Carboplatin and Combination Chemotherapy With or Without Veliparib in Treating Patients With Stage IIB-IIIC Breast Cancer

Overview[ - collapse ][ - ]

Purpose This randomized phase II trial studies how well carboplatin and combination chemotherapy with or without veliparib works in treating patients with stage IIB-IIIC breast cancer. Drugs used in chemotherapy, such as paclitaxel, carboplatin, doxorubicin hydrochloride, and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving carboplatin and combination chemotherapy are more effective with or without veliparib is more effective in treating breast cancer.
ConditionEstrogen Receptor-negative Breast Cancer
HER2-negative Breast Cancer
Progesterone Receptor-negative Breast Cancer
Stage II Breast Cancer
Stage IIIA Breast Cancer
Stage IIIB Breast Cancer
Stage IIIC Breast Cancer
Triple-negative Breast Cancer
InterventionDrug: Paclitaxel
Drug: Carboplatin
Drug: Doxorubicin
Drug: Cyclophosphamide
Drug: Veliparib
PhasePhase 2
SponsorThomas Jefferson University
Responsible PartyThomas Jefferson University
ClinicalTrials.gov IdentifierNCT01818063
First ReceivedMarch 21, 2013
Last UpdatedApril 23, 2014
Last verifiedApril 2014

Tracking Information[ + expand ][ + ]

First Received DateMarch 21, 2013
Last Updated DateApril 23, 2014
Start DateApril 2013
Estimated Primary Completion DateNot Provided
Current Primary Outcome MeasuresPathologic complete response (PCR) [Time Frame: At the time of surgery] [Designated as safety issue: No]PCR is defined as the absence of any residual invasive cancer on hematoxylin and eosin (H&E) evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes. The posterior distribution of the odds ratio will be used to assess whether carboplatin and/or carboplatin +veliparib in combination with paclitaxel has a higher PCR compared to each other and simulations will be used to compare to paclitaxel alone. A 95% credible region will be calculated for the odds ratio comparing the two combination treatments, the odds ratio comparing each treatment to paclitaxel alone, the PCR for each treatment regimen, for the difference in the PCR between each combination regimen, and the difference of each combination regimen to paclitaxel alone.
Current Secondary Outcome Measures
  • Overall clinical response [Time Frame: Up to 3 years] [Designated as safety issue: No]The proportion of subjects with each category of overall clinical response will be summarized by presence of baseline measureable disease (i.e., complete response [CR], partial response [PR], stable disease [SD], progressive disease [PD], unable to evaluate [UE], neurogenerative disease [ND]). Beta will be used as priors for combination regimens in calculating the posterior distribution of the PCR for each respective treatment group. Among subjects with measurable disease, a 95% credible region will be calculated for the odds ratio for each treatment combination relative to each other.
  • Relapse free survival [Time Frame: Up to 3 years] [Designated as safety issue: No]Analyzed using Kaplan-Meier methods, stratified by study group, and the log rank test will be completed.

Descriptive Information[ + expand ][ + ]

Brief TitleCarboplatin and Combination Chemotherapy With or Without Veliparib in Treating Patients With Stage IIB-IIIC Breast Cancer
Official TitleAn Adaptive, Randomized Phase II Trial to Determine Pathologic Complete Response With the Addition of Carboplatin With and Without Veliparib to Standard Chemotherapy in the Neoadjuvant Treatment of Triple-Negative Breast Cancer
Brief Summary
This randomized phase II trial studies how well carboplatin and combination chemotherapy
with or without veliparib works in treating patients with stage IIB-IIIC breast cancer.
Drugs used in chemotherapy, such as paclitaxel, carboplatin, doxorubicin hydrochloride, and
cyclophosphamide, work in different ways to stop the growth of tumor cells, either by
killing the cells or by stopping them from dividing. Veliparib may stop the growth of tumor
cells by blocking some of the enzymes needed for cell growth. It is not yet known whether
giving carboplatin and combination chemotherapy are more effective with or without veliparib
is more effective in treating breast cancer.
Detailed Description
PRIMARY OBJECTIVE:

1) To compare the pathologic complete response (path CR) in patients with stage IIB or stage
III triple negative breast cancer treated with neoadjuvant paclitaxel and carboplatin to the
path CR of patients treated with paclitaxel, carboplatin, and veliparib.

SECONDARY OBJECTIVES:

1. Relapse free survival (follow-up period of 36 months).

2. Overall clinical response to neoadjuvant therapy.

3. To determine whether expression of 5 biomarkers (cytokeratin [CK]5, endothelial growth
factor receptor [EGFR], excision repair cross complementing 1 [ERCC1], Ki67,
poly[adenosine diphosphate (ADP)-ribosyl]transferase [Parp1]) correlate with a higher
pCR in response to a particular treatment combination. 4) To determine whether tumors
with biomarker signatures that are most like breast cancer (BRCA)-mutated tumors (high
expression of CK5 and high expression of EGFR), will correlate with a higher likelihood
of pCR with treatment with a PARP inhibitor in combination with chemotherapy.

5) To determine whether tumors with high expression of the markers ERCC1, Ki67, and Parp1
will correlate with a higher rate of pCR with platinum agents in combination with paclitaxel
or a PARP inhibitor.

6) To correlate response of tumor on imaging (magnetic resonance imaging [MRI], ultrasound
[US], and positron emission tomography [PET]/computed tomography [CT]) with path CR.

7) To correlate levels of circulating tumor cells (CTCs) with pathologic CR.

TERTIARY OBJECTIVES:

1. To evaluate additional exploratory biomarkers based on evidence of possible prognostic
or predictive value: BRCA1/BRCA2 complete mutational and rearrangement test. CK14,
CK17, cyclin B1, cluster of differentiation (CD)44, CD24, cyclin D1, vimentin,
thymidine phosphorylase, inhibitor of differentiation (ID)4, p53, p63, p73,
differentiated embryo-chondrocyte expressed gene (Dec)1, phospho-HistoneH3, thymidylate
synthase, p16, gammaH2AX, geminin, RAD51.

2. To determine which arms are best tolerated by patients with co-morbid conditions, such
as hypertension and diabetes.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive paclitaxel intravenously (IV) and carboplatin IV on day 1 (course 1
only) or day 2 (courses 2-12). Treatment repeats every 7 days for 12 courses in the absence
of disease progression or unacceptable toxicity. Beginning 21 days after the last course,
patients receive doxorubicin hydrochloride IV and cyclophosphamide IV on day 1. Treatment
repeats every 21 days for 4 courses in the absence of disease progression or unacceptable
toxicity.

ARM II: Patients receive veliparib orally (PO) twice daily (BID) on days 1-5. Patients also
receive paclitaxel IV and carboplatin IV on day 3 (course 1 only) or day 4 (courses 2-12).
Treatment repeats every 7 days for 12 courses in the absence of disease progression or
unacceptable toxicity. Beginning 21 days after the last course, patients receive doxorubicin
hydrochloride IV and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4
courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 36 months.
Study TypeInterventional
Study PhasePhase 2
Study DesignAllocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Condition
  • Estrogen Receptor-negative Breast Cancer
  • HER2-negative Breast Cancer
  • Progesterone Receptor-negative Breast Cancer
  • Stage II Breast Cancer
  • Stage IIIA Breast Cancer
  • Stage IIIB Breast Cancer
  • Stage IIIC Breast Cancer
  • Triple-negative Breast Cancer
InterventionDrug: Paclitaxel
Given IV
Other Names:
  • Taxol
  • Abraxane
Drug: Carboplatin
Given IV
Other Names:
  • cis-Diammine(1,1-cyclobutanedicarboxylato)platinum(II)
  • Paraplatin
  • Paraplatin-AQ
Drug: Doxorubicin
Given IV
Other Names:
  • Adriamycin
  • hydroxydaunorubicin
  • Adriamycin PFS
  • Adriamycin RDF
  • Rubex
  • Doxil
Drug: Cyclophosphamide
Given IV
Other Names:
  • Endoxan
  • Cytoxan
  • Neosar
  • Procytox
  • Revimmune
  • cytophosphane
  • Lyophilizedcytoxan
Drug: Veliparib
Given PO
Other Names:
ABT-888
Study Arm (s)
  • Experimental: Arm 1 (paclitaxel, carboplatin)
    Patients receive paclitaxel IV and carboplatin IV on day 1 (course 1 only) or day 2 (courses 2-12). Treatment repeats every 7 days for 12 courses in the absence of disease progression or unacceptable toxicity. Beginning 21 days after the last course, patients receive doxorubicin hydrochloride IV and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
  • Experimental: Arm 2 (veliparib, paclitaxel, carboplatin)
    Patients receive veliparib PO BID on days 1-5. Patients also receive paclitaxel IV and carboplatin IV on day 3 (course 1 only) or day 4 (courses 2-12). Treatment repeats every 7 days for 12 courses in the absence of disease progression or unacceptable toxicity. Beginning 21 days after the last course, patients receive doxorubicin hydrochloride IV and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

Recruitment Information[ + expand ][ + ]

Recruitment StatusRecruiting
Estimated Enrollment80
Estimated Completion DateNot Provided
Estimated Primary Completion DateApril 2018
Eligibility Criteria
Inclusion Criteria:

1. Written informed consent must be obtained prior to any study-related procedures.

2. Histologically confirmed adenocarcinoma of the breast with the following markers:
Estrogen receptor negative (<1%), progesterone receptor negative (<1%), and Her-2/neu
negative (Her-2/neu 0-1+ IHC or FISH ratio <1.8 or average HER2 gene copy number of

3. Female ≥ 18 years old.

4. Clinical stage IIB (T2N1, T3N0) or stage IIIA (T1N2, T2N2, T3N1, T3N2), IIIB, or IIIC
breast cancer with no prior treatment.

5. Complete radiology or tumor assessment within 28 days prior to enrollment

1. Breast MRI

2. Unilateral Breast Ultrasound

3. Bilateral Mammogram

4. Distant metastatic work-up completed with PET/CT.

5. If enlarged axillary lymph nodes are found during staging scans, FNA must be
performed to determine whether the node is involved with cancer.

6. If axillary lymph nodes are clinically negative during initial work-up, sentinel
node biopsy will be performed prior to initiation of chemotherapy.

6. ECOG Performance Status of 0 or 1

7. Adequate organ and hematologic function as evidenced by the following laboratory
studies within 4 weeks of study enrollment:

1. Cardiac Ejection Fraction >/= lower limit of normal as determined by 2-D echo or
MUGA scan according to institutional standards.

2. Hematologic function, as follows: Absolute neutrophil count ≥ 1.5 x 109/L,
Platelet count ≥ 100 x 109/L and ≤ 850 x 109/L, Hemoglobin ≥ 9 g/dL, PTT and INR
< 1.5 x ULN.

3. Renal function, as follows: Serum creatinine
4. Hepatic function, as follows:Aspartate aminotransferase (AST) ≤ 2.5 x ULN,
Alanine aminotransferase (ALT) ≤ 2.5 x ULN , Total bilirubin ≤ 2 x ULN (except
for patients with UGT1A1 promoter polymorphism, i.e. Gilbert syndrome, confirmed
by genotyping or Invader UGT1A1 molecular assay prior to study enrollment.
Patients enrolled with Gilbert syndrome must have total bilirubin < 3 ULN).

8. Patient must be willing and able to undergo MRI as outlined in protocol.

9. Tumor clip placement.

Exclusion Criteria:

1. Known hypersensitivity to doxorubicin, cyclophosphamide, paclitaxel, cremophor or
medications containing cremophor(miconazole, docetaxel, sandimmune, nelfinavir
mesylate, propofol, diazepam injection, vitamin K injection, ixabepilone, aci-jel) or
carboplatin.

2. Known HIV or active Hepatitis B or C infection.

3. Prior treatment for the currently diagnosed breast cancer.

4. Prior treatment with doxorubicin up to 400 mg/m2.

5. Pre-existing Grade 3 or 4 sensory neuropathy.

6. History of bleeding diathesis or extensive bleeding requiring blood transfusion
within 14 days of enrollment.

7. Major surgical procedure within 4 weeks (28 days) prior to enrollment (port placement
is not considered a major surgical procedure).

8. Clinically significant cardiac disease within 12 months of study enrollment,
including myocardial infarction, unstable angina, congestive heart failure, or
ongoing arrhythmias requiring medication or pacemaker.

9. Non-healing wound, ulcer or fracture.

10. Ongoing or active infection.

11. Pregnant (i.e., positive beta-human chorionic gonadotropin test) or lactating

12. Not willing to use a highly effective method of birth control (i.e. those which
result in low failure rates, less than 1% per year), defined as intrauterine devices,
barrier methods (condoms, contraceptive sponges, diaphragms, vaginal rings used with
spermicidal jellies or creams), oral contraceptive pills, or sexual abstinence.
Contraception must be used during the study.

13. History of prior cancer. History of basal cell or squamous cell skin cancer is
permitted.

14. Inflammatory Breast Cancer

15. T0 tumors

16. Active dental infection
GenderFemale
Ages18 Years
Accepts Healthy VolunteersNo
ContactsContact: Tiffany Avery, MD, MPH
215-955-1661
Location CountriesUnited States

Administrative Information[ + expand ][ + ]

NCT Number NCT01818063
Other Study ID Numbers12G.376
Has Data Monitoring CommitteeYes
Information Provided ByThomas Jefferson University
Study SponsorThomas Jefferson University
CollaboratorsSusan G. Komen Breast Cancer Foundation
Investigators Principal Investigator: Tiffany Avery, MD, MPH Thomas Jefferson University
Verification DateApril 2014

Locations[ + expand ][ + ]

Anne Arundel Medical Center
Annapolis, Maryland, United States, 21401
Contact: Lorraine Tafra, MD
Principal Investigator: Lorraine Tafra, MD
Not yet recruiting
Walter Reed National Military Medical Center
Bethesda, Maryland, United States, 20889
Contact: Craig Shriber, MD
Principal Investigator: Craig Shriber, MD
Not yet recruiting
Thomas Jefferson University
Philadelphia, Pennsylvania, United States, 19107
Contact: Tiffany Avery, MD, MPH | 215-955-1661
Principal Investigator: Tiffany Avery, MD, MPH
Recruiting
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States, 15213
Contact: Shannon Pulhalla, MD
Principal Investigator: Shannon Pulhalla, MD
Not yet recruiting