Carboplatin and Nab-Paclitaxel With or Without Vorinostat in Treating Women With Newly Diagnosed Operable Breast Cancer

Sponsor
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Other)
Overall Status
Active, not recruiting
CT.gov ID
NCT00616967
Collaborator
National Cancer Institute (NCI) (NIH)
68
5
2
177.1
13.6
0.1

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 2

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 Design

Study Type:
Interventional
Actual Enrollment :
68 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
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
Study Start Date :
May 1, 2008
Actual Primary Completion Date :
Jun 1, 2014
Anticipated Study Completion Date :
Feb 1, 2023

Arms and Interventions

Arm Intervention/Treatment
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.

Drug: carboplatin
Given IV
Other Names:
  • Paraplatin
  • Drug: paclitaxel albumin-stabilized nanoparticle formulation
    Given IV
    Other Names:
  • Abraxane, nab-Paclitaxel
  • Other: placebo
    Given orally

    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.

    Drug: carboplatin
    Given IV
    Other Names:
  • Paraplatin
  • Drug: paclitaxel albumin-stabilized nanoparticle formulation
    Given IV
    Other Names:
  • Abraxane, nab-Paclitaxel
  • Drug: vorinostat
    Given orally
    Other Names:
  • Zolinza
  • Outcome Measures

    Primary Outcome Measures

    1. Pathological Complete Response (pCR) Rate [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.

    Secondary Outcome Measures

    1. Safety as Measured by Number of Participants Who Experience Adverse Events [up to 30 days post-treatment]

      Number of participants who experience adverse events as defined by NCI CTCAE version 3.0

    2. Number of Participants With Clinical Complete Response (cCR) [12 weeks]

      cCR in the breast on physical is defined as the absence of any palpable abnormality on breast exam Iie: no skin or breast thickening, mass or associated skin or nipple changes)

    3. Change in Standard Uptake Value (SULmax) From Baseline to Day 15 on FDG-PET [Baseline and day 15]

      Change in standard uptake value (SULmax) as measured by percentage reduction of SULmax. The standard uptake value used for the PET analysis was SULmax, which is the standard uptake value normalized for lean body mass.

    4. Absolute Change From Baseline in Ki-67 [Change from baseline to Cycle 1-Day 15]

    5. Change in Cumulative Methylation Index (CMI) [Change from baseline to Day 15]

      Change of CMI from baseline to Day 15 (D15), defined as log(D15 CMI + 1/baseline CMI + 1). The CMI was calculated as a sum of all gene-specific methylation indexes within a panel of 10 genes which included: HIST1H3C, AKR1B1, GPX7, HOXB4, TMEFF2, RASGRF2, COL6A2, ARHGEF7, TM6SF1, and RASSF1A.

    6. Cumulative Methylation Index (CMI) at Day 15 [Day 15]

    7. Number of Participants Who Experience Death During Treatment [Up to 12 weeks]

    8. Number of Participants Who Develop New Cancer [Up to death of last participant (duration unknown)]

    9. Number of Participants With Recurrence of Breast Cancer [Up to death of last participant (duration unknown)]

    10. Overall Survival [Up to death of last participant (duration unknown)]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    Female
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 University of Alabama Comprehensive Cancer Center Birmingham Alabama United States 35249
    2 Indiana University Purdue University of Indianapolis Indianapolis Indiana United States 46202
    3 Anne Arundel Health System Annapolis Maryland United States 21401
    4 Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore Maryland United States 21231-2410
    5 Mayo Clinic Cancer Center Rochester Minnesota United States 55905

    Sponsors and Collaborators

    • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
    • National Cancer Institute (NCI)

    Investigators

    • Study Chair: Vered Stearns, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
    ClinicalTrials.gov Identifier:
    NCT00616967
    Other Study ID Numbers:
    • J0785
    • P30CA006973
    • NA_00012756
    • JHOC-SKCCC-J0785
    • JHOC-J0785
    • CDR0000586335
    First Posted:
    Feb 15, 2008
    Last Update Posted:
    Feb 3, 2022
    Last Verified:
    Jan 1, 2022

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Run-in Phase (Arm 0) Placebo (Arm I) Vorinostat (Arm II)
    Arm/Group Description Phase 0 - To confirm safety and dosing prior to moving to randomized phase 2 portion (Arms 1 and 2). 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. carboplatin: Given IV paclitaxel albumin-stabilized nanoparticle formulation: Given IV vorinostat: Given orally 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. carboplatin: Given IV paclitaxel albumin-stabilized nanoparticle formulation: Given IV placebo: Given orally 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. carboplatin: Given IV paclitaxel albumin-stabilized nanoparticle formulation: Given IV vorinostat: Given orally
    Period Title: Overall Study
    STARTED 6 31 31
    COMPLETED 6 31 30
    NOT COMPLETED 0 0 1

    Baseline Characteristics

    Arm/Group Title Placebo (Arm 1) Vorinostat (Arm 2) Total
    Arm/Group Description 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. carboplatin: Given IV paclitaxel albumin-stabilized nanoparticle formulation: Given IV placebo: Given orally 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. carboplatin: Given IV paclitaxel albumin-stabilized nanoparticle formulation: Given IV vorinostat: Given orally Total of all reporting groups
    Overall Participants 31 31 62
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    48
    48
    48
    Sex: Female, Male (Count of Participants)
    Female
    31
    100%
    31
    100%
    62
    100%
    Male
    0
    0%
    0
    0%
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    Asian
    0
    0%
    0
    0%
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    8
    25.8%
    5
    16.1%
    13
    21%
    White
    19
    61.3%
    24
    77.4%
    43
    69.4%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    4
    12.9%
    2
    6.5%
    6
    9.7%
    Region of Enrollment (Count of Participants)
    United States
    31
    100%
    31
    100%
    62
    100%
    ECOG Performance Status (Count of Participants)
    ECOG 0
    30
    96.8%
    29
    93.5%
    59
    95.2%
    ECOG 1
    1
    3.2%
    2
    6.5%
    3
    4.8%
    Tumor Size (centimeters) [Median (Full Range) ]
    Median (Full Range) [centimeters]
    5
    4
    4
    Nodal Status (Count of Participants)
    Negative
    10
    32.3%
    14
    45.2%
    24
    38.7%
    Positive
    21
    67.7%
    17
    54.8%
    38
    61.3%
    Tumor Grade (Count of Participants)
    Grade 2
    11
    35.5%
    7
    22.6%
    18
    29%
    Grade 3
    20
    64.5%
    24
    77.4%
    44
    71%
    Receptor Status (Count of Participants)
    ER-/PR-
    12
    38.7%
    12
    38.7%
    24
    38.7%
    ER+/PR+
    12
    38.7%
    10
    32.3%
    22
    35.5%
    ER+/PR-
    6
    19.4%
    6
    19.4%
    12
    19.4%
    ER-/PR+
    1
    3.2%
    3
    9.7%
    4
    6.5%

    Outcome Measures

    1. Primary Outcome
    Title Pathological Complete Response (pCR) Rate
    Description 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.
    Time Frame Time of breast cancer surgery

    Outcome Measure Data

    Analysis Population Description
    The information for the primary populations for analysis are included (Placebo and Vorinostat arms). Data for this outcome measure was not collected from the initial "run-in phase" of 6 participants.
    Arm/Group Title Arm I Arm II
    Arm/Group Description 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. carboplatin: Given IV paclitaxel albumin-stabilized nanoparticle formulation: Given IV placebo: Given orally 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. carboplatin: Given IV paclitaxel albumin-stabilized nanoparticle formulation: Given IV vorinostat: Given orally
    Measure Participants 31 31
    Count of Participants [Participants]
    9
    29%
    8
    25.8%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm I, Arm II
    Comments Patients were stratified by hormone receptor status and randomly assigned to either arm 1 or 2. This study was designed using Simon's two-stage design for each arm in parallel. Interim analysis of early stopping for futility was conducted for the first 32 patients (16 patients per arm) and the study proceeded as more than 2 patients achieved a pCR in each arm (31 patients per arm). This design had 80% power to detect a 25% pCR rate versus a null rate of 10% with a type I error rate of 0.10.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Pathological complete response rate
    Estimated Value 0.274
    Confidence Interval (2-Sided) 95%
    0.169 to 0.402
    Parameter Dispersion Type:
    Value:
    Estimation Comments The Estimation Parameter provided above is for overall pCR for both arms combined. We estimated pCR for each arm separately as well.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm I
    Comments
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter pCR in placebo arm (arm 1)
    Estimated Value 0.29
    Confidence Interval (2-Sided) 95%
    0.142 to 0.48
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Arm II
    Comments
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter pCR in vorinostat arm (arm 2)
    Estimated Value 0.258
    Confidence Interval (2-Sided) 95%
    0.119 to 0.446
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Safety as Measured by Number of Participants Who Experience Adverse Events
    Description Number of participants who experience adverse events as defined by NCI CTCAE version 3.0
    Time Frame up to 30 days post-treatment

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Run-in Phase (Arm 0) Placebo (Arm 1) Vorinostat (Arm 2)
    Arm/Group Description Patients receive carboplatin and paclitaxel albumin-stabilized nanoparticle formulation and oral vorinostat on days 1-3. Treatment repeats weekly for 12 weeks in the absence of disease progression or unacceptable toxicity. carboplatin: Given IV paclitaxel albumin-stabilized nanoparticle formulation: Given IV vorinostat: Given orally 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. carboplatin: Given IV paclitaxel albumin-stabilized nanoparticle formulation: Given IV placebo: Given orally 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. carboplatin: Given IV paclitaxel albumin-stabilized nanoparticle formulation: Given IV vorinostat: Given orally
    Measure Participants 6 31 31
    Count of Participants [Participants]
    6
    19.4%
    31
    100%
    31
    50%
    3. Secondary Outcome
    Title Number of Participants With Clinical Complete Response (cCR)
    Description cCR in the breast on physical is defined as the absence of any palpable abnormality on breast exam Iie: no skin or breast thickening, mass or associated skin or nipple changes)
    Time Frame 12 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Placebo (Arm I) Vorinostat (Arm II)
    Arm/Group Description 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. carboplatin: Given IV paclitaxel albumin-stabilized nanoparticle formulation: Given IV placebo: Given orally 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. carboplatin: Given IV paclitaxel albumin-stabilized nanoparticle formulation: Given IV vorinostat: Given orally
    Measure Participants 31 31
    Count of Participants [Participants]
    16
    51.6%
    15
    48.4%
    4. Secondary Outcome
    Title Change in Standard Uptake Value (SULmax) From Baseline to Day 15 on FDG-PET
    Description Change in standard uptake value (SULmax) as measured by percentage reduction of SULmax. The standard uptake value used for the PET analysis was SULmax, which is the standard uptake value normalized for lean body mass.
    Time Frame Baseline and day 15

    Outcome Measure Data

    Analysis Population Description
    16/17 "Responders" (from Outcome 1) had PET data evaluable for analysis; 43/45 "non-responders" (from Outcome 1) had PET data evaluable for analysis. Reasons for PET data not evaluable included technically invalid 18F-FDG PET data (2 participants) and no available Day 15 18F-FDG PET data (1 participant).
    Arm/Group Title Responders Non-Responders
    Arm/Group Description Pooled data from participants who received a pathologic complete response across arms. Pooled data from participants who did not receive a pathologic complete response across arms.
    Measure Participants 16 43
    Median (Full Range) [percentage reduction in SULmax]
    63
    32.9
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm I, Arm II
    Comments The estimates provided are based upon a multivariate analysis using a logistic regression adjusting for hormone receptor status. Patients with ≥50% reduction in SULmax were more likely to achieve a pCR.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.023
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 5.1
    Confidence Interval (2-Sided) 95%
    1.3 to 22.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    5. Secondary Outcome
    Title Absolute Change From Baseline in Ki-67
    Description
    Time Frame Change from baseline to Cycle 1-Day 15

    Outcome Measure Data

    Analysis Population Description
    Only 8/17 and 36/45 specimens were evaluable for Ki-67 at both baseline and Day 15. Nonevaluable samples had no tumor cells present or Ki-67 unavailable at either or both time points.
    Arm/Group Title Responders Non-Responders
    Arm/Group Description Pooled data from participants who received a pathologic complete response across arms. Pooled data from participants who did not receive a pathologic complete response across arms.
    Measure Participants 8 36
    Mean (Standard Deviation) [percent change in Ki-67]
    7.0
    (15.8)
    12.0
    (22.7)
    6. Secondary Outcome
    Title Change in Cumulative Methylation Index (CMI)
    Description Change of CMI from baseline to Day 15 (D15), defined as log(D15 CMI + 1/baseline CMI + 1). The CMI was calculated as a sum of all gene-specific methylation indexes within a panel of 10 genes which included: HIST1H3C, AKR1B1, GPX7, HOXB4, TMEFF2, RASGRF2, COL6A2, ARHGEF7, TM6SF1, and RASSF1A.
    Time Frame Change from baseline to Day 15

    Outcome Measure Data

    Analysis Population Description
    Methylation data was only evaluable in participants with both baseline and D15 tissue (48/62) and serum (58/62) specimens.
    Arm/Group Title Combined Arm I and Arm II
    Arm/Group Description Tissue and serum samples from all participants in the actual study (combination of both arms).
    Measure Participants 62
    Tissue CMI change from baseline
    14
    Serum CMI change from baseline
    0
    7. Secondary Outcome
    Title Cumulative Methylation Index (CMI) at Day 15
    Description
    Time Frame Day 15

    Outcome Measure Data

    Analysis Population Description
    Methylation data was only evaluable in 11/17 and 39/45 participants.
    Arm/Group Title Responders Non-Responders
    Arm/Group Description Pooled data from participants who received a pathologic complete response across arms. Pooled data from participants who did not receive a pathologic complete response across arms.
    Measure Participants 11 39
    Median (Full Range) [CMI]
    10
    44
    8. Secondary Outcome
    Title Number of Participants Who Experience Death During Treatment
    Description
    Time Frame Up to 12 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Run-in Phase (Arm 0) Placebo (Arm I) Vorinostat (Arm II)
    Arm/Group Description Phase 0 - To confirm safety and dosing prior to moving to randomized phase 2 portion (Arms 1 and 2). 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. carboplatin: Given IV paclitaxel albumin-stabilized nanoparticle formulation: Given IV vorinostat: Given orally 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. carboplatin: Given IV paclitaxel albumin-stabilized nanoparticle formulation: Given IV placebo: Given orally 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. carboplatin: Given IV paclitaxel albumin-stabilized nanoparticle formulation: Given IV vorinostat: Given orally
    Measure Participants 6 31 31
    Count of Participants [Participants]
    0
    0%
    0
    0%
    0
    0%
    9. Secondary Outcome
    Title Number of Participants Who Develop New Cancer
    Description
    Time Frame Up to death of last participant (duration unknown)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    10. Secondary Outcome
    Title Number of Participants With Recurrence of Breast Cancer
    Description
    Time Frame Up to death of last participant (duration unknown)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    11. Secondary Outcome
    Title Overall Survival
    Description
    Time Frame Up to death of last participant (duration unknown)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    12. Post-Hoc Outcome
    Title Baseline and Change in Continuous Variables (e.g., Candidate Gene Methylation, Expression Profiles, Tissue, and Peripheral Blood Mononuclear Cell Histone Acetylation)
    Description
    Time Frame Time of breast cancer surgery

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description

    Adverse Events

    Time Frame 30 days following the 12 weeks of treatment
    Adverse Event Reporting Description
    Arm/Group Title Run-in Phase (Arm 0) Arm I Arm II
    Arm/Group Description Phase 0 - To confirm safety and dosing prior to moving to randomized phase 2 portion (Arms 1 and 2). 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. carboplatin: Given IV paclitaxel albumin-stabilized nanoparticle formulation: Given IV vorinostat: Given orally Events summarized in this arm are those that met 5% reporting threshold in Arms I and II. 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. carboplatin: Given IV paclitaxel albumin-stabilized nanoparticle formulation: Given IV placebo: Given orally 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. carboplatin: Given IV paclitaxel albumin-stabilized nanoparticle formulation: Given IV vorinostat: Given orally
    All Cause Mortality
    Run-in Phase (Arm 0) Arm I Arm II
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/6 (0%) 0/31 (0%) 0/31 (0%)
    Serious Adverse Events
    Run-in Phase (Arm 0) Arm I Arm II
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/6 (0%) 3/31 (9.7%) 1/31 (3.2%)
    Blood and lymphatic system disorders
    Febrile neutropenia 0/6 (0%) 0 2/31 (6.5%) 2 1/31 (3.2%) 1
    Musculoskeletal and connective tissue disorders
    Myositis 0/6 (0%) 0 1/31 (3.2%) 1 0/31 (0%) 0
    Other (Not Including Serious) Adverse Events
    Run-in Phase (Arm 0) Arm I Arm II
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 6/6 (100%) 31/31 (100%) 31/31 (100%)
    Blood and lymphatic system disorders
    Amemia (hemoglobin) 3/6 (50%) 3 9/31 (29%) 9 20/31 (64.5%) 20
    Neutropenia (neutrophils) 6/6 (100%) 6 28/31 (90.3%) 28 29/31 (93.5%) 29
    Thrombocytopenia (platelets) 1/6 (16.7%) 1 10/31 (32.3%) 10 15/31 (48.4%) 15
    Eye disorders
    Vision changes 0/6 (0%) 0 4/31 (12.9%) 4 5/31 (16.1%) 5
    Gastrointestinal disorders
    Fatigue 6/6 (100%) 6 31/31 (100%) 31 27/31 (87.1%) 27
    Constipation 2/6 (33.3%) 2 14/31 (45.2%) 14 18/31 (58.1%) 18
    Diarrhea 6/6 (100%) 6 18/31 (58.1%) 18 18/31 (58.1%) 18
    Dry mouth 4/6 (66.7%) 4 2/31 (6.5%) 2 6/31 (19.4%) 6
    Flatulence 1/6 (16.7%) 1 7/31 (22.6%) 7 3/31 (9.7%) 3
    Dyspepsia 3/6 (50%) 3 9/31 (29%) 9 7/31 (22.6%) 7
    Mucositis 3/6 (50%) 3 10/31 (32.3%) 10 6/31 (19.4%) 6
    Nausea 5/6 (83.3%) 5 25/31 (80.6%) 25 29/31 (93.5%) 29
    Taste alteration 5/6 (83.3%) 5 13/31 (41.9%) 13 17/31 (54.8%) 17
    Vomiting 2/6 (33.3%) 2 10/31 (32.3%) 10 19/31 (61.3%) 19
    Abdominal pain 1/6 (16.7%) 1 4/31 (12.9%) 4 6/31 (19.4%) 6
    General disorders
    Chills 1/6 (16.7%) 1 4/31 (12.9%) 4 5/31 (16.1%) 5
    Immune system disorders
    Allergic reaction 0/6 (0%) 0 10/31 (32.3%) 10 1/31 (3.2%) 1
    Infections and infestations
    Upper respiratory infection 0/6 (0%) 0 10/31 (32.3%) 10 7/31 (22.6%) 7
    Investigations
    ALT (elevated) 0/6 (0%) 0 4/31 (12.9%) 4 1/31 (3.2%) 1
    Metabolism and nutrition disorders
    Anorexia 5/6 (83.3%) 5 17/31 (54.8%) 17 19/31 (61.3%) 19
    Musculoskeletal and connective tissue disorders
    Arthralgia 4/6 (66.7%) 4 13/31 (41.9%) 13 15/31 (48.4%) 15
    Myalgia 1/6 (16.7%) 1 11/31 (35.5%) 11 13/31 (41.9%) 13
    Nervous system disorders
    Dizziness 2/6 (33.3%) 2 4/31 (12.9%) 4 1/31 (3.2%) 1
    Peripheral sensory neuropathy 6/6 (100%) 6 25/31 (80.6%) 25 20/31 (64.5%) 20
    Headache 3/6 (50%) 3 8/31 (25.8%) 8 5/31 (16.1%) 5
    Psychiatric disorders
    Insomnia 2/6 (33.3%) 2 6/31 (19.4%) 6 5/31 (16.1%) 5
    Respiratory, thoracic and mediastinal disorders
    Epistaxis 1/6 (16.7%) 1 14/31 (45.2%) 14 5/31 (16.1%) 5
    Cough 1/6 (16.7%) 1 3/31 (9.7%) 3 1/31 (3.2%) 1
    Dyspnea 1/6 (16.7%) 1 7/31 (22.6%) 7 0/31 (0%) 0
    Skin and subcutaneous tissue disorders
    Alopecia 6/6 (100%) 6 31/31 (100%) 31 29/31 (93.5%) 29
    Nail changes 1/6 (16.7%) 1 8/31 (25.8%) 8 3/31 (9.7%) 3
    Pruritus 0/6 (0%) 0 3/31 (9.7%) 3 1/31 (3.2%) 1
    Rash 3/6 (50%) 3 9/31 (29%) 9 9/31 (29%) 9
    Vascular disorders
    Hot flashes 3/6 (50%) 3 8/31 (25.8%) 8 7/31 (22.6%) 7

    Limitations/Caveats

    A proportion of women received additional preoperative chemotherapy after study treatment,complicating the evaluation of primary endpoint and role of FDG-PET in predicting response. Limited matched samples for Ki67 analysis.

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Dr. Vered Stearns
    Organization Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
    Phone 443-287-6489
    Email vstearn1@jhmi.edu
    Responsible Party:
    Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
    ClinicalTrials.gov Identifier:
    NCT00616967
    Other Study ID Numbers:
    • J0785
    • P30CA006973
    • NA_00012756
    • JHOC-SKCCC-J0785
    • JHOC-J0785
    • CDR0000586335
    First Posted:
    Feb 15, 2008
    Last Update Posted:
    Feb 3, 2022
    Last Verified:
    Jan 1, 2022