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An 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


Phase 2
18 Years
N/A
Open (Enrolling)
Female
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

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Trial Information

An 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


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.


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

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Pathologic complete response (PCR)

Outcome Description:

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.

Outcome Time Frame:

At the time of surgery

Safety Issue:

No

Principal Investigator

Tiffany Avery, MD, MPH

Investigator Role:

Principal Investigator

Investigator Affiliation:

Thomas Jefferson University

Authority:

United States: Food and Drug Administration

Study ID:

12G.376

NCT ID:

NCT01818063

Start Date:

April 2013

Completion Date:

Related Keywords:

  • 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
  • Breast Neoplasms

Name

Location

Anne Arundel Medical CenterAnnapolis, Maryland  21401
University of Pittsburgh Medical CenterPittsburgh, Pennsylvania  15213
Thomas Jefferson UniversityPhiladelphia, Pennsylvania  19107-6541
Walter Reed National Military Medical CenterBethesda, Maryland  20889