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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
AVEO Pharmaceuticals, Inc.
Information provided by (Responsible Party):
Mark Agulnik, Northwestern University
ClinicalTrials.gov Identifier:
NCT01782313
First received: January 30, 2013
Last updated: June 23, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Recurrent Adult Soft Tissue Sarcoma
Stage III Adult Soft Tissue Sarcoma
Stage IV Adult Soft Tissue Sarcoma
Drug: tivozanib
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study of Tivozanib in Patients With Metastatic and Non-resectable Soft Tissue Sarcomas

Resource links provided by NLM:


Further study details as provided by Northwestern University:

Primary Outcome Measures:
  • Progression-free survival from study disease will be evaluated using imaging scans (CT or MRI) [ Time Frame: Evaluation takes place after 16 weeks of treatment ] [ Designated as safety issue: No ]
    Progression-free survival from study disease will be evaluated using imaging scans (CT or MRI) following 16 weeks of treatment.


Secondary Outcome Measures:
  • Determine overall response rate [ Time Frame: Every 2 cycles (8 weeks) up to 2 years ] [ Designated as safety issue: No ]
    The response to study treatment will be assessed after every 8 weeks (2 cycles) of therapy using CT or MRI scan images.

  • Determine the clinical benefit rate [ Time Frame: Every 2 cycles (8 weeks) up to 2 years ] [ Designated as safety issue: No ]
    The clinical benefit of study treatment will be assessed after 8 weeks (2 cycles) of therapy using scanning images (CT or MRI).

  • Determine overall survival [ Time Frame: Time from the first dose of study treatment up to 2 years beyond disease progression ] [ Designated as safety issue: No ]
    Patients will be followed-up with from first dose of study drug up to 2 years following the date of disease progression.

  • Evaluate proteins and correlate with response to therapy [ Time Frame: Tissue collected during screening process (prior to study start date) ] [ Designated as safety issue: Yes ]
    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.

  • Treatment toxicity as measured by adverse events experienced while on treatment [ Time Frame: After every 4 weeks (1 cycle) ] [ Designated as safety issue: Yes ]
    Toxicity will be assessed after 4 weeks (1 cycle).


Estimated Enrollment: 54
Study Start Date: February 2013
Estimated Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (tivozanib)
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
Given PO
Other Names:
  • AV-951
  • oral VEGF receptor tyrosine kinase inhibitor AV-951
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01782313

Locations
United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611
United States, Iowa
University of Iowa
Iowa City, Iowa, United States, 52246
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, Missouri
Washington University
St. Louis, Missouri, United States, 63110
United States, Wisconsin
University of Wisconsin
Madison, Wisconsin, United States, 53792
Sponsors and Collaborators
Northwestern University
AVEO Pharmaceuticals, Inc.
Investigators
Principal Investigator: Mark Agulnik, MD Northwestern University
  More Information

No publications provided

Responsible Party: Mark Agulnik, Principal Investigator, Northwestern University
ClinicalTrials.gov Identifier: NCT01782313     History of Changes
Other Study ID Numbers: NU 12S02, NCI-2012-03188, STU00073826
Study First Received: January 30, 2013
Last Updated: June 23, 2014
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Additional relevant MeSH terms:
Sarcoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms

ClinicalTrials.gov processed this record on July 20, 2014