Details

Details

Title A Randomized, Placebo-Controlled, Double-Blind, Phase 3 Study Evaluating Safety and Efficacy of the Addition of Veliparib Plus Carboplatin Versus the Addition of Carboplatin to Standard Neoadjuvant Chemotherapy Versus Standard Neoadjuvant Chemotherapy in Subjects with Early Stage Triple Negative Breast Cancer (TNBC)

IRB ABBV1114

CC 15-808

Hospital Fairview, Hillcrest, Independence, Main Campus, Strongsville

Phase Phase 3

Disease Breast

Drug Carboplatin, Cyclophosphamide , Doxorubicin, Paclitaxel , Veliparib

Description

Description

Primary Objective
  • To assess the pathological complete response (pCR) in breast and any resected lymph node tissue after treatment with neoadjuvant veliparib in combination with carboplatin and paclitaxel followed by doxorubicin + cyclophosphamide compared to two neoadjuvant chemotherapy regimens (carboplatin + paclitaxel followed by doxorubicin + cyclophosphamide or paclitaxel alone followed by doxorubicin + cyclophosphamide) in subjects with early stage TNBC.
Secondary Objective
  • To assess rate of eligibility for breast conservation (BCR) after neoadjuvant therapy.
Tertiary Objectives
  • To assess event free survival (EFS), overall survival (OS), clinical response rate (CRR) at 12 weeks, residual cancer burden (RCB), Eastern Cooperative Oncology Group (ECOG) performance status, and quality of life (QoL).
Inclusion Criteria

Inclusion Criteria

  1. Women ≥ 18 years of age.
  2. Histologically confirmed invasive breast cancer by core needle or incisional biopsy (excisional biopsy is not allowed). Clinical stage T2-3 N0-2 or T1 N1-2 by physical exam or radiologic studies. At the time of presentation, subjects must be candidates for potentially curative surgery by surgeon's assessment. Inflammatory breast cancer or neuroendocrine carcinoma is not allowed. If multiple (up to 2) suspicious lesions are present, each must be biopsied to evaluate for invasive disease, and all invasive lesions in the same breast must be triple-negative as defined below. Subjects with synchronous bilateral invasive breast cancers are not eligible.
  3. Documented BRCA germline mutation testing. All subjects regardless of BRCA mutation status (i.e., wildtype BRCA or germline BRCA mutation) are eligible for study participation. If testing has been performed by a laboratory other than the Sponsor core laboratory, subjects may be enrolled but must be re-tested by Sponsor core laboratory for confirmation of BRCA1 and/or BRCA2 germline mutation. Subjects who complete informed consent and screening procedures will not be denied protocol therapy due to delays in BRCA testing results. For those subjects who meet other enrollment criteria but have not received BRCA germline mutation testing results at the completion of the screening period, randomization to a treatment group based on other stratifications factors will be permitted upon Sponsor approval. Subjects will be analyzed according to results of BRCA testing as described in the statistical methods.
  4. ER-, PR-, and HER2-negative (triple-negative) cancer of the breast. Randomization based on local results will be permitted, and all results will be confirmed by central pathology reading. Triple-negative tumors are defined as:
    • For ER- and PR-negative: less than or equal to 1% tumor staining by immunohistochemistry (IHC).
    • HER2-negative disease, defined as IHC 0 - 1+ OR HER2-neu negative according to ASCO-CAP guideline recommendations (Appendix H).
  5. ECOG Performance status of 0 to 1.
  6. Adequate organ function as follows:
    • Bone Marrow: Absolute neutrophil count (ANC) ≥ 1500/mm3 (1.5 x 109/L); Platelets ≥ 100,000/mm3 (100 x 109/L); Hemoglobin ≥ 9.5 g/dL (5.6 mmol/L); Leukocytes > 3,000/mm3;
    • Renal Function: Calculated creatinine clearance ≥ 50 mL/min by the Cockroft-Gault formula;
    • Hepatic Function: Aspartate aminotransferase (AST) or alanine transaminase (ALT) ≤ 2.5 x upper limit of normal (ULN); bilirubin ≤ 1.5 x ULN. Subjects with Gilbert's syndrome may have a bilirubin > 1.5 x ULN, if no evidence of biliary obstruction exists;
    • Activated Partial Thromboplastin Time (APTT) must be ≤ 1.5 x ULN and international normalized ratio (INR) < 1.5 x ULN. Subjects on anticoagulant therapy will have an appropriate APTT and INR as determined by the Investigator;
    • Adequate cardiopulmonary reserve to undergo surgery with general anesthesia;
    • Left ventricular ejection fraction greater than or equal to 50% by MUGA or echocardiogram.
  7. Women must be determined to be not of childbearing potential (surgically sterile, or postmenopausal defined as amenorrheic for at least 12 months) by the Investigator OR they must have a negative serum pregnancy test prior to randomization. Women of childbearing potential must agree to use adequate contraception (one of the following listed below) prior to study entry, while receiving study treatment, and for 6 months (or per local labels) following completion of therapy.
    • Total abstinence from sexual intercourse as the preferred lifestyle of the subject; periodic abstinence is not acceptable;
    • Sexual intercourse with only a vasectomized partner;
    • Double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal ring with spermicidal jellies or cream);
    • Intra-Uterine Device (IUD).
  8. Capability of understanding and complying with parameters as outlined in the protocol and able to sign and date the informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to initiation of any screening or study-specific procedures.
  9. Capability of taking oral medication.
Exclusion Criteria

Exclusion Criteria

  1. Previous anti-cancer treatment (cytotoxic chemotherapy, immunotherapy, biologic therapy radiotherapy or investigational agents) with therapeutic intent for current breast cancer.
  2. Previous treatment with carboplatin, paclitaxel, doxorubicin, or cyclophosphamide.
  3. Prior therapy with a Poly-(ADP-ribose)-Polymerase (PARP) inhibitor.
  4. Concurrent treatment with an ovarian hormonal replacement therapy or with hormonal agents such as raloxifene, tamoxifen or other selective estrogen receptor modulator (SERM). Subjects must have discontinued use of such agents prior to beginning study treatment.
  5. A history of seizure within 12 months prior to study entry.
  6. Pre-existing neuropathy from any cause in excess of Grade 1.
  7. Known history of allergic reactions to cremophor-containing medications, including Polyoxyl 35 Castor Oil.
  8. Clinically significant uncontrolled condition(s) including but not limited to the following:
    • Active infection;
    • Symptomatic congestive heart failure;
    • Unstable angina pectoris or cardiac arrhythmia;
    • Myocardial infarction within last 6 months;
    • Contraindications to surgery with general anesthetic or regional radiotherapy
    • Psychiatric illness/social situations that would limit compliance with study requirements;
    • Hemorrhagic cystitis;
    • Uncontrolled hypertension despite optimal medical management;
    • Major surgery or significant traumatic injury, within 4 weeks of starting study treatment;
    • History of Hepatitis B (HBV) or Hepatitis C (HCV) infection. Subjects with positive history of HBV or HCV may undergo confirmatory testing if not performed within 3 months prior to initiation of study treatment. Tested subjects with positive HBcAb or positive HCV RNA are excluded; or
    • Any medical condition which in the opinion of the Investigator places the subject at an unacceptably high risk for toxicities.
  9. A previous or concurrent cancer that is distinct in primary site or histology from the cancer under study, except cervical carcinoma in situ, non-melanoma carcinoma of the skin, or in situ carcinoma of the bladder. Any cancer curatively treated greater than 3 years prior to entry is permitted.
  10. Pregnant or breastfeeding.