HDAC Inhibitor Vorinostat (SAHA) With Capecitabine (Xeloda) Using a New Weekly Dose Regimen for Advanced Breast Cancer

A Dose-escalating and Phase II Clinical Trial of the Histone Deacetylase (HDAC) Inhibitor Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA, ZolinzaTM) in Combination With Capecitabine (XelodaTM) Using a New Weekly Dose Regimen for Advanced Breast Cancer

The purpose of this study is to determine the safety profile, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), of oral vorinostat in combination with oral capecitabine given on days 1-7 and 15-21 of a 28 day cycle in patients with advanced breast cancer, using RECIST criteria.

This study was originally intended to be a phase 1/phase 2. The protocol was amended to make this study a phase 1 only.

Study Overview

• Status: Completed
• Conditions: Advanced Breast Cancer
• Intervention / Treatment: Drug: Vorinostat

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06219
      • Yale University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Patients must have histologically confirmed advanced breast cancer
• For the dose escalation phase: Patients must be refractory to standard therapy or for which no curative standard therapy exists, to be considered.
• For the phase II: Patients with histologically confirmed metastatic breast cancer who have had no more than 2 prior chemotherapy regimens for treatment of their metastatic breast cancer.
• Metastatic disease should not be progressing so as to require palliative treatment within 4 weeks of enrollment based on clinical assessment by the investigator.
• Development of new lesions or an increase in preexisting lesions on bone scintigraphy, CT, MRI or by physical examination. Patients in whom the sole criterion for progression is an increase in a biochemical marker, e.g., carcinoembryonic antigen (CEA), or an increase in symptoms, are not eligible.
• No radiotherapy, treatment with cytotoxic agents, or treatment with biologic agents within the 4 weeks prior to beginning treatment on this study (6 weeks for mitomycin or nitrosoureas). At least 2 weeks must have elapsed from any prior surgery or hormonal therapy. Patients must have fully recovered from the acute toxicities of any prior treatment with cytotoxic drugs, radiotherapy or other anti-cancer modalities (returned to baseline status as noted before most recent treatment). Patients with persisting, stable chronic toxicities from prior treatment ≤ grade 1 are eligible.
• Age ≥18 years.
• ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A).
• Life expectancy of greater than 3 months

• Patients must have normal organ and marrow function as defined below:

  • leukocytes ≥3,000/mcL
  • absolute neutrophil count ≥1,500/mcL
  • platelets ≥100,000/mcL
  • total bilirubin within normal institutional limits
  • AST(SGOT)/ALT(SGPT) ≤2.5 X institutional upper limit of normal
  • creatinine within normal institutional limits OR
  • creatinine clearance ≥60 mL/min/1.73 m² for patients with creatinine levels above institutional normal.
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
• 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.
• Patients may not be receiving any other investigational agents.
• Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to vorinostat or capecitabine.
• 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.
• Women that are pregnant or breast-feeding are excluded from this study.
• HIV-positive patients are ineligible because these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy and the potential pharmacokinetic interaction between antiretroviral therapy and the investigational agents.
• Patient had prior treatment with an HDAC inhibitor. Patients who have received compounds with HDAC inhibitor-like activity, such as valproic acid, as anti-tumor therapy should not enroll in this study. Patients who have received such compounds for other indications, e.g. valproic acid for epilepsy, may enroll after a 30-day washout period.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 1	Drug: Vorinostat; BID days -7, 1-7 and 15-21, 200 mg; Other Names: SAHA; Zolinza; suberoylanilide hydroxamic acid; HDAC inhibitor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To determine the safety, dose-limiting toxicities and maximum tolerated dose of oral capecitabine in combination with oral vorinostat given twice a day and to determine the objective response rate using RECIST criteria	Upon completion of study

Secondary Outcome Measures

Outcome Measure	Time Frame
To determine the clinical benefit, time to progression, and duration of response, in patients with metastatic breast cancer treated with this combination	Upon completion of study

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Maysa Abu-Khalaf, M.D., Yale Unviversity School of Medicine

Study record dates

Study Major Dates

• Study Start: December 1, 2008
• Primary Completion (ACTUAL): June 1, 2013
• Study Completion (ACTUAL): June 1, 2013

Study Registration Dates

• First Submitted: July 18, 2008
• First Submitted That Met QC Criteria: July 18, 2008
• First Posted (ESTIMATE): July 22, 2008

Study Record Updates

• Last Update Posted (ACTUAL): March 3, 2017
• Last Update Submitted That Met QC Criteria: March 1, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Histone Deacetylase Inhibitors; Vorinostat
• Other Study ID Numbers: 0803003591