Study Evaluating Neratinib In Combination With Vinorelbine In Subjects With Advanced Or Metastatic Solid Tumors

A Phase 1 Study Of Neratinib (HKI-272) In Combination With Vinorelbine In Japanese Subjects With Advanced Or Metastatic Solid Tumors

The purposes of this study are to evaluate the safety and tolerability of neratinib in combination with vinorelbine at the maximum tolerated dose (MTD) determined in a previous study, or to determine a lower MTD of the two drugs, as well as to obtain preliminary information on whether the combination of the two drugs has any effect on solid tumors in Japanese patients.

Inclusion Criteria:

• Confirmed pathologic diagnosis of a solid tumor that is not curable with available therapies for which neratinib plus vinorelbine is a reasonable treatment option.

• At least 1 measurable lesion as defined by Response Evaluation Criteria in Solid Tumors.

• Eastern Cooperative Oncology Group performance status of 0 to 2 (not declining within 2 weeks before signing the informed consent form).

• Recovery from all clinically significant AEs related to prior therapies (excluding alopecia).

• Left ventricular ejection fraction within the study site's limits of normal.

• Screening laboratory values within the following parameters:

  • Absolute neutrophil count: 1.5 × 109/L
  • Platelet count: 100 × 109/L
  • Hemoglobin: 9.0 g/dL
  • Serum creatinine: 1.5 × upper limit of normal
  • Total bilirubin: 1.5 × ULN
  • Aspartate aminotransferase and alanine aminotransferase: 2.5 × ULN (<= 5 × ULN if liver metastases are present).

• For women of childbearing potential, a negative urine or serum pregnancy test result before study entry.

• All female and male subjects who are biologically capable of having children must agree and commit to the use of a reliable method of birth control for the duration of the study and for 28 days after the last dose of test article. A subject is biologically capable of having children if he or she is using contraceptives or if his or her sexual partner is sterile or using contraceptives.

Exclusion Criteria:

• Prior treatment with anthracyclines with a cumulative dose of doxorubicin of >400 mg/m^2, or of epirubicin >800 mg/m^2, or the equivalent dose for other anthracyclines or derivatives.
• Major surgery, chemotherapy, radical (curative intent) radiotherapy, investigational agents, or other cancer therapy within at least 2 weeks before treatment day 1.
• Bone as the only site of disease.
• Active central nervous system 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 are off anticonvulsants and steroids for at least 4 weeks before cycle 1 day 1) .
• QT (QTc) interval > 0.47 s or a known history of QTc prolongation or Torsades de Pointes.
• Presence of clinically significant or uncontrolled cardiac disease, including congestive heart failure (New York Heart Association 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.
• Pregnant or breastfeeding women. Significant chronic or recent acute gastrointestinal disorder with diarrhea as a major symptom (eg, Crohn disease, malabsorption, or grade 2 diarrhea of any etiology at baseline).
• Inability or unwillingness to swallow tablets (neratinib).
• Preexisting grade 2 or greater motor or sensory neuropathy.
• Subject known to be human immunodeficiency virus seropositive and/or have acute or chronic hepatitis B infection (hepatitis B surface antigen [HBsAg] positive) or hepatitis C infection (anti-HCV positive).
• History of known hypersensitivity to vinorelbine and any of its components.
• 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.
• Clinically significant ongoing or recent infection within 2 weeks before treatment day 1.
• 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 (ie, requiring intravenous antibiotic or antiviral agent) or uncontrolled major seizure.