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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00368875
First received: August 24, 2006
Last updated: December 6, 2013
Last verified: December 2013
  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. 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.


Condition Intervention Phase
Male Breast Cancer
Stage IIIB Breast Cancer
Stage IIIC Breast Cancer
Stage IV Breast Cancer
Drug: vorinostat
Drug: paclitaxel
Biological: bevacizumab
Other: laboratory biomarker analysis
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II Study of a Combination of Suberoylanilide Hydroxyamic Acid (Vorinostat) Plus Paclitaxel and Bevacizumab in Patients With Advanced Metastatic and/or Local Chest Wall Recurrent Breast Cancer

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Recommended phase II dose as assessed by NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (Phase I) [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    Exact 95% confidence intervals around the toxicity proportions will be calculated to assess the precision of the obtained estimates.

  • Objective response rate (CR + PR) [ Time Frame: Up to 12 months ] [ Designated as safety issue: No ]
    Estimated and a 95% confidence interval will be estimated via binomial proportions.


Secondary Outcome Measures:
  • Progression-free survival (PFS), [ Time Frame: From first treatment day until objective or symptomatic progression, assessed up to 12 months ] [ Designated as safety issue: No ]
    Assessed by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formulae.

  • Time to treatment failure (TTF) [ Time Frame: Time from the first treatment day until disease progression or discontinuation of treatment due to toxicity, assessed up to 12 months ] [ Designated as safety issue: No ]
    Assessed by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formulae.

  • Overal survivall (OS) [ Time Frame: Time from first treatment day until death, assessed up to 12 months ] [ Designated as safety issue: No ]
    Assessed by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formulae.


Estimated Enrollment: 58
Study Start Date: July 2006
Primary Completion Date: October 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (vorinostat, paclitaxel, bevacizumab)
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.
Drug: vorinostat
Given orally
Other Names:
  • L-001079038
  • SAHA
  • suberoylanilide hydroxamic acid
  • Zolinza
Drug: paclitaxel
Given IV
Other Names:
  • Anzatax
  • Asotax
  • TAX
  • Taxol
Biological: bevacizumab
Given IV
Other Names:
  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRYMARY OBJECTIVES:

I. To determine the recommended phase II dose of oral suberoylanilide hydroxyamic 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 hydroxyamic 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have 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
  • Patient must have 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
  • PRIOR CHEMOTHERAPY: Patients are eligible if they have received no prior chemotherapy for metastatic disease; patients previously treated with a taxane (docetaxel or paclitaxel) are eligible if they received taxanes as a component of adjuvant and/or neoadjuvant therapy, and have relapsed at least 12 months after completion of the taxane; (NOTE: effective with version 2.5 dated 9/15/09 patients are eligible if they have received 0-2 prior chemotherapy regimens for metastatic disease; patients previously treated with a taxane (docetaxel or paclitaxel) are eligible if they received taxanes as a component of adjuvant and/or neoadjuvant therapy, or for metastatic disease, and have not experienced progressive disease during or within 3 months of completing taxane therapy)
  • PRIOR HORMONAL THERAPY, TRASTUZUMAB (HERCEPTIN), OR BEVACIZUMAB (AVASTIN): Patients may have received any prior number of hormonal therapies; hormonal therapy should be discontinued at least 1 week before the patient is enrolled on this study; patients previously treated with Herceptin are eligible if Herceptin is discontinued, and there is at least a 4 week interval between the last Herceptin dose and registration, and the left ventricular ejection fraction is performed within 4 weeks prior to registration and demonstrates an LVEF that is at or above the lower institutional limit of normal range; patient who have received prior bevacizumab are ineligible
  • 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; Note: UPC ratio of spot urine is an estimation of the 24 urine protein excretion - a UPC ratio of 1 is roughly equivalent to a 24-hour urine protein of 1 gm; UPC ratio is calculated using on of the following formula: [urine protein]/[urine creatinine] - if both protein and creatinine are reported in mg/dL [(urine protein) x 0.088]/[urine creatinine] - if urine creatinine is reported in mmol/L
  • Patients on full-dose anticoagulants (e.g., warfarin) with PT INR > 1.5 are eligible provided that both of the following criteria are met: (a) The patient has an 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; (b) the patient has no active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)
  • 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)
  • The effects of vorinostat on the developing human fetus at the recommended therapeutic dose are unknown; women of childbearing potential must agree to use adequate contraceptive measures during study therapy and for at least 6 months after the completion of bevacizumab therapy; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; a negative serum or urine pregnancy test is required within 2 weeks of registration for women of childbearing potential
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier; other exclusions for prior therapy include prior hormonal therapy within one week of registration, prior trastuzumab within 4 weeks of registration, or prior bevacizumab at any time
  • Patients 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)
  • 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
  • Pregnant women are excluded from this study the effects of vorinostat on the developing human fetus at the recommended therapeutic dose are unknown; breastfeeding should be discontinued if the mother is treated with vorinostat; these potential risks may also apply to other agents used in this study; women must agree to use adequate contraceptive measures during study therapy and for at least 6 months after the completion of bevacizumab therapy
  • HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with vorinostat or other agents administered during the study
  • Serious or non-healing wound, ulcer or bone fracture
  • History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 28 days
  • Invasive procedures defined as follows: (a) major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to Day 1 therapy, (b) anticipation of need for major surgical procedures during the course of the study, (c) core biopsy within 7 days prior to D1 therapy

    • NOTE: Patients who undergo the pretreatment core biopsy for optional correlative studies may be enrolled within 7 days prior to the planned day 1 if delaying therapy to meet this criterion is not feasible, and if there are no bleeding complications as a consequence of the biopsy; in addition, patients may also undergo the second post-treatment core biopsy (ie, this would not be regarded as an eligibility or protocol violation)
  • Evidence of CNS metastases; all patients are required to undergo a CT scan or MRI of the brain with contrast within 4 weeks of registration
  • Patients with clinically significant cardiovascular disease: (a) History of CVA within 6 months, (b) uncontrolled hypertension, (c) myocardial infarction or unstable angina within 6 months, (d) New York heart association grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, unstable angina pectoris, (e) clinically significant peripheral vascular disease
  • Evidence of bleeding diathesis or coagulopathy; PT INR > 1.5, unless the patient is on full dose warfarin
  • Patients with known hypersensitivity of Chinese hamster ovary cell products or other recombinant human antibodies
  • Patients may not be receiving any other investigational agents nor had prior treatment with histone deacetylase (HDAC) inhibitors (i.e. Valproic acid, PXD-001, Depsipeptide, MS-275 and LAQ-824); patients who have received such agents for other indications, (i.e. epilepsy) may enroll in the trial after a 30 day washout period)
  • Inability to take oral medications on a continuous basis, or history of GI surgery or other procedures that might, in the opinion of the investigator, interfere with the absorption or swallowing of the study drugs
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00368875

Locations
United States, New York
Montefiore Medical Center
Bronx, New York, United States, 10467-2490
Sponsors and Collaborators
Investigators
Principal Investigator: Joseph Sparano Montefiore Medical Center
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00368875     History of Changes
Other Study ID Numbers: NCI-2012-03012, NCI-2012-03012, 06-05-291, 7703, N01CM62204, N01CM62207, N01CM62205, N01CM62209
Study First Received: August 24, 2006
Last Updated: December 6, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Breast Neoplasms
Breast Neoplasms, Male
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Antibodies
Antibodies, Monoclonal
Paclitaxel
Vorinostat
Bevacizumab
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Therapeutic Uses
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors

ClinicalTrials.gov processed this record on August 21, 2014