Details

Details

Title A STUDY OF NERATINIB PLUS CAPECITABINE VERSUS LAPATINIB PLUS CAPECITABINE IN PATIENTS WITH HER2+ METASTATIC BREAST CANCER WHO HAVE RECEIVED TWO OR MORE PRIOR HER2-DIRECTED REGIMENS IN THE METASTATIC SETTING (NALA)

IRB PUMA1113

CC CC031421C

Hospital Main Campus

Disease Breast

Drug Capecitabine, Lapatinib , Neratinib

Description

Description

Primary Objective
  • to compare independently adjudicated PFS following treatment with neratinib plus capecitabine versus lapatinib plus capecitabine in patients with HER2+ MBC who have received two or more prior HER2-directed regimens in the metastatic setting.
  • to compare OS following treatment with neratinib plus capecitabine versus lapatinib plus capecitabine in this population.
Secondary Objectives

The secondary objectives of this study are to compare between the two treatment groups:

  • Investigator-assessed PFS.
  • Objective response rate (ORR), duration of response (DOR) and clinical benefit rate (CBR) (complete response [CR] or partial response [PR] or stable disease [SD] ≥24 weeks).
  • Time to intervention for symptomatic metastatic central nervous system (CNS) disease.
  • Safety (AEs, serious adverse events [SAEs]).
  • Health outcomes assessments.
Exploratory Objective
  • To assess the population PK of neratinib when administered in combination with capecitabine.
Inclusion Criteria

Inclusion Criteria

  1. Aged ≥18 years at signing of informed consent.
  2. Histologically confirmed MBC, current stage IV.
  3. Documented HER2 overexpression or gene-amplified tumor (immunohistochemistry [IHC] 3+; or IHC 2+ with confirmatory fluorescence in situ hybridization [FISH]+). (Note: Patients who are IHC 0 or 1+ are not eligible to participate in the study). Tumor samples will be evaluated for HER2 expression by IHC (HercepTest™) and if required for gene amplification by FISH analysis (IQFISH pharmDx™).
  4. Prior treatment with at least two HER2-directed regimens for metastatic breast cancer. A new regimen is defined as a modification in a planned course of therapy to include other treatment agents (alone or in combination) as a result of disease progression, relapse, or toxicity (Rajkumar et al., 2011). A new regimen also starts when a planned period of observation off therapy is interrupted by a need for additional treatment for the disease.
  5. At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.1 (Eisenhauer et al., 2009), see Appendix 7). Specifically, no ascites, pleural or pericardial effusions, osteoblastic bone metastases, or carcinomatous lymphangitis of the lung as the only lesion are allowed.
  6. Left ventricular ejection fraction (LVEF) ≥50% measured by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO).
  7. Eastern Cooperative Oncology Group (ECOG) status of 0 to 1 (see Appendix 3).
  8. Negative β-human chorionic gonadotropin (hCG) pregnancy test for premenopausal women of reproductive capacity (those who are biologically capable of having children) and for women less than 12 months after menopause.
  9. Women of childbearing potential must agree and commit to the use of a highly effective method of contraception, as determined to be acceptable by the Investigator, from the time of informed consent until 28 days after the last dose of the investigational products. Men must agree and commit to use a barrier method of contraception while on treatment and for 3 months after last dose of investigational products.
  10. Provide written, informed consent to participate in the study and follow the study procedures.
Exclusion Criteria

Exclusion Criteria

  1. Received previous therapy with capecitabine, neratinib, lapatinib, or any other HER2-directed tyrosine kinase inhibitor.
  2. Received prior therapy resulting in a cumulative epirubicin dose >900 mg/m2 or cumulative doxorubicin dose >450 mg/m2. If another anthracycline or more than one anthracycline has been used, the cumulative dose must not exceed the equivalent of 450 mg/m2 doxorubicin.
  3. Any major surgery ≤28 days prior to the initiation of investigational products, or received anti-cancer therapy (including chemotherapy, biological therapy, hormonal therapy, investigational agents, or other anti-cancer therapy) administered ≤21 days prior to the initiation of investigational products.
  4. Received radiation therapy ≤14 days prior to initiation of investigational products.
  5. Symptomatic or unstable brain metastases. (Note: Asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days prior to randomization are eligible to participate in the study).
  6. Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of ≥2), unstable angina, myocardial infarction within 12 months of enrollment, or ventricular arrhythmia.
  7. QTc interval >0.450 seconds or known history of QTc prolongation or Torsades de Pointes.
  8. Screening laboratory assessments outside the following limits:
    • Absolute neutrophil count (ANC) <1500/μL (<1.5 x 109/L)
    • Platelet count <100,000/μL (<100 x 109/L)
    • Hemoglobin (Hb) <8 g/dL (transfusions allowed); transfusions must be at least 14 days prior to randomization.
    • Total bilirubin >1.5 x institutional upper limit of normal (ULN)
    • Aspartate aminotransferase (AST) and/or Alanine aminotransferase (ALT) >3 x institutional ULN (>5 x ULN if liver metastases are present)
    • Creatinine clearance <50 mL/min (as calculated by Cockroft and Gault formula or modification of Diet in Renal Disease [MDRD] formulab)
  9. Active infection or unexplained fever >38.5oC (101.3oF).
  10. Other malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix or vulva; c) prostate cancer of Gleason Score 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas.
  11. Currently breast-feeding.
  12. Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn's disease, malabsorption, or Grade ≥2 (NCI CTCAE v.4.0) diarrhea of any etiology at screening).
  13. Active infection with hepatitis B or hepatitis C virus.
  14. Known dihydropyrimidine dehydrogenase deficiency.
  15. Known hypersensitivity to 5-fluorouracil or to any component of the investigational products or compounds of similar chemical composition.
  16. Unable or unwilling to swallow tablets.
  17. Evidence of significant medical illness, abnormal laboratory finding, or psychiatric illness/social situations that would, in the Investigator's judgment, make the patient inappropriate for this study.