A Phase 1/2 Study Of HKI-272 (Neratinib) in Combination With Trastuzumab (Herceptin) In Subjects With Advanced Breast Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety and efficacy of HKI-272 (neratinib) in combination with trastuzumab in patients with advanced breast cancer.

Detailed Description
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Open label phase 1/2 study of ascending multiple oral doses of HKI-272 in combination with IV trastuzumab in subjects with advanced human epidermal growth factor receptor 2 positive (HER2+) breast cancer. Three to six subjects will be enrolled in each dose group. Adverse events and dose limiting toxicities will be assessed from the first dose of study drug though day 21. When the maximum tolerated dose (MTD) of HKI-272 plus trastuzumab is determined, an additional 30 subjects will be enrolled at that dose level, and followed for progression free survival for approximately 1 year.

Official Title
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A Phase I/II Study of HKI-272 in Combination With Trastuzumab (Herceptin) in Subjects With Advanced Breast Cancer

Conditions
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Advanced Breast Cancer

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologic diagnosis of breast cancer with current stage IIIB, IIIC or IV not curable by available therapy Progression following at least one Herceptin-containing cytotoxic chemotherapy regimen (neoadjuvant, adjuvant, or metastatic setting) HER2 positive breast cancer At least one measurable target lesion Adequate performance status Adequate cardiac, kidney, and liver function Adequate blood counts Willingness of all subjects who are not surgically sterile or post menopausal to use acceptable methods of birth control Exclusion Criteria: More than 3 prior cytotoxic chemotherapy regimens for locally advanced or metastatic disease Major surgery, chemotherapy, radiotherapy, investigational agents, Herceptin or other cancer therapy within 2 weeks of treatment day 1 Prior treatment with anthracyclines with cumulative dose of >400 mg/m^2 Extensive visceral disease Active central nervous system metastases Pregnant or breast feeding women Significant chronic or recent acute gastrointestinal disorder with diarrhea as a major symptom Prior exposure to HKI-272 or other HER2 targeted agents (except Herceptin and Tykerb) Significant cardiac disease or dysfunction History of life-threatening hypersensitivity to Herceptin Inability or unwillingness to swallow HKI-272 capsules 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

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: Part 1 - dose level 1 (160 mg)<br>All subjects receiving HKI-272 dose level 1 in combination with trastuzumab | Drug: HKI-272<br>* HKI-272 by mouth<br>* Other names: neratinib;Drug: trastuzumab<br>* trastuzumab 4 mg/kg IV as a loading dose followed by trastuzumab 2 mg/kg weekly thereafter<br>* Other names: Herceptin;|
| Experimental: Part 1 - dose level 2 (240 mg)<br>All subjects receiving HKI-272 dose level 2 in combination with trastuzumab | Drug: HKI-272<br>* HKI-272 by mouth<br>* Other names: neratinib;Drug: trastuzumab<br>* trastuzumab 4 mg/kg IV as a loading dose followed by trastuzumab 2 mg/kg weekly thereafter<br>* Other names: Herceptin;|
| Experimental: Part 2 - expanded MTD cohort<br>All subjects receiving HKI-272 in combination with trastuzumab | Drug: HKI-272<br>* HKI-272 by mouth<br>* Other names: neratinib;Drug: trastuzumab<br>* trastuzumab 4 mg/kg IV as a loading dose followed by trastuzumab 2 mg/kg weekly thereafter<br>* Other names: Herceptin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 16-week Progression-free Survival (PFS) Rate | 16-week progression-free survival (PFS) rate for subjects with advanced breast cancer who receive neratinib at the maximum tolerated dose (MTD) in combination with trastuzumab, evaluable population. | From first dose date to progression status (PD or death) at 16-week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | Percentage of participants with partial response (PR) or complete response (CR) per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v.1.0: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; and Non-PD for non-target lesions, and no new lesions. | From first dose date to progression or last tumor assessment, up to five and a half years. | 
| Duration of Response (DOR) | Duration of response was measured from the time at which response criteria were met for complete response (CR) or partial response (PR) (whichever status was recorded first) until the first date on which recurrence or PD was objectively documented, taking as the reference for PD the smallest measurements recorded since the test article administration started. | From start date of response to first PD, assessed up to five and half years after the first subject was randomized | 
| Progression Free Survival (PFS) | Progression Free Survival was measured from the date of the first dose of test article until the first date on which recurrence or progression, or death due to any cause, was documented, censored at the last evaluation, investigator assessment. | From first dose date to progression or death, assessed up to five and half years. | 
| Clinical Benefit Rate (CBR) | The percentage of participants with a best overall response of a complete response (CR) or partial response (PR) or stable disease (SD) >=24 weeks. | From first dose date to progression or last tumor assessment, assessed up to five and half years. | 
| Area Under the Curve of Neratinib Concentration | Area Under the Curve of Neratinib concentration at day 22 following Administration of Neratinib 240 mg in combination with Trastuzumab 2 mg/kg in Subjects with Cancer. | Prior to the first dose, and at hours 1, 2, 4, 6, 8 and 24 on days 22. | 
| Terminal-phase Elimination Half-life of Neratinib in Combination With Trastuzumab. | Terminal-phase elimination half-life of Neratinib at day 22 following Administration of Neratinib 240 mg in combination with Trastuzumab 2 mg/kg to Subjects with Cancer. | Prior to the first dose, on days 22 through 23 of month 1, and on day 1 in months 2 through 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HKI-272, neratinib, trastuzumab, breast cancer, Nerlynx, PB-272, HER2