A Phase II Study of Tivozanib in Patients With Metastatic and Non-resectable Soft Tissue Sarcomas
Condition: Recurrent Adult Soft Tissue Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma
MeSH terms: Sarcoma
Intervention: tivozanib; laboratory biomarker analysis
Intervention description: Given PO; Correlative studies
Intervention MeSH terms: Tyrosine Protein Kinase Inhibitors; Tivozanib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 58.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        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