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A Biomarker Study of Tivozanib in Subjects With Advanced Renal Cell Carcinoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01297244
Recruitment Status : Completed
First Posted : February 16, 2011
Results First Posted : October 27, 2020
Last Update Posted : October 27, 2020
Sponsor:
Information provided by (Responsible Party):
AVEO Pharmaceuticals, Inc.

Tracking Information
First Submitted Date  ICMJE February 14, 2011
First Posted Date  ICMJE February 16, 2011
Results First Submitted Date  ICMJE July 7, 2020
Results First Posted Date  ICMJE October 27, 2020
Last Update Posted Date October 27, 2020
Study Start Date  ICMJE January 2011
Actual Primary Completion Date October 2012   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 5, 2020)
  • Biomarkers in Blood and Archived Tissue Samples, and Their Correlation With Clinical Activity in Subjects With Advanced Renal Cell Cancer Treated With Tivozanib. [ Time Frame: Cycle 1 day 1, cycle 1 day 15 and cycle 2 day 1. ]
    To Evaluate CD68, HIF (hypoxia induced factor) 1/HIF2, VEGF A, VEGF-B, VEGF-C, VEGF-D, HGF (hepatocyte growth factor), CAIX, and PLGF (placental growth factor) levels and a biomarker signature based on transcriptional profiles.
  • Biomarkers in Blood and Archived Tissue Samples, and Their Correlation With Treatment-related Toxicity in Subjects With Advanced Renal Cell Cancer Treated With Tivozanib. [ Time Frame: Cycle 1 day 1, cycle 1 day 15 and cycle 2 day 1. ]
    To Evaluate biomarkers like VEGF-A, VEGF-B, VEGF-C, VEGF-D, HGF, and PLGF levels, protein expression and metabolite patterns.
  • Number of Tivozanib-treated Subjects Who Are Progression-free at 6 Months [ Time Frame: Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib). ]
    Subjects were considered to be progression-free at 6 months if they did not have disease progression or death by Day 182 and if they had an evaluation of confirmed PR, unconfirmed PR, or SD on or after Day 144.
Original Primary Outcome Measures  ICMJE
 (submitted: February 15, 2011)
  • To evaluate archived tumor tissue samples and their correlation with clinical activity and/or treatment related toxicity. [ Time Frame: Archived tumor tissue will be collected from subjects that meet eligibility criteria and will be enrolled on the study. ]
    These biomarkers may include but are not limited to: CD68, HIF (hypoxia induced factor)1/HIF2, VEGF A, VEGF-B, VEGF-C, VEGF-D, HGF (hepatocyte growth factor), CAIX, and PLGF (placental growth factor) levels and a biomarker signature based on transcriptional profiles.
  • To evaluate biomarkers in blood and their correlation with clinical activity and/or treatment related toxicity. [ Time Frame: Biomarker blood samples will be collected for all enrolled subjects at cycle 1 day 1, cycle 1 day 15 and cycle 2 day 1. ]
    These biomarkers may include but are not limited to VEGF-A, VEGF-B, VEGF-C, VEGF-D, HGF, and PLGF levels, protein expression and metabolite patterns.
  • To estimate the percentage of tivozanib-treated subjects who are progression-free at 6 months [ Time Frame: Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib). ]
    Disease status will be summarized by cycle, including changes from baseline.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 5, 2020)
  • Number of Subjects With Objective Response Rate (ORR) [ Time Frame: Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib). ]
    Objective response rate (ORR) is defined as the proportion of evaluable subjects who had a best overall response of complete response (CR) or partial response (PR). Based on RECIST v1.1 for target lesions, CR is the disappearance of all target lesions, reduction in short axis of any pathological lymph nodes (whether target or non-target) to < 10 mm and PR is at least a 30% decrease from baseline in the sum of diameters of target lesions.
  • Kaplan-Meier Estimate of Progression-free Survival (PFS) [ Time Frame: Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib). ]
    PFS is defined as the duration in days from the date of first dose of study drug to the date of first documentation of Progressive Disease (PD) or death (whichever came first), censored at the last tumor assessment documenting the absence of PD prior to the start of further anti-cancer therapy. Based on RECIST v1.1, progressive Disease (PD) is defined as an increase of at least 20%, and an absolute increase of at least 5 mm, in the sum of diameters of target lesions, taking as reference the smallest sum on study.
  • Number of Subjects With Adverse Events [ Time Frame: Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. ]
    Subjects were monitored throughout the treatment and 30 day follow-up period for occurrence of adverse events as well as for changes in clinical status, vital signs, and laboratory data. Safety parameters to be measured/assessed include eligibility assessment, medical history, performance status evaluation, vital signs, physical examination, subjective reports, hematology, serum chemistries, thyroid function tests, coagulation parameters, urinalysis, pregnancy test, and ECG.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 15, 2011)
  • To estimate the objective response rate (ORR) of subjects with advanced RCC treated with tivozanib [ Time Frame: Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib). ]
    Disease status will be summarized by cycle, including changes from baseline.
  • To estimate the overall progression-free survival (PFS) of subjects with advanced RCC treated with tivozanib [ Time Frame: Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib). ]
    Disease status will be summarized by cycle, including changes from baseline.
  • To further assess the safety and tolerability of tivozanib To further assess the safety and tolerability of tivozanib [ Time Frame: Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. ]
    Subjects will be monitored throughout the treatment and 30 day follow-up period for occurrence of adverse events as well as for changes in clinical status, vital signs, and laboratory data. Safety parameters to be measured/assessed include eligibility assessment, medical history, performance status evaluation, vital signs, physical examination, subjective reports, hematology, serum chemistries, thyroid function tests, coagulation parameters, urinalysis, pregnancy test, and ECG.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Biomarker Study of Tivozanib in Subjects With Advanced Renal Cell Carcinoma
Official Title  ICMJE A Phase 2 and Biomarker Study of Tivozanib in Subjects With Advanced Renal Cell Carcinoma
Brief Summary This is an open-label, single arm, multicenter study. Subjects will be stratified by histology (clear cell versus non-clear cell). Enrollment of non-clear cell subjects will be limited to ≤ 30% of the entire study population.
Detailed Description

This is a Phase 2, open-label, single arm, multi-center, study of orally administered tivozanib to approximately 100 subjects with advanced renal cell carcinoma (RCC). This study is designed to evaluate biomarkers in blood and archived tissue samples, and their correlation with clinical activity and/or treatment-related toxicity in subjects with advanced RCC, and estimate the percentage of tivozanib-treated subjects who are progression-free at 6 months, overall response rate (ORR), progression free survival (PFS), safety and tolerability, and pharmacokinetics (PK). Subjects will be stratified by histology (clear cell vs. non-clear cell). Enrollment of non-clear cell subjects will be limited to ≤ 30% of the entire study population.

Study enrollment is anticipated to complete in approximately 9 months. Treatment duration is estimated to last approximately 6 months from the subject's first dose of tivozanib with a follow-up period of 30 days. After 6 months, treatment with tivozanib may continue by participation in a rollover protocol (AV-951-09-901). Maximum duration of subject participation in this Phase 2 study is approximately 8 months.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Renal Cell Carcinoma
Intervention  ICMJE Drug: Tivozanib
Subjects will receive 1.5 mg tivozanib once daily beginning on Day 1 for 3 weeks followed by 1 week off treatment. One cycle will be defined as 4 weeks of treatment. Cycles will be repeated every 4 weeks.
Study Arms  ICMJE Experimental: Tivozanib
Subjects will receive 1.5 mg tivozanib once daily beginning on Day 1 for 3 weeks followed by 1 week off treatment. One cycle will be defined as 4 weeks of treatment. Cycles will be repeated every 4 weeks.
Intervention: Drug: Tivozanib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 1, 2012)
105
Original Estimated Enrollment  ICMJE
 (submitted: February 15, 2011)
100
Actual Study Completion Date  ICMJE October 2012
Actual Primary Completion Date October 2012   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. ≥ 18 year old males or females
  2. Subjects with unresectable locally recurrent or metastatic renal cell carcinoma (RCC)
  3. Histologically or cytologically confirmed clear cell renal cell carcinoma (≥ 50% clear cell) or non-clear cell RCC (all histologies)
  4. Subjects must have undergone prior nephrectomy (complete or partial) for excision of the primary tumor.
  5. Measurable disease per RECIST criteria Version 1.1 (see Appendix A)
  6. Treatment naïve subjects or subjects who have received no more than one prior systemic treatment (immunotherapy, including interferon-alfa or interleukin-2 based therapy, chemotherapy, hormonal therapy or an investigational agent) for metastatic RCC.
  7. Eastern Cooperative Oncology Group performance status of 0 or 1, and life expectancy ≥ 3 months
  8. If female and of childbearing potential, documentation of negative pregnancy test prior to enrollment
  9. Willingness to provide archival paraffin embedded tumor tissue, if available.
  10. Ability to give written informed consent and comply with protocol requirements

Exclusion Criteria:

  1. Any prior vascular endothelial growth factor (VEGF)-directed therapy including VEGF antibody (eg, bevacizumab), VEGF receptor tyrosine kinase inhibitor (eg, sunitinib, sorafenib, axitinib, pazopanib, etc.), VEGF trap (eg, aflibercept), or any other agent or investigational agent targeting the VEGF pathway.
  2. Any prior therapy with an agent targeting the mechanistic target of rapamycin pathway (eg, temsirolimus, everolimus, etc)
  3. Primary central nervous system (CNS) malignancies or CNS metastases; subjects with previously treated brain metastasis will be allowed if the brain metastasis have been stable without steroid treatment for at least 3 months following prior treatment (radiotherapy or surgery).
  4. Any of the following hematologic abnormalities:

    • Hemoglobin < 9.0 g/dL
    • Absolute neutrophil count (ANC) < 1500 per mm3
    • Platelet count < 100,000 per mm3
    • International Normalized Ratio >1.5 or partial thromboplastin time >1.5 × upper limit of normal (ULN)
  5. Any of the following serum chemistry abnormalities:

    • Total bilirubin > 1.5 × ULN (or > 2.5 × ULN for subjects with Gilbert's syndrome)
    • Aspartate aminotransferase or alanine aminotransferase > 2.5 × ULN (or > 5 × ULN for subjects with liver metastasis)
    • Alkaline phosphatase > 2.5 × ULN (or > 5 × ULN for subjects with liver or bone metastasis)
    • Creatinine > 2.0 × ULN
    • Proteinuria > 3+ by urinalysis or urine dipstick
  6. Significant cardiovascular disease, including:

    • Active clinically symptomatic left ventricular failure.
    • Uncontrolled hypertension: Systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg on 2 or more antihypertensive medications, documented on 2 consecutive measurements taken at least 24 hours apart.
    • Myocardial infarction, severe angina, or unstable angina within 6 months prior to administration of first dose of study drug.
    • History of serious ventricular arrhythmia (ie, ventricular tachycardia or ventricular fibrillation)
    • Cardiac arrhythmias requiring anti-arrhythmic medications (except for atrial fibrillation that is well controlled with anti-arrhythmic medication)
    • Coronary or peripheral artery bypass graft within 6 months of screening
  7. Non-healing wound, bone fracture, or skin ulcer.
  8. Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, or other gastrointestinal condition with increased risk of perforation; history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 4 weeks prior to administration of first dose of study drug
  9. Serious/active infection or infection requiring parenteral antibiotics.
  10. Inadequate recovery from any prior surgical procedure or major surgical procedure within 4 weeks prior to administration of first dose of study drug.
  11. Significant thromboembolic or vascular disorders within 6 months prior to administration of first dose of study drug, including but not limited to:

    • Deep vein thrombosis
    • Pulmonary embolism
    • Cerebrovascular accident (CVA) or transient ischemic attack (TIA)
    • Peripheral arterial ischemia > Grade 2 (per CTCAE Version 3.0)
  12. Significant bleeding disorders within 6 months prior to administration of first dose of study drug, including but not limited to.

    • Hematemesis, hematochezia, melena or other gastrointestinal bleeding Grade 2 (per CTCAE Version 3.0)
    • Hemoptysis or other pulmonary bleeding Grade 2 (per CTCAE Version 3.0)
  13. Currently active second primary malignancy, including hematologic malignancies (leukemia, lymphoma, multiple myeloma, etc.), other than non-melanoma skin cancers, non-metastatic prostate cancer, in situ cervical cancer, and ductal or lobular carcinoma in situ of the breast. Subjects are not considered to have a currently active malignancy if they have completed anti-cancer therapy and have been disease free for >2 years.
  14. Pregnant or lactating females.
  15. History of genetic or acquired immune suppression disease such as HIV; subjects on immune suppressive therapy for organ transplant.
  16. Life-threatening illness or organ system dysfunction compromising safety evaluation.
  17. Requirement for hemodialysis or peritoneal dialysis.
  18. Inability to swallow pills, malabsorption syndrome or gastrointestinal disease that severely affects the absorption of tivozanib, major resection of the stomach or small bowel, or gastric bypass procedure.
  19. Psychiatric disorder or altered mental status precluding informed consent or protocol-related testing.
  20. Sexually active pre-menopausal female subjects (and female partners of male subjects) must use adequate contraceptive measures, while on study and for 30 days after the last dose of study drug. All fertile male and female subjects must agree to use a highly effective method of contraception (including their partner). Effective birth control includes:

    • intrauterine device plus one barrier method or 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01297244
Other Study ID Numbers  ICMJE AV-951-10-202
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party AVEO Pharmaceuticals, Inc.
Study Sponsor  ICMJE AVEO Pharmaceuticals, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account AVEO Pharmaceuticals, Inc.
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP