Breast Cancer
Conditions
Keywords
stage II breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer, ductal breast carcinoma, lobular breast carcinoma
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.
Interventions
DRUGcarboplatin
Given IV
DRUGpaclitaxel albumin-stabilized nanoparticle formulation
Given IV
DRUGvorinostat
Given orally
OTHERplacebo
Given orally
Sponsors
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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) |
| 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. |
| Absolute Change From Baseline in Ki-67 | Change from baseline to Cycle 1-Day 15 | — |
| 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. |
| Cumulative Methylation Index (CMI) at Day 15 | Day 15 | — |
| Number of Participants Who Experience Death During Treatment | Up to 12 weeks | — |
| Number of Participants Who Develop New Cancer | Up to death of last participant (duration unknown) | — |
| Number of Participants With Recurrence of Breast Cancer | Up to death of last participant (duration unknown) | — |
| Overall Survival | Up to death of last participant (duration unknown) | — |
Countries
United States
Contacts
STUDY_CHAIRVered Stearns, MD
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo (Arm 1) 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 | 31 |
| Vorinostat (Arm 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 | 31 |
| Total | 62 |
Baseline characteristics
| Characteristic | Total | Placebo (Arm 1) | Vorinostat (Arm 2) |
|---|---|---|---|
| Age, Continuous | 48 years | 48 years | 48 years |
| ECOG Performance Status ECOG 0 | 59 Participants | 30 Participants | 29 Participants |
| ECOG Performance Status ECOG 1 | 3 Participants | 1 Participants | 2 Participants |
| Nodal Status Negative | 24 Participants | 10 Participants | 14 Participants |
| Nodal Status Positive | 38 Participants | 21 Participants | 17 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 13 Participants | 8 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) White | 43 Participants | 19 Participants | 24 Participants |
| Receptor Status ER-/PR- | 24 Participants | 12 Participants | 12 Participants |
| Receptor Status ER-/PR+ | 4 Participants | 1 Participants | 3 Participants |
| Receptor Status ER+/PR- | 12 Participants | 6 Participants | 6 Participants |
| Receptor Status ER+/PR+ | 22 Participants | 12 Participants | 10 Participants |
| Region of Enrollment United States | 62 Participants | 31 Participants | 31 Participants |
| Sex: Female, Male Female | 62 Participants | 31 Participants | 31 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Tumor Grade Grade 2 | 18 Participants | 11 Participants | 7 Participants |
| Tumor Grade Grade 3 | 44 Participants | 20 Participants | 24 Participants |
| Tumor Size | 4 centimeters | 5 centimeters | 4 centimeters |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 31 | 0 / 31 |
| other Total, other adverse events | 6 / 6 | 31 / 31 | 31 / 31 |
| serious Total, serious adverse events | 0 / 6 | 3 / 31 | 1 / 31 |
Outcome results
Primary
Pathological Complete Response (pCR) Rate
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
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I | Pathological Complete Response (pCR) Rate | 9 Participants |
| Arm II | Pathological Complete Response (pCR) Rate | 8 Participants |
Comparison: 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 0.10.95% CI: [0.169, 0.402]
95% CI: [0.142, 0.48]
95% CI: [0.119, 0.446]
Secondary
Absolute Change From Baseline in Ki-67
Time frame: Change from baseline to Cycle 1-Day 15
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I | Absolute Change From Baseline in Ki-67 | 7.0 percent change in Ki-67 | Standard Deviation 15.8 |
| Arm II | Absolute Change From Baseline in Ki-67 | 12.0 percent change in Ki-67 | Standard Deviation 22.7 |
Secondary
Change in Cumulative Methylation Index (CMI)
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
Population: Methylation data was only evaluable in participants with both baseline and D15 tissue (48/62) and serum (58/62) specimens.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm I | Change in Cumulative Methylation Index (CMI) | Tissue CMI change from baseline | 14 CMI |
| Arm I | Change in Cumulative Methylation Index (CMI) | Serum CMI change from baseline | 0 CMI |
Secondary
Change in Standard Uptake Value (SULmax) From Baseline to Day 15 on FDG-PET
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
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I | Change in Standard Uptake Value (SULmax) From Baseline to Day 15 on FDG-PET | 63 percentage reduction in SULmax |
| Arm II | Change in Standard Uptake Value (SULmax) From Baseline to Day 15 on FDG-PET | 32.9 percentage reduction in SULmax |
Comparison: 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.p-value: 0.02395% CI: [1.3, 22.7]Regression, Logistic
Secondary
Cumulative Methylation Index (CMI) at Day 15
Time frame: Day 15
Population: Methylation data was only evaluable in 11/17 and 39/45 participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I | Cumulative Methylation Index (CMI) at Day 15 | 10 CMI |
| Arm II | Cumulative Methylation Index (CMI) at Day 15 | 44 CMI |
Secondary
Number of Participants Who Develop New Cancer
Time frame: Up to death of last participant (duration unknown)
Secondary
Number of Participants Who Experience Death During Treatment
Time frame: Up to 12 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I | Number of Participants Who Experience Death During Treatment | 0 Participants |
| Arm II | Number of Participants Who Experience Death During Treatment | 0 Participants |
| Vorinostat (Arm 2) | Number of Participants Who Experience Death During Treatment | 0 Participants |
Secondary
Number of Participants With Clinical Complete Response (cCR)
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I | Number of Participants With Clinical Complete Response (cCR) | 16 Participants |
| Arm II | Number of Participants With Clinical Complete Response (cCR) | 15 Participants |
Secondary
Number of Participants With Recurrence of Breast Cancer
Time frame: Up to death of last participant (duration unknown)
Secondary
Overall Survival
Time frame: Up to death of last participant (duration unknown)
Secondary
Safety as Measured by Number of Participants Who Experience Adverse Events
Number of participants who experience adverse events as defined by NCI CTCAE version 3.0
Time frame: up to 30 days post-treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I | Safety as Measured by Number of Participants Who Experience Adverse Events | 6 Participants |
| Arm II | Safety as Measured by Number of Participants Who Experience Adverse Events | 31 Participants |
| Vorinostat (Arm 2) | Safety as Measured by Number of Participants Who Experience Adverse Events | 31 Participants |
Post Hoc
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