Clinical trial NCT00616967: Carboplatin and Nab-Paclitaxel With or Without Vorinostat in Treating Women With Newly Diagnosed Operable Breast Cancer
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 type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Breast Cancer
Keywords: stage II breast cancer
stage IIIA breast cancer
stage IIIB breast cancer
stage IIIC breast cancer
ductal breast carcinoma
lobular breast carcinoma
Lead sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2008-02-15
Enrollment: 68
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Pathological Complete Response (pCR) Rate
timeFrame: Time of breast cancer surgery
Secondary outcomes:
measure: Safety as Measured by Number of Participants Who Experience Adverse Events
timeFrame: up to 30 days post-treatment
measure: Number of Participants With Clinical Complete Response (cCR)
timeFrame: 12 weeks
measure: Change in Standard Uptake Value (SULmax) From Baseline to Day 15 on FDG-PET
timeFrame: Baseline and day 15
measure: Absolute Change From Baseline in Ki-67
timeFrame: Change from baseline to Cycle 1-Day 15
measure: Change in Cumulative Methylation Index (CMI)
timeFrame: Change from baseline to Day 15
measure: Cumulative Methylation Index (CMI) at Day 15
timeFrame: Day 15
measure: Number of Participants Who Experience Death During Treatment
timeFrame: Up to 12 weeks
measure: Number of Participants Who Develop New Cancer
timeFrame: Up to death of last participant (duration unknown)
measure: Number of Participants With Recurrence of Breast Cancer
timeFrame: Up to death of last participant (duration unknown)
measure: Overall Survival
timeFrame: Up to death of last participant (duration unknown)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama Comprehensive Cancer Center
state: Alabama
city: Indianapolis
country: United States
facility: Indiana University Purdue University of Indianapolis
state: Indiana
city: Annapolis
country: United States
facility: Anne Arundel Health System
state: Maryland
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
city: Rochester
country: United States
facility: Mayo Clinic Cancer Center
state: Minnesota
Study officials:
affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
name: Vered Stearns, MD
role: STUDY_CHAIR
References:
citation: Connolly RM, Leal JP, Goetz MP, Zhang Z, Zhou XC, Jacobs LK, Mhlanga J, O JH, Carpenter J, Storniolo AM, Watkins S, Fetting JH, Miller RS, Sideras K, Jeter SC, Walsh B, Powers P, Zorzi J, Boughey JC, Davidson NE, Carey LA, Wolff AC, Khouri N, Gabrielson E, Wahl RL, Stearns V. TBCRC 008: early change in 18F-FDG uptake on PET predicts response to preoperative systemic therapy in human epidermal growth factor receptor 2-negative primary operable breast cancer. J Nucl Med. 2015 Jan;56(1):31-7. doi: 10.2967/jnumed.114.144741. Epub 2014 Dec 4.
citation: 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.