Study Evaluating HKI-272 in Tumors

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and tolerability as well as find the maximum tolerated dose (MTD) for HKI-272. In addition, this study will examine the effects of the study drug on your tumor, and how your body uses and eliminates HKI-272.

Official Title
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An Ascending Single and Multiple Dose Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of HKI-272 Administered Orally to Subjects With HER-2/NEU or HER-1/EGFR-Positive Tumors

Conditions
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Breast Neoplasms

Intervention / Treatment
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* Drug: neratinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Her2/neu or Her1/EGFR positive cancer Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) Exclusion Criteria: Prior treatment with anthracyclines with a cumulative dose of doxorubicin or equivalent of greater than 300 mg/m^2 Patients with significant cardiac risk factors Active central nervous system metastasis

Ages Eligible for Study
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Minimum Age: 18 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 trial was an open-label, phase 1, ascending single and multiple oral dose study of HKI-272 administered to subjects with erbB-2- or erbB-1-positive tumors. Each subject participated in only 1 dose group and received a single dose of test article, followed by a 1-week observation period, and then received the test article administered once daily by mouth for up to 6 months (6 cycles). Daily dose administration could continue beyond 6 cycles at the same dose level if HKI-272 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 40 mg<br> | Drug: neratinib<br>* HKI-272<br>|
| Experimental: Neratinib 80 mg<br> | Drug: neratinib<br>* HKI-272<br>|
| Experimental: Neratinib 120 mg<br> | Drug: neratinib<br>* HKI-272<br>|
| Experimental: Neratinib 180 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>|
| Experimental: Neratinib 400 mg<br> | Drug: neratinib<br>* HKI-272<br>|
| Experimental: Neratinib 320 mg MTD<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 is defined as any neratinib-related nonhematologic grade 3 or any grade 4 adverse event (AE) according to the National Cancer Institute (NCI) common terminology criteria (CTC) for AEs version 3.0. DLTs were assessed from the first single dose to 14 days of continuous daily administration. | From first dose date to day 14 | 
| Maximum Tolerated Dose (MTD) | If 2 or more, of 3 to 6 subjects, at a dose level had an neratinib-related dose limiting toxicity (DLT) by day 14 of continuous daily dose administration, dose escalation stopped and the prior dose level was considered the MTD. | From first dose date to day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Best Overall Response | Best Overall response by tumor type, evaluable population per Response Evaluation Criteria In Solid Tumors Criteria v1.0 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in sum of the longest diameter (LD) of target lesions in reference to baseline sum of LD of target lesions; Progressive Disease (PD), >=20% increase in sum of LD of target lesions, taking as reference the smallest sum of recorded LD of target lesions since treatment started or appearance of 1 or more new lesions; Stable disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of LD of target lesions since the treatment start. The best overall response was the best response recorded from start of treatment until PD/recurrence. In general, the subject's best response assignment depended on achievement of both measurement and confirmation criteria. | From first dose date to progression or last tumor assessment, up to 39 weeks. | 
| Duration of Response | Duration of response of responders (PR+) by Kaplan-Meier estimate | From start date of response to first PD, up to 39 weeks. | 
| Progression Free Survival | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | From first dose date to progression or death, up to 39 weeks. | 
| Objective Response Rate | Patients with PR or higher responses, evaluable population | From first dose date to progression/death or last assessment, up to 39 weeks | 
| Clinical Benefit Rate | Patients with PR or higher responses or SD>=24 weeks, evaluable population | From first dose date to progression/death or last assessment, up to 39 weeks. | 

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