Metastatic breast cancer remains incurable and represents an area of unmet medical need globally. Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) activation occurs in breast cancer. This activation contributes to the development and metastatic potential of breast cancer. Dual EGFR/HER2 inhibitors may have activity in the treatment of prior trastuzumab treated HER2 positive metastatic breast cancer. MedDRA version: 9.1 Level: LLT Classification code 10
Conditions
Sponsors
Wyeth Research Division of Wyeth Pharmaceuticals Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Aged >=18 years. 2.Subjects enrolled into Part 1 must have confirmed pathologic diagnosis of a solid tumor that is not curable with available therapy for which HKI-272 plus paclitaxel is a reasonable treatment option 3. Subjects enrolled into Part 2 must have confirmed pathologic diagnosis of HER2 + breast cancer (current stage IV) for which paclitaxel plus HKI-272 is a reasonable treatment option. 4. Subjects must have received prior treatment (neoadjuvant, adjuvant, or metastatic) with a trastuzumab containing regimen (unless trastuzumab contraindicated or unavailable). (Part 2 only) 5. For subjects with breast cancer, HER2 gene amplified tumor (FISH) or HER2 overexpression (IHC 3 +). Documentation of HER2 status by validated test required. Otherwise tumor tissue must be available and adequate for centralized FISH testing prior to study day 1. (Part 2 only) 6. At least 1 measurable lesion as defined by modified RECIST criteria. 7. Eastern Cooperative Oncology Group (ECOG) 0 to 1 (not declining in the past two weeks) 8. LVEF within institutional limits of normal (by MUGA or ECHO). 9. Screening laboratory values within the following parameters: ANC: >=1.5 × 10^9/L (1,500/mm^3) Platelet count: >=75 × 10^9/L (75,000/mm^3) Hemoglobin: >= 9.0 g/dL (90g/L) Serum creatinine: =65 years) yes F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. More than 1 prior cytotoxic chemotherapy treatment regimen for metastatic disease (Part 2, Arm A only) or more than 3 prior cytotoxic chemotherapy regimen for metastatic disease (Part 2, Arm B only). 2. Prior treatment with anthracyclines with a cumulative dose of doxorubicin of >400 mg/m2, epirubicin dose of >800 mg/m2, or the equivalent dose for other anthracyclines or derivatives. 3. Major surgery, chemotherapy, radical (curative intent) radiotherapy, investigational agents, or other cancer therapy within 2 weeks of treatment day 1 and recovery from all clinically significant acute adverse effects of prior therapies (excluding alopecia). 4. Subjects with bone or skin as the only site of disease. 5. Active 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 allowable if they have been definitively treated and have been clinically stable for at least three months, and off steroids or anticonvulsants, before first dose of test article). 6. QTc interval >0.47 second or known history of QTc prolongation or Torsade de Pointes (TdP). 7. Known hypersensitivity to paclitaxel or Cremophor EL (polyoxyethylated castor oil). 8. Pregnant or breast feeding women. 9. Significant chronic or recent acute gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn’s disease, malabsorption, or Grade >=2 diarrhea of any etiology at baseline). 10. Inability or unwillingness to swallow the HKI-272. 11. Prior exposure to HKI-272 or any other HER2 targeted agents, except trastuzumab (Part 2 only) Prior lapatinib is permitted in Arm B of Part 2. 12. Treatment with a taxane within 3 months of treatment day 1. 13. Pre-existing grade 2 or greater motor or sensory neuropathy. 14. Any other cancer within 5 years prior to screening with the exception of contralateral breast carcinoma, adequately treated cervical carcinoma in situ, or adequately treated basal or squamous cell carcinoma of the skin. 15. Presence of clinically significant or uncontrolled cardiac disease, including congestive heart failure (New York Heart Association [NYHA] functional classification of >2), angina requiring treatment, myocardial infarction within the past 12 months, or any clinically significant supraventricular arrhythmia or ventricular arrhythmia requiring treatment or intervention. 16. Evidence of significant medical illness or abnormal laboratory finding that would, in the investigator’s judgment, make the subject inappropriate for this study. Examples include, but are not limited to, serious active infection (i.e. requiring intravenous antibiotic or antiviral agent), uncontrolled major seizure disorder, or significant pulmonary disorder (e.g. interstitial pneumonitis, pulmonary hypertension).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Part 1: The primary objectives of part 1 are to assess the safety and tolerability, and to define the MTD of HKI-272 in combination with paclitaxel in subjects with advanced solid tumors Part 2: The primary objective of part 2 of this study is to estimate the overall response rate (ORR) for subjects with HER2 positive breast cancer treated at the MTD of HKI-272 in combination with paclitaxel.;Secondary Objective: Part 1: The secondary objectives of Part 1 are to obtain preliminary anti-tumor activity and PK information. Part 2: The secondary objectives of Part 2 are to confirm the MTD identified in part 1 of the study, to obtain safety and PK information and assess additional efficacy parameters including clinical benefit (CR + PR + SD >=24 weeks), 16 week PFS rate, and duration of response of HKI 272 in combination with paclitaxel.;Primary end point(s): To determine safe and tolerable dose and schedule of the combination in subjects with advanced solid tumors and estimate clinical overall response rates in metastatic HER2+ breast cancer. | — |
Countries
Belgium
Outcome results
None listed