Study Evaluating The Combination Of Neratinib And Capecitabine In Solid Tumors And Breast Cancer

Study Overview
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Brief Summary
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This is a world wide phase 1/2, open-label, study of neratinib in combination with capecitabine, conducted in 2 parts. In Part 1, 3 to 9 subjects with solid tumors will be enrolled in each dose group of the combination of neratinib and capecitabine. Each subject will participate in only 1 dose group. Additional subjects may be included at any dose level to further assess the safety and tolerability at that dose level. In Part 2, up to 60 subjects with erbB-2 positive metastatic breast cancer will receive treatment with the combination of neratinib and capecitabine at the maximum tolerated dose level, as determined in Part 1. In addition 20 subjects with prior lapatinib exposure will be enrolled in Part 2. Depending on the safety and activity profile observed during the dose escalation phase, the dose selected for Part 2 may be adjusted, if appropriate. In case one test article of the combination is discontinued due to intolerance the other test article can be administered alone. The primary objectives of Part 1 are to assess the safety and tolerability, and to define the maximum tolerated dose (MTD) of neratinib in combination with capecitabine in subjects with advanced solid tumors. The primary objective of Part 2 of this study is to confirm the MTD determined in Part 1. The secondary objective of Part 1 is to collect information on preliminary anti-tumor activity of the combination of neratinib and capecitabine. Secondary objectives for Part 2 are to collect pharmacokinetic information and to obtain additional efficacy data, such as Objective Response Rate, for subjects with erbB-2 positive breast cancer treated at the MTD of neratinib + capecitabine.

Official Title
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A Phase 1/2, Open-Label Study Of Neratinib (HKI-272) In Combination With Capecitabine In Subjects With Solid Tumors And ErbB-2 Positive Metastatic Or Locally Advanced Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Neratinib
* Drug: Capecitabine


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA PART 1: confirmed pathologic diagnosis of a solid tumor not curable with available therapies for which neratinib plus capecitabine is a reasonable treatment option. PART 2: confirmed histologically and/or cytologically confirmed diagnosis of breast cancer, metastatic or locally advanced. erbB-2 gene amplified tumor (FISH or CISH) or erbB-2 overexpression (IHC 3+, or IHC2+ with FISH or CISH confirmation), based on local testing, or based on centralized FISH testing prior to day 1. disease progression on or following at least 1 prior trastuzumab containing treatment regimen (at least 6 weeks) for metastatic or locally advanced disease. (Prior adjuvant trastuzumab is allowed but not required). A 2 week period is required between the last dose of trastuzumab treatment and first dose of the test article. Prior treatment with a taxane in the neoadjuvant, adjuvant, locally advanced, and/or metastatic disease treatment setting. PARTS 1 and 2: At least 1 measurable lesion as defined by RECIST criteria. LVEF within institutional range of normal as measured by multi-gated acquisition (MUGA) or echocardiogram (ECHO). EXCLUSION CRITERIA PART 2: prior treatment with capecitabine, lapatinib (20 subjects with prior lapatinib exposure will be enrolled) or any erbB-2 targeted agents except trastuzumab. Treatment with erbB-2 targeted therapy must exceed 2 weeks (14 days) in order to be exclusionary. prior treatment with anthracyclines with a cumulative dose of doxorubicin of greater than 400 mg/m², epirubicin dose of greater than 800 mg/m², or the equivalent dose for other anthracyclines. PARTS 1 and 2: Subjects with bone as the only site of disease. Active uncontrolled or symptomatic central nervous system (CNS) 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 considered definitively treated and are off anticonvulsants and steroids for at least 4 weeks before the first dose of test article. Any other cancer within 5 years prior to screening with the exception of 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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neratinib and Capecitabine (Dose Level 1)<br>Neratinib 160 mg and Capecitabine 1500 mg/m^2 | Drug: Neratinib<br>* Neratinib orally once daily continually<br>* Other names: HKI-272;Drug: Capecitabine<br>* Capecitabine orally on days 1-14 of each 21 day cycle<br>* Other names: Xeloda;|
| Experimental: Neratinib and Capecitabine (Dose Group 2)<br>Neratinib 240 mg and Capecitabine 1500 mg/m^2 | Drug: Neratinib<br>* Neratinib orally once daily continually<br>* Other names: HKI-272;Drug: Capecitabine<br>* Capecitabine orally on days 1-14 of each 21 day cycle<br>* Other names: Xeloda;|
| Experimental: Neratinib and Capecitabine (Dose Group 3)<br>Neratinib 240 mg and Capecitabine 2000 mg/m^2 | Drug: Neratinib<br>* Neratinib orally once daily continually<br>* Other names: HKI-272;Drug: Capecitabine<br>* Capecitabine orally on days 1-14 of each 21 day cycle<br>* Other names: Xeloda;|
| Experimental: Neratinib and Capecitabine (Dose Group 4)<br>Neratinib 200 mg and Capecitabine 2000 mg/m^2 | Drug: Neratinib<br>* Neratinib orally once daily continually<br>* Other names: HKI-272;Drug: Capecitabine<br>* Capecitabine orally on days 1-14 of each 21 day cycle<br>* Other names: Xeloda;|
| Experimental: Neratinib and Capecitabine (Dose Group 5)<br>Neratinib 160 mg and Capecitabine 2000 mg/m^2 | Drug: Neratinib<br>* Neratinib orally once daily continually<br>* Other names: HKI-272;Drug: Capecitabine<br>* Capecitabine orally on days 1-14 of each 21 day cycle<br>* Other names: Xeloda;|
| Experimental: Neratinib and Capecitabine MTD (Dose Group 6)<br>Neratinib and Capecitabine Maximum Tolerated Dose without prior lapatinib | Drug: Neratinib<br>* Neratinib orally once daily continually<br>* Other names: HKI-272;Drug: Capecitabine<br>* Capecitabine orally on days 1-14 of each 21 day cycle<br>* Other names: Xeloda;|
| Experimental: Neratinib and Capecitabine MTD (Dose Group 7)<br>Neratinib and Capecitabine Maximum Tolerated Dose with prior lapatinib | Drug: Neratinib<br>* Neratinib orally once daily continually<br>* Other names: HKI-272;Drug: Capecitabine<br>* Capecitabine orally on days 1-14 of each 21 day cycle<br>* Other names: Xeloda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities | Number of participants reporting Adverse Events Causing Dose Limiting Toxicities (DLT). | From first dose date to day 21 | 
| Maximum Tolerated Dose (MTD) of Neratinib | MTD reflects the highest dose of neratinib plus capeciteabine that did not cause a selected Grade 3 toxicity in >= 2 participants, which is any of 1) Grade 3 or 4 non-hematologic toxicity (Grade 3 asthenia was not considered a DLT unless lasting >3 days, 2) Grade 3 diarrhea lasting >2 days on optimal medical therapy or associated with fever or dehydration. 3) Grade 4 neutropenia lasting ≥ 3 days or Grade 4 febrile neutropenia, 4) Grade 4 thrombocytopenia lasting ≥3 days or associated with bleeding or requiring platelet transfusion, 5) Delayed recovery [to ≥ National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or baseline] from one of the above listed toxicities that were related to neratinib and/or capecitabine that delayed the initiation of the next dose by more than 3 weeks. | From first dose date to day 21. | 
| Maximum Tolerated Dose (MTD) of Capecitabine | MTD reflects the highest dose of capecitabine in combination with neratinib that did not cause a selected Grade 3 toxicity in >= 2 participants, which is any of 1) Grade 3 or 4 non-hematologic toxicity (Grade 3 asthenia was not considered a DLT unless lasting >3 days, 2) Grade 3 diarrhea lasting >2 days on optimal medical therapy or associated with fever or dehydration. 3) Grade 4 neutropenia lasting ≥ 3 days or Grade 4 febrile neutropenia, 4) Grade 4 thrombocytopenia lasting ≥3 days or associated with bleeding or requiring platelet transfusion, 5) Delayed recovery [to ≥ National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or baseline] from one of the above listed toxicities that were related to neratinib and/or capecitabine that delayed the initiation of the next dose by more than 3 weeks. | From first dose date to day 21. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Number of Subjects with Complete or Partial Response 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 three years. | 
| Clinical Benefit Rate | The percentage of subjects with Complete Response, Partial Response, or Stable Disease at least 24 weeks per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.0: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. | From first dose date to progression or last tumor assessment, up to three years. | 
| Duration of Response | 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 of recurrence or progressive disease (PD) or death per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.0: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions. | From start date of response to first PD/death, up to three years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Solid Tumor, erbB2+ Breast Cancer, Prior trastuzumab, Metastatic, Neratinib, HKI-272, Nerlynx, HER2, PB-272