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

Sidney Kimmel Cancer Center at Thomas Jefferson University

Status and phase: Completed; Phase 2

Conditions: Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Progesterone Receptor-negative Breast Cancer; Triple-negative Breast Cancer; Stage IIIC Breast Cancer; Stage II Breast Cancer; Estrogen Receptor-negative Breast Cancer; HER2-negative Breast Cancer

Treatments: Drug: Paclitaxel; Drug: Cyclophosphamide; Drug: Carboplatin; Drug: Veliparib; Drug: Doxorubicin

Study type: Interventional

Funder types: Other

Identifiers

NCT01818063

JT 2997 (Other Identifier)

12G.376

2012-47 (Other Identifier)

Details and patient eligibility

About

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.

Full 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.

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.

Enrollment: 9 patients

Sex: Female

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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 <four signal/nucleus for test systems without internal control probe).

3. Female ≥ 18 years old.

4. Clinical stage IIA (T2N0), 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. Distant metastatic work-up completed with PET/CT.
   4. If enlarged axillary lymph nodes are found during staging scans, FNA must be performed to determine whether the node is involved with cancer.
   5. 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 </= 1.4 mg/dL).
   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.

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. T0 tumors
14. Active dental infection

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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9 participants in 2 patient groups

Arm 1 (paclitaxel, carboplatin)

Experimental group

Description:

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.

Treatment:

Drug: Doxorubicin

Drug: Carboplatin

Drug: Cyclophosphamide

Drug: Paclitaxel

Arm 2 (veliparib, paclitaxel, carboplatin)

Experimental group

Description:

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.

Treatment:

Drug: Doxorubicin

Drug: Veliparib

Drug: Carboplatin

Drug: Cyclophosphamide

Drug: Paclitaxel