A Phase 1/2 Study of HKI-272 (Neratinib) in Combination With Paclitaxel (Taxol) in Subjects With Solid Tumors and Breast Cancer

Study Overview
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Brief Summary
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The purpose of this study is to learn whether it is safe and effective to administer HKI-272 (neratinib) in combination with paclitaxel in patients with breast cancer.

Official Title
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A Phase 1/2 Study of HKI-272 in Combination With Paclitaxel in Subjects With Solid Tumors and Breast Cancer

Conditions
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Advanced Breast Cancer, Advanced Malignant Solid Tumors, Breast Neoplasms

Intervention / Treatment
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* Drug: HKI-272
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion criteria for both parts of clinical trial: Good performance status Normal ejection fraction Adequate cardiac, kidney, and liver function Adequate blood counts At least one measurable target lesion Negative pregnancy test for female subjects Inclusion Criteria for Part 1 Only: - Pathologically confirmed solid tumor not curable with available standard therapy Inclusion Criteria for Part 2 Only: Pathologically confirmed breast cancer HER2 positive tumor Prior treatment with Herceptin Exclusion Criteria: Exclusion criteria for both parts of clinical trial: Major surgery, radiotherapy, chemotherapy or investigational agents within two weeks of treatment day 1 Subjects with bone or skin as the only site of disease Active central nervous system metastases Significant cardiac disease or dysfunction Significant gastrointestinal disorder Inability or unwillingness to swallow HKI-272 capsules Prior exposure to HKI-272 or other HER2 targeted agents, except trastuzumab (Part 2 only). Prior lapatinib is permitted in arm B of part 2. Treatment with a taxane within 3 months of treatment day 1 Grade 2 or greater motor or sensory neuropathy Pregnant or breast feeding women Known hypersensitivity to paclitaxel or Cremophor EL Prior treatment with anthracyclines with cumulative dose of >400 mg/m^2 Any other cancer within 5 years with the exception of contralateral breast cancer, adequately treated cervical carcinoma in situ, or adequately treated basal or squamous cell carcinoma of the skin Exclusion Criteria for Part 2 Only: - More than 1 (arm A) or 3 (arm B) prior cytotoxic chemotherapy regimen for metastatic disease

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HKI-272 dose level 1<br>Part 1: Subjects with solid tumors receiving HKI-272 (neratinib) 160 mg daily by mouth in combination with paclitaxel 80 mg/m^2 weekly IV. | Drug: HKI-272<br> <br> * Other names: Neratinib;Drug: Paclitaxel<br> <br> |
| Experimental: HKI-272 dose level 2<br>Part 1: Subjects with solid tumors receiving HKI-272 (neratinib) 240 mg daily by mouth in combination with paclitaxel 80 mg/m^2 weekly IV. | Drug: HKI-272<br> <br> * Other names: Neratinib;Drug: Paclitaxel<br> <br> |
| Experimental: HKI-272 expanded MTD cohort, arm A<br>Part 2: Subjects with metastatic breast cancer who have not received more than 1 prior cytotoxic chemotherapy treatment regimen for metastatic disease receiving HKI-272 (neratinib) 240 mg daily by mouth in combination with paclitaxel 80 mg/m^2 weekly IV. | Drug: HKI-272<br> <br> * Other names: Neratinib;Drug: Paclitaxel<br> <br> |
| Experimental: HKI-272 expanded MTD cohort, arm B<br>Part 2: Subjects with metastatic breast cancer who have not received more than 3 prior cytotoxic chemotherapy treatment regimen for metastatic disease receiving HKI-272 (neratinib) 240 mg daily by mouth in combination with paclitaxel 80 mg/m^2 weekly IV. | Drug: HKI-272<br> <br> * Other names: Neratinib;Drug: Paclitaxel<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicity Incidence of Neratinib in Combination With Paclitaxel | Dose Limiting Toxicity in subjects with solid tumors treated with neratinib, administered daily, in combination with paclitaxel 80 mg/m² IV on days 1, 8, and 15 of a 28 day cycle. | From first dose date through day 28 | 
| Maximum Tolerated Dose | Maximum Tolerated Dose (MTD) of neratinib, daily, in combination with paclitaxel 80 mg/m², intravenous at days 1, 8, and 15, associated with the dose limiting toxicity data. | From first dose date through day 28. | 
| Objective Response Rate | Subjects with partial response (PR) or complete response (CR) with ERBB2 positive breast cancer treated at the maximum tolerated dose (MTD) of neratinib in combination with paclitaxel, per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v.1.0: CR, disappearance of all target lesions; PR, >=30% decrease in the sum of the longest diameter of target lesions; and no progressive disease (PD) for non-target lesions, and no new lesions. | From first dose date to progression or last tumor assessment, up to 140 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration of Neratinib | Maximum plasma concentration of neratinib; after each dosing of neratinib on Cycle 1 of Day 15, blood samples taken at regular time points. | Samples taken at 0 hour and at 1, 2, 4, 6, 8, and 24 hours postdose on Day 15 of Cycle 1, and 1 predose sample on Day 1 in Cycle 1. | 
| Area Under the Concentration-time Curve 0-24 | Area under the concentration-time curve of neratinib; after each dosing of neratinib on Cycle 1 of Day 15, blood samples taken at regular time points. | Samples taken at 0 hour and at 1, 2, 4, 6, 8, and 24 hours postdose on Day 15 of Cycle 1, and 1 predose sample on Day 1 in Cycle 1. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cancer, HKI-272, neratinib, paclitaxel, Taxol, breast cancer, Nerlynx