PTK787 + Trastuzumab for HER2 Overexpressing Metastatic Breast Cancer

Study Overview
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Brief Summary
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HER2 gene amplification increases VEGF production in breast cancers; combined inhibition of HER2 and VEGF enhances response in xenograft models. The upregulation of VEGF in HER2-overexpressing breast cancers may contribute to the aggressive phenotype observed in HER2-positive breast cancer. New therapeutics targeting VEGF and/or its receptors may enhance the efficacy of trastuzumab monotherapy. This trial will investigate the safety and efficacy of combined HER2 and VEGF inhibition.

Detailed Description
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OUTLINE: This is a multi-center study. PTK787 daily plus trastuzumab 4 mg/kg IV week 1, followed by 2 mg/kg weekly with disease evaluation every other cycle. Patients may continue treatment until disease progression or toxicity intervenes. Performance Status: ECOG 0 or 1 Life Expectancy: Not specified Hematopoietic: ANC > 1500 mm3 Platelets > 100,000 mm3 Hemoglobin > 9 g/dL PTT and INR < 1.5 x ULN Hepatic: ALT and AST < 3 x ULN (< 5 x ULN in patients with known liver metastases) Alkaline phosphatase < 2.5 x ULN Serum bilirubin < 1.5 x ULN Renal: Serum creatinine < 1.5 x ULN Proteinuria < 1+ by dipstick OR total urinary protein < 500 mg/24 hours with measured creatinine clearance (CrCl) ≥ 50 mL/min Cardiovascular: No clinically significant cardiac disease (e.g. congestive heart failure, symptomatic coronary artery disease and cardiac arrhythmias not well controlled with medication) or myocardial infarction within the last 6 months. LVEF > LLN by MUGA or ECHO (obtained within 28 days prior to being registered for protocol therapy) Pulmonary: Not specified

Official Title
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A Phase I/II Study of PTK787 in Combination With Trastuzumab in Patients With Newly Diagnosed HER2 Overexpressing Locally Recurrent or Metastatic Breast Cancer: Hoosier Oncology Group Trial BRE04-80

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: PTK787
* Drug: Trastuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologic or cytologic diagnosis of breast cancer with evidence of measurable (1) unresectable, locally recurrent, or (2) metastatic disease. Locally recurrent disease must not be amenable to resection OR radiation with curative intent. Patient's disease may not involve more than 3 metastatic sites. In addition, patient may not be symptomatic from pulmonary metastasis or have liver metastasis involving > 50% of parenchyma. HER2 gene amplification by FISH. HER protein overexpression by immunohistochemistry will not be sufficient for entry. Negative pregnancy test Exclusion Criteria: No prior cytotoxic chemotherapy or trastuzumab for locally recurrent or metastatic disease. No prior treatment with any VEGF inhibiting agents No history or presence of central nervous system (CNS) disease. No other forms of cancer therapy including radiation, chemotherapy and hormonal therapy within 21 days prior to being registered for protocol therapy. No major surgery within 28 days prior to being registered for protocol therapy. No uncontrolled hypertension (SBP > 170, DBP > 90), history of labile hypertension or history of poor compliance with antihypertensive therapy. No requirement for therapeutic anticoagulation, regular aspirin (> 325 mg/day) or NSAID use. No current breast feeding. No impairment of gastrointestinal (GI) function that may significantly alter the absorption of PTK787. No evidence of other serious concomitant systemic disorders incompatible with the study (at the discretion of the investigator).

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Group Assignment<br>Trastuzumab + PTK787 for HER2 positive patients | Drug: PTK787<br>* PTK787 daily<br>Drug: Trastuzumab<br>* Trastuzumab 4 mg/kg IV week 1, followed by 2 mg/kg weekly with disease evaluation every other cycle*<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I Cohorts: |  | 18 months | 
| The primary objective is to ensure the safety and tolerability of the combination of Trastuzumab and PTK787, |  | 18 months | 
| Phase II Cohorts: |  | 18 months | 
| To assess response rate of PTK787 combined with trastuzumab in patients with newly diagnosed HER2 overexpressing |  | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase II Cohorts: |  | 12 months | 
| To assess the safety and tolerability of PTK787 combined with trastuzumab |  | 12 months | 
| To assess the time to progression and clinical benefit of PTK787 combined with trastuzumab |  | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer