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

Study Overview
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Brief Summary
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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.

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

Conditions
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Advanced Malignant Solid Tumors

Intervention / Treatment
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* Drug: Neratinib
* Drug: Vinorelbine


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neratinib and Vinorelbine<br>Neratinib: 240 mg administered daily by mouth continuously, Vinorelbine: 25 mg/m^2 administered IV on Day 1 and 8 of 21 day cycle | Drug: Neratinib<br> <br> * Other names: Nerlynx;Drug: Vinorelbine<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicity (DLT) | Number of participants experiencing DLT of neratinib in combination with vinorelbine in Japanese patients. | From first dose date to 21st day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response | Best Overall Response in Evaluable Population per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | From first dose date to progression or last tumor assessment, up to 40 weeks. | 
| Duration of Objective Response | The duration of objective response was measured from the time at which measurement criteria were met for Complete Response (CR) or Partial Response (PR) (whichever status was recorded first) until the first date on which recurrence or Progressive Disease (PD) was objectively documented, taking as reference for PD the smallest measurements recorded since the treatment started. | From first response date to PD/death, up to 40 weeks. | 
| Objective Response Rate (ORR) | Proportion of subjects who achieved complete response or partial response per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | From first dose date to progression or last tumor assessment, up to 40 weeks. | 
| Progression Free Survival | Number of weeks between the date of the first dose of test article and the first date of disease recurrence or progression, or death due to any cause, was documented, censored at the last evaluation, investigator assessment. Disease Progression (PD) is defined using Response Evaluation Criteria in Solid Tumors Criteria (v1.0), at least a 20% increase in the sum of the longest diameters (LD) of target lesions, taking as reference the nadir LD, meaning the smallest sum of the LDs recorded since the treatment started; or unequivocal progression of existing nontarget lesions; or the appearance of any new lesions. | From first dose to last evaluation, up to 40 weeks. | 
| Area Under the Curve (AUC) Tau | AUC of Neratinib at day 8 following administration of Neratinib 240 mg in combination with Vinorelbine 25 mg/m^2 to Japanese Subjects with Cancer. | Predose, and hour 1, 2, 4, 6, 8 and 24 on day 8. | 
| Terminal-phase Elimination Half-life | Terminal-phase elimination half-life of Neratinib at day 8 following Administration of Neratinib 240 mg in combination with Vinorelbine 25 mg/m^2 to Japanese Subjects with Cancer. | Predose, and hour 1, 2, 4, 6, 8 and 24 on day 8. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HKI-272, Vinorelbine, Combination, Solid Tumor, Neratinib, Nerlynx, PB-272