A Study Of The Safety And Tolerability Of HKI-272 Administered Orally To Japanese Subjects With Advanced Solid Tumors

Study Overview
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Brief Summary
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The purpose of this study is to assess the tolerability and safety of HKI-272, and to determine the maximum dose that can safety be given. The secondary purpose of this study is to determine how the body uses and gets rid of HKI-272 and to assess whether HKI-272 is effective for the treatment of advanced solid tumors.

Detailed Description
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This is a phase 1 open-label sequential-group study of ascending single and multiple oral doses administered to subjects with advanced solid tumors. Each subject will participate in only 1 dose group and will receive a single dose of test article, followed by a 1-week observation period, and then will receive the test article administered once-daily by mouth in cycles consisting of 28 days. Subjects will be enrolled in groups of 3 to 6. Adverse events and dose-limiting toxicities will be assessed from the first single dose.

Official Title
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An Ascending and Multiple Dose Study of the Safety, Tolerability, and Pharmacokinetics of HKI-272 Administered Orally to Japanese Subjects With Advanced Solid Tumors

Conditions
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Tumors

Intervention / Treatment
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* Drug: neratinib


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Diagnosis of metastatic or advanced cancer that has failed standard effective therapy Life expectancy of at least 12 weeks and adequate performance status Adequate bone marrow, kidney and liver function Willingness of male and female subjects who are not surgically sterile or post-menopausal to use adequate methods of birth control Exclusion Criteria Any anticancer chemotherapy, radiotherapy immunotherapy or investigational agents within 4 weeks of first dose of HKI-272 Inadequate cardiac function Surgery within 2 weeks of first dose of HKI-272 Active central nervous system metastases (i.e., symptomatic, required use of corticosteroids and/or progressive growth) Significant gastrointestinal disorder with diarrhea as a major symptom Pregnant or breast feeding women

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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: This was an open-label, phase 1, ascending single and multiple oral dose study of neratinib administered to subjects with advanced solid tumors. Each subject participated in only 1 dose group and received a single dose of neratinib. This was followed by a 1-week observation period, and the subject then received neratinib administered as a continual oral daily dose for up to 6 months (6 cycles). Daily dose administration could continue beyond 6 cycles at the same dose level after consultation with the sponsor if neratinib was well tolerated and there was no evidence of progressive disease.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neratinib 80 mg<br> | Drug: neratinib<br>* HKI-272<br>|
| Experimental: Neratinib 160 mg<br> | Drug: neratinib<br>* HKI-272<br>|
| Experimental: Neratinib 240 mg<br> | Drug: neratinib<br>* HKI-272<br>|
| Experimental: Neratinib 320 mg<br> | Drug: neratinib<br>* HKI-272<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicity (DLT) | DLT was defined as any drug-related nonhematologic grade 3 or any grade 4 adverse event (AE) according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 3.0, except the grade 3 nausea, vomiting, diarrhea, or rash, unless the subject was receiving appropriate medical therapy. Additional DLTs included the following: grade 2 or 3 diarrhea lasting 2 or more days for which the subject was receiving medical therapy or that was associated with fever or dehydration. | First dose date through 21 days | 
| Maximum Tolerated Dose (MTD) | MTD is defined as the prior dose level of the dose level which has >=2 of 3 to 6 subjects that experience a neratinib-related DLT during 21 days from first dose date. A DLT is defined as any HKI-272-related nonhematologic grade 3 or any grade 4 AE according to the Common Terminology Criteria for Adverse Events version 3.0 except: Grade 3 nausea, vomiting, diarrhea, or rash unless subject was receiving appropriate medical therapy. | First dose date through 21 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR is defined as the proportion of subjects who had either a complete response (CR) or partial response (PR), according to a modified Response Evaluation Criteria in Solid Tumors (RECIST). The modified RECIST is defined as CR: Disappearance of all target lesions, PR: At least a 30% decrease in the sum of the Longest Diameters (LDs) of target lesions, taking as reference the baseline sum LDs. Response required confirmation. | From first dose date to disease progression or last tumor assessment, up to 9.2 months | 
| Clinical Benefit Rate | Subjects with confirmed Complete Response (CR) or confirmed Partial Response (PR), or Stable Disease (SD) >= 24 weeks, according to a modified Response Evaluation Criteria in Solid Tumors (RECIST). SD is defined as SD in target lesions and a non-progressive disease (PD) in nontarget lesions; A PR is defined as either a PR in target lesions and a non-PD in nontarget lesions, or a CR in target lesions and an incomplete response or SD in nontarget lesions; and a CR is defined as a CR in target lesions and a CR in nontarget lesions. | From first dose date to progression/death or last assessment, up to 9.2 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced Malignant Solid Tumors, HKI-272, Neratinib, Nerlynx