Safety Study of AMG 386 to Treat HER2-positive Locally Recurrent or Metastatic Breast Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine if AMG 386 in combination with either paclitaxel and trastuzumab or capecitabine and lapatinib is safe and well tolerated in subjects with HER2-positive locally recurrent or metastatic breast cancer. This is an open-label phase 1b trial and has 2 study parts. Study part 1 is a dose escalation study to determine a tolerable dose of AMG 386 in combination with paclitaxel and trastuzumab (cohort A) or with capecitabine and lapatinib (cohort B). Study part 2 is cohort expansion of the tolerable doses determined in part 1.

Official Title
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An Open-Label Study of AMG 386 in Combination With Either Paclitaxel and Trastuzumab or Capecitabine and Lapatinib in Subjects With HER2-positive Locally Recurrent or Metastatic Breast Cancer

Conditions
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Breast Cancer, Breast Neoplasms, Breast Tumors, Cancer, Locally Recurrent and Metastatic Breast Cancer, Metastases, Metastatic Cancer, Oncology, Solid Tumors, Tumors

Intervention / Treatment
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* Drug: AMG 386 30 mg/kg, Paclitaxel and Trastuzumab
* Drug: AMG 386 30 mg/kg, Capecitabine and Lapatinib
* Drug: AMG 386 10 mgkg, Paclitaxel and Trastuzumab
* Drug: AMG 386 10 mg/kg, Capecitabine and Lapatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: histologically or cytologically confirmed adenocarcinoma of the breast with locally recurrent or metastatic disease not amenable to any local treatment with curative intent. HER2-positive by FISH, CISH, or IHC 3+ ECOG performance status 0 or 1 Left ventricular ejection fraction greater than or equal to institutional lower limit of normal Adequate laboratory studies (hematological, chemistries and urinalysis) Life expectancy greater than or equal to 3 months Cohort A only: Trastuzumab naïve or trastuzumab in the neo-adjuvant setting No clinically significant drop in cardiac function prior exposure to trastuzumab No prior chemotherapy for metastatic or locally recurrent breast cancer No prior lapatinib therapy At least 3 weeks from enrollment since prior chemotherapeutic agents, including taxanes, in the neoadjuvant or adjuvant setting At least 3 months from enrollment since prior trastuzumab in the neoadjuvant or adjuvant setting Cohort B only: Must have failed trastuzumab in the first-line metastatic setting. Trastuzumab must be discontinued for at least 3 weeks prior to enrollment Must have received prior chemotherapy as adjuvant therapy or for metastatic disease Prior chemotherapy treatment must be discontinued for at least 3 weeks prior to enrollment No prior capecitabine No prior lapatinib Exclusion Criteria: Inflammatory breast cancer Central nervous system metastasis Clinically significant cardiovascular disease Radiation therapy ≤ 14 days prior to enrollment. Concurrent anticoagulation therapy, excluding aspirin, anti-platelet agents, low molecular weight heparin or low dose warfarin per protocol. Uncontrolled hypertension defined as diastolic blood pressure > 90 mmHg OR systolic blood pressure > 140 mmHg. Subjects with a history of prior malignancy, except: For Cohort B only: Current or prior history of long QT syndrome Baseline ECG report of QTc interval of > 480 milliseconds Severe chronic liver disease (Child Pugh C)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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: Cohort A1<br> | Drug: AMG 386 10 mgkg, Paclitaxel and Trastuzumab<br>* AMG 386 10 mg/kg IV QW, paclitaxel 80 mg/m2 IV QW, trastuzumab: initial dose 8 mg/kg IV week 1, then 6 mg/kg IV Q3W<br>|
| Experimental: Cohort A3<br> | Drug: AMG 386 30 mg/kg, Paclitaxel and Trastuzumab<br>* AMG 386 30 mg/kg IV QW, paclitaxel 80 mg/m2 IV QW, trastuzumab: initial dose 8 mg/kg IV week 1, then 6 mg/kg IV Q3W<br>|
| Experimental: Cohort B1<br> | Drug: AMG 386 10 mg/kg, Capecitabine and Lapatinib<br>* AMG 386 10 mg/kg IV QW, capecitabine 2000 mg/m2 divided into 2 doses given PO Q12 hrs, days 1-14 every 21 days, lapatinib 1250 mg PO QD<br>|
| Experimental: Cohort B3<br> | Drug: AMG 386 30 mg/kg, Capecitabine and Lapatinib<br>* AMG 386 30 mg/kg IV QW, capecitabine 2000 mg/m2 divided into 2 doses given PO Q12 hrs, days 1-14 every 21 days, lapatinib 1250 mg PO QD<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary objective is to identify the incidence of adverse events and clinical laboratory abnormalities defined as a dose limiting toxicity in subjects treated with AMG 386 plus paclitaxel and trastuzumab or with AMG 386 plus capecitabine and lapatinib |  | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the incidence of adverse events and clinical laboratory abnormalities not defined as DLTs |  | 24 months | 
| To evaluate the pharmacokinetics (PK) of AMG 386, trastuzumab, and paclitaxel (cohort A) or AMG 386, lapatinib, and capecitabine (and its active metabolite, 5-FU; cohort B) when administered in combination |  | 24 months | 
| To estimate the incidence of anti AMG 386 antibody formation |  | 24 months | 
| To evaluate the treatment effect as measured by the following: objective response rate (ORR), duration of response (DOR), change in tumor burden and progression-free survival (PFS) |  | 23 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AMG 386, Paclitaxel, Trastuzumab, Capecitabine, Lapatinib, HER2-positive, metastatic breast cancer, locally recurrent breast cancer, Taxol, Herceptin, Xeloda, Tykerb, anti-angiogenic therapy