ErbB2 Positive Locally Recurrent or Metastatic Breast Cancer MedDRA version: 20.0 Level: LLT Classification code 10027475 Term: Metastatic breast cancer System Organ Class: 100000004864
Conditions
Interventions
Product Name: Neratinib
Product Code: PB-272 maleate
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Neratinib
CAS Number:
Sponsors
Puma Biotechnology, Inc
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Female subjects aged 18 years or older. 2. Subjects must have histologically and/or cytologically confirmed diagnosis of breast cancer. 3. Subjects must have locally recurrent or metastatic breast cancer that is not amenable to curative surgery and/or radiation. 4. Documentation of erbB-2 gene amplification by FISH (as defined by a ratio >2.2) or chromogenic in situ hybridization (CISH, as defined by the manufacturer’s kit instruction) or documentation of erbB-2-overexpression by IHC (defined as IHC3+, or IHC2+ with FISH or CISH confirmation) based on local laboratory or initial diagnostic results utilizing one of the sponsor-approved assays. If erbB-2 status is unavailable or was determined using a test other than a sponsor-approved assay (as defined in the protocol) and cannot be assessed using one of these assays prior to randomization, testing and study eligibility must be obtained from the sponsor-identified central laboratory prior to randomization. 5. All subjects must have tumor tissue (ie, most recent archived formalin fixed-paraffin embedded tissue [block or unstained slides])available for central review of erbB-2 expression levels by FISH testing performed by a sponsor identified central laboratory. 6. Documentation of ER/PgR status (positive or negative) based on local laboratory or initial diagnostic results must be available before study entry. If results are unavailable, tumor tissue may be sent to the sponsor-identified central vendor for assessment prior to study entry as per investigator’s discretion. 7. Subjects must have at least 1 measurable lesion as defined by modified Response Evaluation Criteria in Solid Tumors (RECIST 1.0) criteria (specifically, no ascites, pleural or pericardial effusions, osteoblastic bone metastases, or carcinomatous lymphangitis of the lung as only lesion). 8. Subjects must have Eastern Cooperative Oncology Group (ECOG) status of 0 to 2 (not declining within 2 weeks prior to the first does of investigational product). 9. Subjects must have left ventricular ejection fraction (LVEF) within institutional range of normal as measured by multiple gated acquisition (MUGA) or echocardiogram (ECHO). 10. Screening laboratory values must be within the following parameters: - Absolute neutrophil count (ANC) =1.5 x 109 /L (1500/mm3) - Platelet count =100 x 109/L (100,000/mm3) - Hemoglobin =9.0 g/dL (90 g/L) - Serum creatinine =1.5 x upper limit of normal (ULN) - Total bilirubin =1.5 x ULN (<3 ULN if Gilbert’s disease) - Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT =2.5 x ULN (=5 x ULN if liver metastases are present) 11. Subjects must have recovered (to grade 1 or baseline) from all clinically significant acute adverse effects of prior therapies (excluding alopecia). 12. All subjects who are not surgically sterile or postmenopausal must agree and commit to the use of a reliable method of birth control starting 2 weeks prior to the administration of the first dose of investigational product until 28 days after the last dose of investigational product. A woman of childbearing potential is one who is biologically capable of becoming pregnant. This includes women wh
Exclusion criteria
Exclusion criteria: 1. Prior systemic anti-cancer therapy (including cytotoxic chemotherapy, signal transduction inhibitors [eg, lapatinib], biologic [eg, trastuzumab]), or other investigational anticancer therapy) for locally recurrent or metastatic disease. Prior endocrine therapy in any setting is allowed. 2. Prior treatment with an erbB-2 inhibitor, other than trastuzumab, lapatinib, or the combination of the two in the neoadjuvant or adjuvant setting. 3. Prior treatment with neoadjuvant or adjuvant anthracyclines with a cumulative dose of doxorubicin of >400 mg/m2, epirubicin dose >800 mg/m2, or the equivalent dose for other anthracyclines or derivatives (eg, 72 mg/m2 of mitoxantrone). 4. Subjects with recurrence or progression of disease within 12 months after completion of adjuvant or neoadjuvant systemic anticancer therapy (including cytotoxic chemotherapy, signal transduction inhibitors [eg, lapatinib], biologic [eg, trastuzumab], or other investigational anticancer therapy), other than endocrine therapy, for early breast cancer. 5. Subjects with bone or skin as the only site of measurable disease. Subjects with skin lesions measurable by computed tomography (CT) scans or magnetic resonance imaging (MRI) as only site of measurable disease are allowed. 6. Major surgery, chemotherapy, radiotherapy, any investigational agents, or other cancer therapy within 2 weeks before the administration of the first dose of investigational product. 7. Subjects with active uncontrolled or symptomatic central nervous system (CNS) metastases, as indicated by clinical symptoms, cerebral edema, and/or progressive growth. Subjects with a history of CNS metastases or cord compression are eligible if they have been definitively treated and are off anticonvulsants and steroids for at least 4 weeks before first dose of investigational product. Subjects with newly detected asymptomatic CNS metastases must be definitively treated (eg. radiotherapy, stereotactic surgery) before being considered for the trial. 8. Subjects with active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of =3), unstable angina, and myocardial infarction (within 12 months of study entry). 9. Subjects with inadequately controlled hypertension (ie, systolic blood pressure [BP] > 180 mm Hg or diastolic BP > 100 mm Hg). 10. Subjects with family or personal history of congenital long or short QT syndrome, Brugada syndrome or QTc interval > 0.45 second or known history of QTc prolongation or torsade de pointe (TdP). 11. Subject with significant chronic gastrointestinal disorder with diarrhea as a major symptom (eg, Crohn’s disease, malabsorption, or grade =2 diarrhea of any etiology at baseline). 12. Subject with preexisting grade 2 or greater motor or sensory neuropathy. 13. Subjects with history of life-threatening hypersensitivity reaction to taxanes, trastuzumab or their excipients. 14. Subjects with clinical contraindication to steroids preventing their use as part of paclitaxel premedication. 15. Women who are pregnant, breast-feeding or women of child bearing potential who are not using effective contraception during participation in the study and do not agree t
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: - To compare the investigator assessed progression-free survival following treatment with neratinib in combination with paclitaxel versus trastuzumab plus paclitaxel in subjects who have not received previous treatment for erbB-2-positive locally recurrent or metastatic breast cancer. ; Secondary Objective: - To compare investigator assessed clinical activity between treatment arms by measuring objective response rate, duration of response, and clinical benefit rate (complete response + partial response + stable disease = 24 weeks). - To compare safety (adverse events and serious adverse events) between treatment arms. - To compare the frequency of and time to symptomatic or progressive central nervous system lesions in both treatment arms. Treatment Extension Period The objective of the Treatment Extension Period is to provide the study subjects who continue to derive benefit from IP the opportunity to continue to receive study drug with a reduced number of protocol required assessments. ; Primary end point(s): Progression Free Survival (PFS) PFS is the interval from the date of randomization until the first date on which recurrence or progression, or death due to any cause, is documented, censored at the last assessable evaluation or at the initiation of new anticancer therapy. ;Timepoint(s) of evaluation of this end point: PFS: every 8 weeks from first dose of investigational product. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1) To compare investigator assessed clinical activity between treatment arms by measuring: ORR, duration of response (DOR), and clinical benefit rate (CBR; CR + PR + stable disease [SD] = 24 weeks). 2) To compare safety (AEs; serious adverse events [SAEs]) between treatment arms. 3) To compare the frequency of and time to symptomatic or progressive central nervous system (CNS) lesions in both treatment arms. ; Timepoint(s) of evaluation of this end point: ORR/DOR/CBR/CNS met. evaluation: Every 8 weeks from first dose of investigational product Safety: weekly assessment | — |
Countries
Australia, Bahamas, Belarus, Belgium, Bulgaria, Canada, China, Croatia, Denmark, France, Germany, Greece, Hong Kong, Hungary, India, Israel, Italy, Japan, Korea, Republic of, Latvia, Lithuania, Malaysia, Malta, Poland, Portugal, Serbia, Singapore, South Africa, Spain, Switzerland, Taiwan, Turkey, Ukraine, United Kingdom, United States
Contacts
Public ContactRobert Charnas
Puma Biotechnology, Inc
Outcome results
None listed