Study of Pazopanib and Ixabepilone in Patients With Solid Tumors

Study Overview
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Brief Summary
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This is a Phase I study; dose escalating the combination of pazopanib when taken daily and ixabepilone when administered on day 1 of a 3 week treatment course.

Detailed Description
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Treatment with ixabepilone will be given at an assigned dose as a 3 hour intravenous infusion on day 1 of a 21 day cycle. Treatment with pazopanib will be given at an assigned dose by mouth once a day, beginning on day 1 and continuing daily. Disease assessment will be done every 2 cycles (6 weeks) with treatment continuing until disease progression, unacceptable toxicity or patient refusal.

Official Title
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Phase I Study of Pazopanib and Ixabepilone in Patients With Solid Tumors

Conditions
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Breast Cancer, Lung Cancer, Colon Cancer, Pancreatic Cancer, Head and Neck Cancer, Kidney Cancer, Sarcoma, Hepatocellular Cancer

Intervention / Treatment
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* Drug: Pazopanib
* Drug: Ixabepilone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of advanced non-hematologic solid tumor malignancy, including, but not limited to breast, lung, colon, pancreatic, head and neck, kidney or sarcoma that has failed or become intolerant to standard therapy and is no longer likely to respond to such therapy Effective with the August 2011 version of the protocol, enrollment is limited to squamous cell carcinoma of the head and neck (refer to section 1.4 for rationale). Note: Patients with a primary diagnosis of hepatocellular carcinoma will be eligible for enrollment into dose level 1 or 2 only, provided they met all other inclusion/exclusion criteria - the maximum tolerated dose (MTD) for pazopanib monotherapy in patients with hepatocellular cancer was found to be 600 mg daily. Measureable or evaluable disease per Response Evaluation Criteria in Solid Tumors (RECIST). Prior systemic chemotherapy, immunotherapy, or biological therapy is allowed; however prior use of either pazopanib or ixabepilone alone or in combination is not allowed. At least 14 days must have elapsed since 1) previous systemic therapy (28 days for bevacizumab) before the 1st dose of study drug, 2) last dose of radiation therapy or surgery (28 days for major surgery). Patient must have recovered from the acute toxic effects of previous anti-cancer treatment prior to study enrollment. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Adequate organ function within 14 days of enrollment defined as: Absolute neutrophil count (ANC) >1.5 x 10^9/L Hemoglobin > or = 9 g/dL Platelets > or = 100 x 10^9/L Prothrombin time or international normalized ratio, and partial thromboplastin time (PTT) < or = 1.2 x upper limit of normal (ULN) Total bilirubin < or = ULN Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < or = 2.5 x ULN Serum creatinine < or = 1.5 mg/dL Urine protein to Creatinine Ratio < 1 Total serum calcium < 12.0 mg/dL Men and women with child-bearing potential must adhere to protocol criteria to prevent conception during study Exclusion Criteria: Women who are pregnant or nursing. Prior radiation to > =or = 30% of major bone marrow containing areas (pelvis, lumbar spine) History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis Clinically significant gastrointestinal abnormalities that may increase the risk of GI bleeding or may affect absorption of investigational product History of another malignancy - must be at least 3 years disease-free Presence of uncontrolled infection Prolongation of corrected QT interval (QTc) > 480 msecs History of any one or more of the following cardiovascular conditions within the past 6 months: Cardiac angioplasty or stenting Myocardial infarction Unstable angina Coronary artery bypass graft surgery Symptomatic peripheral vascular disease Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA) Poorly controlled hypertension History of cerebrovascular accident,pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months Prior major surgery or trauma within 28 days prior to 1st dose of study drug Evidence of active bleeding or bleeding diathesis Known endobronchial lesions or involvement of large pulmonary vessels by tumor Hemoptysis with 6 weeks of 1st dose of study drug Neuropathy Grade 1

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: Optimum Tolerated Dose Determination<br>Patient receives assigned dose level: Dose Level 1 = 400 milligrams (mg) of pazopanib and ixabepilone 32 mg/m2. Dose Level 2 = 400 milligrams (mg) of pazopanib and ixabepilone 40 mg/m2. Dose Level 3 = 600 milligrams (mg) of pazopanib and ixabepilone 32 mg/m2. Dose Level 4 = 800 milligrams (mg) of pazopanib and ixabepilone 32 mg/m2. | Drug: Pazopanib<br>* Escalating doses 400-800 mg by mouth once daily beginning day 1 and continuing.<br>* Other names: GW786034B;Drug: Ixabepilone<br>* Escalating doses 25-32 mg/m2 by intravenous infusion on day 1 of each 21 day cycle<br>* Other names: IXEMPRA(TM);|
| Experimental: Optimum Tolerated Dose Confirmation<br>Dose Level 3 = 600 milligrams (mg) of pazopanib and ixabepilone 32 mg/m2. | Drug: Pazopanib<br>* Escalating doses 400-800 mg by mouth once daily beginning day 1 and continuing.<br>* Other names: GW786034B;Drug: Ixabepilone<br>* Escalating doses 25-32 mg/m2 by intravenous infusion on day 1 of each 21 day cycle<br>* Other names: IXEMPRA(TM);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Optimal Tolerated Regimen of Pazopanib and Ixabepilone When Used in Combination | The optimal tolerated regimen is the regimen where ≤ 1 out of 6 patients experiences a dose limiting toxicity (DLT). DLT is defined as one of the following events occurring during cycle 1: grade 4 or greater treatment related hematologic toxicity for > 7 days during the first cycle (21 days) of therapy; grade 3 or greater treatment related clinical non-hematological toxicity (excluding ≥ grade 3 nausea, vomiting, or diarrhea without maximal medical intervention and/or prophylaxis) during the first cycle (21 days) of therapy; or a delay of cycle 2 treatment start by more than 2 weeks due to incomplete hematologic recovery (ANC > 1.5 x 109/L or platelets 100 x 109/L) or unresolved treatment related grade 3 or greater non-hematologic toxicity. | Week 3 of each dose level | 
| Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) | A DLT was defined as one of the following events occurring during cycle 1: (1) grade 4 or greater treatment-related hematologic toxicity for >7 days; (2) grade 3 or greater treatment-related clinical non-hematologic toxicity (excluding >/= grade 3 nausea, vomiting, or diarrhea without maximal medical intervention and/or prophylaxis); or (3) delay of starting cycle 2 treatment by >2 weeks due to incomplete hematologic recovery (absolute neutrophil count > 1.5 X 10^9/L or platelets >100 X 10^9/L) or unresolved treatment-related grade 3 or greater non-hematologic toxicity. Adverse events were classified according to Common Terminology Criteria for Adverse Events V 3.0 (CTCAE). | Week 3 of each dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Related Adverse Events | Includes all treatment-related adverse events experienced during and subsequent to Cycle 1. | Up to 30 days post treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Solid tumor malignancy, breast cancer, lung cancer, colon cancer, pancreatic cancer, head and neck cancer, kidney cancer, sarcoma, hepatocellular cancer