearance of all target lesions; Partial Response (PR): \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR+PR.

Secondary Outcome Measures

Name	Time	Method
Progression-free Survival (PFS),	From first treatment day until objective or symptomatic progression, assessed up to 12 months	Assessed by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formulae.
Overall Survival(OS)	Time from first treatment day until death, assessed up to 12 months	Assessed by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formulae.
Time to Treatment Failure (TTF)	Time from the first treatment day until disease progression or discontinuation of treatment due to toxicity, assessed up to 12 months	Assessed by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formulae. Time to treatment failure was not reported for this study.