A Phase II Study of Tivozanib in Patients With Metastatic and Non-resectable Soft Tissue Sarcomas

Study Overview
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Brief Summary
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This study is for patients who have been diagnosed with soft tissue sarcoma that has spread (metastasized) or that is not eligible for removal by surgery. The purpose of this study is to determine how soft tissue sarcomas respond to treatment with an investigational drug called tivozanib. In some lab and clinical studies, tivozanib has been shown to interfere with the growth of some types of tumors. The study will also evaluate how safe the study treatment is by observing how many and what kind of adverse events (side effects) participants experience.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the progression-free survival (defined as complete response [CR] + partial response [PR] + stable disease [SD]) assessed at 16 weeks for patients treated with tivozanib. SECONDARY OBJECTIVES: I. Overall response rate (defined as CR + PR). II. Clinical benefit rate (CR + PR + SD). III. Overall survival (up to 2 years beyond progression). IV. Correlation of clinical outcome with antibodies for vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR2. V. Assess Safety and tolerability. OUTLINE: Patients receive tivozanib orally (PO) daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity, or until discontinuation per patient preference or physician recommendation. After completion of study treatment, patients are followed up every 3 months for 2 years.

Official Title
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A Phase II Study of Tivozanib in Patients With Metastatic and Non-resectable Soft Tissue Sarcomas

Conditions
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Recurrent Adult Soft Tissue Sarcoma, Stage III Adult Soft Tissue Sarcoma, Stage IV Adult Soft Tissue Sarcoma

Intervention / Treatment
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* Drug: tivozanib
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically confirmed sarcoma of soft tissue Patients must have metastatic and/or locally advanced or locally recurrent disease Patients must have measurable disease within 4 weeks prior to registration by RECIST 1.1, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan; tumor lesions that are situated in a previously irradiated area may be considered measurable for the purposes of this study only if there is evidence of growth of the area following a course of irradiation that cannot be attributed to necrosis or bleeding into the tumor Patients must have had a minimum of 1 and a maximum of 4 prior chemotherapy regimens for recurrent/metastatic disease (it will be up to the treating investigator to define what constitutes a regimen in each case); the last dose of systemic therapy (include tyrosine kinase inhibitors) must have been given at least 4 weeks prior to initiation of therapy; patients receiving BCNU or mitomycin C must have received their last dose of such therapy at least 6 weeks prior to initiation of therapy Patients with brain metastasis that have been treated with definitive surgery or radiation and have been clinically stable for 3 months following the procedure with no neurological signs or symptoms and no requirement for systemic glucocorticoids are eligible for study Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Absolute neutrophil count >= 1.5 x 10^9/l Platelets >= 75 x 10^9/l Total bilirubin =< 1.5 x upper limit of normal (ULN) (except for patients with known Gilbert Syndrome) Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN Serum creatinine =< 1.5 x ULN If urine protein:creatinine (UPC) >= 1, then a 24-hour urine protein must be assessed; patients must have a 24-hour urine protein value < 1g to be eligible Patients must not have current evidence of another malignancy; there are no restrictions regarding prior history of malignancy If female and of childbearing potential, documentation of negative pregnancy test is required within 7 days prior to first dose; sexually active males and females of childbearing potential must agree to use adequate contraceptive measures, while on study and for 30 days after the last dose of study drug; all subjects (and their partners) must agree to use a highly effective method of contraception; effective birth control includes (a) intrauterine device (IUD) plus one barrier method; or (b) 2 barrier methods; effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm) Note: oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are not considered effective for this study Adverse events related to prior tumor-specific therapy must have resolved to less than or equal to National Cancer Institute (NCI) Common Terminology Criteria of Adverse Events (CTCAE) (version 4) grade 1 prior to study entry (except alopecia) Patients taking cytochrome P450 (CYP)3A4 inducers at the time of screening/registration are still eligible for participation, but whenever possible these medications should be discontinued or changed to one that is not an inducer NOTE: No washout period is required NOTE: It will be up to the treating investigator's discretion to assess whether or not the risk of discontinuing or changing the medication is higher or lower than the risk of continuing it while on study for the individual patient Patients must have the ability to understand and the willingness to sign a written informed consent document; signed and dated informed consent must be obtained prior to registration on trial Exclusion Criteria: Patients with any one of the following sarcoma histological subtypes will not be eligible for participation: alveolar soft-part sarcoma, chondrosarcoma, dermatofibrosarcoma, Ewing sarcoma, gastrointestinal stromal tumor (GIST), Kaposi sarcoma, mixed mesodermal tumor/carcinosarcoma, osteosarcoma, and low grade (grade 1) sarcomas; NOTE: Myxoid liposarcoma with t(12;16) or t(22;22) is permitted; rhabdomyosarcoma (Embryonal, Alveolar, pleomorphic), interdigitating dendritic sarcoma, giant cell tumor of bone Patients who have had major surgery within 21 days or those who have not recovered from adverse events associated with surgery to =< grade 1 will not be eligible for participation; excluded from such considerations are surgical changes not expected to improve, e.g. removal of muscle tissue; patients may be on replacement glucocorticoids for pre-existing glucocorticoid deficiency (e.g. Addison's disease) Patients receiving any other investigational agents will not be eligible for participation Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to tivozanib will not be eligible for participation Patients with serious and/or unstable pre-existing medical, psychiatric, or other conditions that could interfere with safety, provision of informed consent, or compliance to study procedures and requirements will not be eligible for participation, including but not limited to: Uncontrolled intercurrent illness Ongoing or active infection including HIV, active hepatitis B or C) Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia Psychiatric illness/social situations that would limit compliance with study requirements will not be eligible for participation Pregnant women and women who are breast-feeding will not be eligible for participation Patients with a history or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis will not be eligible for participation; NOTE: Individuals who have previously-treated CNS metastases, are asymptomatic, and have had no requirement for steroids or anti-seizure medications for 3 months prior to first dose of study drug are the exception; screening with CNS imaging studies such as CT or magnetic resonance imaging (MRI) is required only if clinically indicated or if the subject has a history of CNS metastases Patients with clinically significant gastrointestinal (GI) abnormalities that may increase the risk for GI bleeding will not be eligible for participation; these include, but are not limited to: Active peptic ulcer disease Known intraluminal metastatic lesion/s with risk of bleeding Inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), or other GI conditions with increased risk of perforation History of abdominal fistula, GI perforation, or intra-abdominal abscess within 28 days prior to beginning study treatment Clinically significant (> 1/2 teaspoon) hemoptysis or gastrointestinal hemorrhage in the past 6 months Patients with evidence of active bleeding or bleeding diathesis will not be eligible for participation; recent hemoptysis would be >= 1/2 teaspoon of red blood within 8 weeks before first dose of study drug Patients with clinically significant GI abnormalities that may affect absorption of investigational product will not be eligible for participation; these include but are not limited to: Malabsorption syndrome Major resection of the stomach or small bowel Patients with a corrected QT interval (QTc) > 480 msecs using Bazett's formula (QT Interval / square root(RR interval)) will not be eligible for participation Patients with left ventricular ejection fraction (LVEF) < 50% will not be eligible for participation NOTE: patients who do not meet the cutoff for LVEF may be re-screened at a later date and, if eligible then, may be enrolled in the study Patients with a history of any one or more of the following cardiovascular conditions within the past 6 months will not be eligible for participation: 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) Patients with poorly controlled hypertension [defined as systolic blood pressure (SBP) of >= 140 mmHg or diastolic blood pressure (DBP) of >= 90mmHg] will not be eligible for participation Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry; following antihypertensive medication initiation or adjustment, blood pressure (BP) must be re-assessed three times at approximately 2-minute intervals; at least 24 hours must have elapsed between anti-hypertensive medication initiation or adjustment and BP measurement; these three values will be averaged to obtain the mean diastolic blood pressure and the mean systolic blood pressure; the mean SBP / DBP ratio must be < 140/90 mmHg in order for a subject to be eligible for the study Patients with cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months will not be eligible for participation Note: subjects with recent DVT who have been therapeutically coagulated for at least 6 weeks are eligible Patients who had major surgery or trauma within 28 days prior to first dose of investigational product and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major surgery) will not be eligible for participation Patients with known endobronchial lesions and/or lesions infiltrating major pulmonary vessels will not be eligible for participation Note: tumor abutting the vessel is acceptable, but contiguous tumor and vessel is not; CT with contrast is strongly recommended to evaluate such lesions

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (tivozanib)<br>Patients receive tivozanib PO daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: tivozanib<br>* Given PO<br>* Other names: oral VEGF receptor tyrosine kinase inhibitor AV-951;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With Progression-free Survival at 16 Weeks. | Progression-free survival from study disease will be evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) Committee, version 1.1 assessed using imaging scans (CT or MRI) and clinical assessment following 16 weeks of treatment. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions, or similar definition as accurate and appropriate. | At 16 weeks of treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate Defined as Complete Response and Partial Response. | The response to study treatment will be assessed after every 8 weeks (2 cycles) of therapy using CT or MRI scan images.Overall response rate will be measured per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT or MRI: Complete response (CR) = disappearance of all target lesions. Partial Response (PR), = at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. | Every 2 cycles (8 weeks) up to 2 years | 
| Clinical Benefit Rate as Defined by Complete Response, Partial Response and Stable Disease. | The clinical benefit of study treatment will be assessed after 8 weeks (2 cycles) of therapy using scanning images (CT or MRI). Clinical benefit rate will be measured per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT or MRI: Complete Response (CR) = disappearance of all target lesions. Partial Response (PR), = at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Progressive Disease (PD) = At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Stable Disease (SD) = Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. | Every 2 cycles (8 weeks) up to 2 years | 
| Overall Survival up to 2 Years Beyond Progression | Patients will be followed-up with from first dose of study drug up to 2 years following the date of disease progression. | Time from the first dose of study treatment up to 2 years beyond disease progression | 
| Number of Patients With 0-3 VEGFR1 and VEGFR2 Protein Expression and Time in Days on Treatment | Tissue from biopsy will be collected during screening and proteins (VEGFR1 and VEGFR2) will be evaluated to see if there is a correlation with patient response to treatment. VERGFR = vascular endothelial growth factor receptor To determine if there was a correlation between response to Tivozanib and VEGFR expression, immunohistochemical (IHC) analysis on archival tumor tissue was performed. We performed standard IHC and applied combined intensity score (from 0 to 3) for antigen expression and proportional score of 0-3 for the cells that were positive. For antigen expression, 0 was no staining, +1 being 1-25% staining, +2 being 26-50% staining and +3 being 50% or greater staining. Number of patients with VEGFR1 expression was correlated with time patients were on treatment in days. | Tissue collected during screening process, prior to first treatment and response measured until 350 days. | 
| Treatment Toxicity as Measured by Adverse Events Experienced While on Treatment During Systematic Assessment. | Toxicity will be assessed after 4 weeks (1 cycle) and every 4 weeks during treatment according to the National Cancer Institute's Common Toxicity Criteria for adverse events version 4.0 (CTCAE v4.0). In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE | After every 4 weeks (1 cycle) until treatment discontinuation and up to a maximum of 2 years and 10 months. |