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Trial record 1 of 1 for:    NCT00616967
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Carboplatin and Nab-Paclitaxel With or Without Vorinostat in Treating Women With Newly Diagnosed Operable Breast Cancer

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ClinicalTrials.gov Identifier: NCT00616967
Recruitment Status : Completed
First Posted : February 15, 2008
Results First Posted : July 16, 2014
Last Update Posted : July 16, 2014
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Tracking Information
First Submitted Date  ICMJE February 14, 2008
First Posted Date  ICMJE February 15, 2008
Results First Submitted Date  ICMJE April 8, 2014
Results First Posted Date  ICMJE July 16, 2014
Last Update Posted Date July 16, 2014
Study Start Date  ICMJE May 2008
Actual Primary Completion Date June 2012   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 16, 2014)
Pathological Complete Response (pCR) Rate [ Time Frame: Time of breast cancer surgery ]
The primary end point was pCR, defined as no viable invasive cancer in breast and axilla. All other cases were defined as non-pCR. The pCR rate was determined in each arm separately by performing an intent-to-treat (ITT) analysis of all randomized patients. Patients with unknown pCR status were considered non-responders. Computation of associated 90% confidence intervals did not account for the sequential design.
Original Primary Outcome Measures  ICMJE
 (submitted: February 14, 2008)
Pathological Complete Response (pCR) Rate
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 16, 2014)
  • Safety as Measured by NCI CTCAE Version 3.0 [ Time Frame: Active treatment until 30 days post-treatment ]
  • Clinical Complete Response (cCR) Rate [ Time Frame: Time of breast cancer surgery ]
  • Standard Uptake Values as Measured by Baseline and Changes (Day 15) on FDG-PET [ Time Frame: Baseline and day 15 ]
    The standard uptake value used for the PET analysis was SULmax, which is the standard uptake value normalized for lean body mass.
  • Baseline and Change in Markers of Apoptosis and Proliferation [ Time Frame: Time of breast cancer surgery ]
  • Long Term Outcomes [ Time Frame: Indefinite survival analysis ]
  • Baseline and Change in Continuous Variables (e.g., Candidate Gene Methylation, Expression Profiles, Tissue, and Peripheral Blood Mononuclear Cell Histone Acetylation) [ Time Frame: Time of breast cancer surgery ]
Original Secondary Outcome Measures  ICMJE
 (submitted: February 14, 2008)
  • Safety as Measured by NCI CTCAE Version 3.0
  • Clinical Complete Response (cCR) Rate
  • Standard Uptake Values as Measured by Baseline and Changes (Day 15) on FDG-PET
  • Baseline and Change in Markers of Apoptosis and Proliferation
  • Long Term Outcomes
  • Baseline and change in continuous variables (e.g., candidate gene methylation, expression profiles, tissue, and peripheral blood mononuclear cell histone acetylation
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Carboplatin and Nab-Paclitaxel With or Without Vorinostat in Treating Women With Newly Diagnosed Operable Breast Cancer
Official Title  ICMJE A Multi-Institutional Double-Blind Phase II Study Evaluating Response and Surrogate Biomarkers to Carboplatin and Nab-Paclitaxel (CP) With or Without Vorinostat as Preoperative Chemotherapy in HER2-negative Primary Operable Breast Cancer
Brief Summary

RATIONALE: Drugs used in chemotherapy, such as carboplatin and paclitaxel albumin-stabilized nanoparticle formulation, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Vorinostat may also help carboplatin and paclitaxel albumin-stabilized nanoparticle formulation work better by making tumor cells more sensitive to the drugs. Giving chemotherapy with or without vorinostat before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

PURPOSE: This randomized phase II trial is studying how well giving carboplatin together with paclitaxel albumin-stabilized nanoparticle formulation works with or without vorinostat in treating women with breast cancer that can be removed by surgery.

Detailed Description

OBJECTIVES:

Primary

  • To determine pathological complete response (pCR) rates in patients with HER2-negative primary operable breast cancer treated with neoadjuvant therapy comprising carboplatin and paclitaxel albumin-stabilized nanoparticle formulation (CP) with vs without vorinostat.

Secondary

  • To evaluate the safety of these regimens in these patients.
  • To estimate clinical complete response (cCR) rates in patients treated with these regimens.
  • To correlate baseline and change (day 15) in surrogate uptake values (SUV) on FDG-PET with pathological and clinical response in patients treated with these regimens, and to determine what percent of women with ≥ 25% or ≥ 50% reduction in SUV on day 15 achieve a pCR and a cCR to CP with vs without vorinostat.
  • To correlate baseline and change in markers of proliferation with pathological and clinical response in patients treated with these regimens.
  • To evaluate long term outcomes (e.g., recurrence of the breast cancer, development of a new cancer, or death) for patients treated with these regimens.

Tertiary

  • To evaluate baseline and change in candidate gene methylation and expression profiles.
  • To evaluate baseline and change in tissue and peripheral blood mononuclear cell histone acetylation.
  • To compare cCR and pCR in women with basal-like features versus other subtypes.

OUTLINE: This is a multicenter, randomized, double-blind, phase II study (primary study portion) with a 6-12 patient run-in portion.

  • Run-in portion: Patients receive carboplatin IV and paclitaxel albumin-stabilized nanoparticle formulation IV on day 1 and oral vorinostat on days 1-3. Treatment repeats weekly for 12 weeks in the absence of disease progression or unacceptable toxicity. Once safety of the combination of chemotherapy and vorinostat is confirmed, subsequently enrolled patients are entered to the primary study portion.
  • Primary study portion: Patients are stratified by hormone receptor status (estrogen receptor [ER]-negative and progesterone receptor [PR]-negative vs ER-positive and/or PR-positive). Patients are randomized to 1 of 2 treatment arms.

    • Arm I: Patients receive carboplatin IV and paclitaxel albumin-stabilized nanoparticle formulation IV on day 1 and an oral placebo on days 1-3. Treatment repeats weekly for 12 weeks in the absence of disease progression or unacceptable toxicity.
    • Arm II: Patients receive carboplatin and paclitaxel albumin-stabilized nanoparticle formulation as in arm I and oral vorinostat on days 1-3. Treatment repeats weekly for 12 weeks in the absence of disease progression or unacceptable toxicity.

Within 2-4 weeks after completion of neoadjuvant chemotherapy, patients undergo breast conserving surgery or mastectomy at the discretion of the treating physician.

Patients undergo tumor tissue biopsy at baseline, day 15, and at the time of definitive surgery. Samples are analyzed by immunohistochemistry (IHC), RNA extraction, and gene expression analysis using RT-PCR to identify candidate markers for response and molecular profiles that may be relevant to an understanding of drug mechanisms. Methylation of relevant genes (e.g., ERalpha, APC-1, RARbeta, cyclin D2, Twist, RASSF1A, and HIN-1) are evaluated by quantitative multiplex methylation-specific PCR. Changes in gene expression as a result of treatment are determined by IHC or quantitative RT-PCR. Blood samples are collected at baseline, day 15, at the time of definitive surgery, and 4 weeks after surgery for DNA methylation studies, pharmacogenomic studies, and histone acetylation assays. Patients also undergo fludeoxyglucose F 18-positron emission tomography (FDG-PET) or PET/CT at baseline and day 15 to assess treatment response as measured by standardized uptake values.

After completion of study treatment, patients are followed every 6 months.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Breast Cancer
Intervention  ICMJE
  • Drug: carboplatin
    Given IV
    Other Name: Paraplatin
  • Drug: paclitaxel albumin-stabilized nanoparticle formulation
    Given IV
    Other Name: Abraxane, nab-Paclitaxel
  • Drug: vorinostat
    Given orally
    Other Name: Zolinza
  • Other: placebo
    Given orally
Study Arms  ICMJE
  • Active Comparator: Arm I
    Patients receive carboplatin IV and paclitaxel albumin-stabilized nanoparticle formulation IV on day 1 and an oral placebo on days 1-3. Treatment repeats weekly for 12 weeks in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: carboplatin
    • Drug: paclitaxel albumin-stabilized nanoparticle formulation
    • Other: placebo
  • Experimental: Arm II
    Patients receive carboplatin and paclitaxel albumin-stabilized nanoparticle formulation as in arm I and oral vorinostat on days 1-3. Treatment repeats weekly for 12 weeks in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: carboplatin
    • Drug: paclitaxel albumin-stabilized nanoparticle formulation
    • Drug: vorinostat
Publications * Connolly RM, Fackler MJ, Zhang Z, Zhou XC, Goetz MP, Boughey JC, Walsh B, Carpenter JT, Storniolo AM, Watkins SP, Gabrielson EW, Stearns V, Sukumar S. Tumor and serum DNA methylation in women receiving preoperative chemotherapy with or without vorinostat in TBCRC008. Breast Cancer Res Treat. 2018 Jan;167(1):107-116. doi: 10.1007/s10549-017-4503-2. Epub 2017 Sep 16.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 16, 2014)
68
Original Enrollment  ICMJE
 (submitted: February 14, 2008)
74
Actual Study Completion Date  ICMJE February 2014
Actual Primary Completion Date June 2012   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

DISEASE CHARACTERISTICS:

  • Histologically confirmed infiltrating ductal breast cancer by core needle biopsy

    • Mixed ductal and lobular disease allowed
    • Infiltrating lobular cancer allowed in the run-in portion only
  • Unresected, clinically measurable disease, meeting 1 of the following clinical staging criteria:

    • T2, T3, or T4 lesion, any N, M0
    • T1c, N1-3,M0
  • Patients with skin metastases to the ipsilateral breast for whom chemotherapy is planned prior to definitive surgery are eligible for the primary study portion
  • HER2-negative disease
  • Hormone receptor status* meeting 1 of the following criteria:

    • Estrogen receptor (ER)-negative and progesterone receptor (PR)-negative
    • ER-positive (grade II or III) and PR-positive or PR-negative NOTE: *Any ER or PR status for the run-in portion

PATIENT CHARACTERISTICS:

  • ECOG performance status 0-1
  • Menopausal status not specified
  • ANC ≥ 1,500/mm³
  • Platelet count ≥ 150,000/mm³
  • Hemoglobin ≥ 9 g/dL
  • Creatinine ≤ 1.5 times the upper limit of normal (ULN)
  • Creatinine clearance ≥ 50 mL/min
  • Total bilirubin normal
  • AST(SGOT) and ALT(SGPT) ≤ 2.5 times (ULN)
  • alkaline phosphatase ≤ 2.5 times ULN
  • PT such that INR ≤ 1.5 (or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of therapeutic warfarin) and PTT ≤ ULN
  • Adequate cardiac function defined as no evidence of PR prolongation or AV block on baseline electrocardiogram (ECG)
  • Willing to use effective, non-hormonal contraception while on treatment and for at least 3 months thereafter
  • Not pregnant or nursing
  • No pre-existing peripheral neuropathy ≥ grade 2
  • No history of severe hypersensitivity reaction to any drug formulated with polysorbate 80 or to E. coli-derived products
  • No history of allergic reactions attributed to compounds of similar chemical or biologic composition to vorinostat
  • No medical condition which, in the opinion of the investigator, puts the patient at risk of potentially serious complications while on this therapy

PRIOR CONCURRENT THERAPY:

  • At least 4 weeks since prior valproic acid or other histone deacetylase inhibitor
  • No prior chemotherapy, radiotherapy, or endocrine therapy for this cancer

    • Prior tamoxifen or raloxifene or another agent for prevention of breast cancer allowed as long as the patient has discontinued the treatment ≥ 1 month prior to baseline study biopsy
  • No systemic treatment for prior cancer within the past 5 years (primary study portion)
  • No prior or ongoing systemic treatment for this cancer (primary study portion)
  • No concurrent combination antiretroviral therapy for HIV-positive patients
  • No other concurrent histone deacetylase inhibitor
  • No other concurrent chemotherapy, antiestrogen therapy, radiotherapy, or other investigational systemic therapy
  • No other concurrent biologic therapy
  • No other concurrent investigational drugs
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00616967
Other Study ID Numbers  ICMJE JHOC-J0785, CDR0000586335
P30CA006973 ( U.S. NIH Grant/Contract )
JHOC-SKCCC-J0785 ( Other Identifier: SKCCC at Johns Hopkins )
NA_00012756 ( Other Identifier: JHMIRB )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study Sponsor  ICMJE Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Study Chair: Vered Stearns, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
PRS Account Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Verification Date June 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP