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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
AVEO Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:
NCT01297244
First received: February 14, 2011
Last updated: November 4, 2013
Last verified: November 2013
  Purpose

This is an open-label, single arm, multicenter study. 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.


Condition Intervention Phase
Renal Cell Carcinoma
Drug: Tivozanib
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 2 and Biomarker Study of Tivozanib in Subjects With Advanced Renal Cell Carcinoma

Resource links provided by NLM:


Further study details as provided by AVEO Pharmaceuticals, Inc.:

Primary Outcome Measures:
  • 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. ] [ Designated as safety issue: Yes ]
    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. ] [ Designated as safety issue: Yes ]
    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). ] [ Designated as safety issue: Yes ]
    Disease status will be summarized by cycle, including changes from baseline.


Secondary Outcome Measures:
  • 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). ] [ Designated as safety issue: Yes ]
    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). ] [ Designated as safety issue: Yes ]
    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. ] [ Designated as safety issue: Yes ]

    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.



Enrollment: 105
Study Start Date: January 2011
Study Completion Date: October 2012
Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
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.

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. ≥ 18 year old males or females
  2. Subjects with unresectable locally recurrent or metastatic renal cell carcinoma
  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. ECOG 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 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 mTOR pathway (eg, temsirolimus, everolimus, etc)
  3. Primary 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
    • INR >1.5 or PTT >1.5 × ULN
  5. Any of the following serum chemistry abnormalities:

    • Total bilirubin > 1.5 × ULN (or > 2.5 × ULN for subjects with Gilbert‟s syndrome)
    • AST or ALT > 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:

    • IUD 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
  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: NCT01297244

  Show 25 Study Locations
Sponsors and Collaborators
AVEO Pharmaceuticals, Inc.
  More Information

No publications provided

Responsible Party: AVEO Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT01297244     History of Changes
Other Study ID Numbers: AV-951-10-202
Study First Received: February 14, 2011
Last Updated: November 4, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by AVEO Pharmaceuticals, Inc.:
AV-951
Tivozanib
Advanced Renal Cell Carcinoma
RCC
Biomarkers

Additional relevant MeSH terms:
Carcinoma, Renal Cell
Carcinoma
Adenocarcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases

ClinicalTrials.gov processed this record on October 01, 2014