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NEXT: Subsequent Exposure to Tyrosine Kinase Inhibition at Recurrence After Adjuvant Therapy in Renal Cell Carcinoma (PrE0801)

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ClinicalTrials.gov Identifier: NCT01649180
Recruitment Status : Terminated (Closed due to prolonged enrollment timelines)
First Posted : July 25, 2012
Results First Posted : April 20, 2017
Last Update Posted : May 23, 2017
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
PrECOG, LLC.

Tracking Information
First Submitted Date  ICMJE July 21, 2012
First Posted Date  ICMJE July 25, 2012
Results First Submitted Date  ICMJE December 6, 2016
Results First Posted Date  ICMJE April 20, 2017
Last Update Posted Date May 23, 2017
Study Start Date  ICMJE July 2012
Actual Primary Completion Date January 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 9, 2017)
Progression-free Survival [ Time Frame: Assessed every 12 weeks up to 36 months ]
Progression-free survival is defined as the time from registration to disease progression or death, whichever occurs first. 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.
Original Primary Outcome Measures  ICMJE
 (submitted: July 21, 2012)
Clinical Benefit [ Time Frame: 36 months ]
To determine the clinical benefit that retreatment with VEGFR2 TKI therapy confers to patients with recurrent ccRCC after adjuvant treatment.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 20, 2017)
  • Overall Response Rate [ Time Frame: Assessed every 12 weeks up to 36 months ]
    Best overall response was evaluated using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v 1.0). Response is defined as complete response or partial response. Complete Response (CR): disappearance of all target lesions Partial Response (PR): >=30% decrease in the sum of the longest diameter of target lesions
  • Biospecimen Banking for IL-8 and VEGF-A [ Time Frame: Baseline and 8 weeks ]
    To bank biospecimens for the retrospective determination of whether baseline or changes in cytokine levels of IL-8 and VEGF-A predict response to treatment in this setting. Banking of plasma and serum is optional but strongly encouraged. Note: The assays to assess cytokine levels of IL-8 and VEGF-A were not performed because the study stopped early and only 3 patients were enrolled. Therefore, the analysis to evaluate the associations between response and IL-8 as well as VEGF-A was not be done.
  • Biospecimen Banking for SNPs Analysis [ Time Frame: Baseline ]
    To bank biospecimens for the retrospective determination of whether baseline single nucleotide polymorphisms (SNPs) in angiogenesis-related genes predict response to treatment (candidate gene approach). Banking of PBMC is optional but strongly encouraged. Note: The SNP genotyping analysis was not performed because the study stopped early and only 3 patients were enrolled. Therefore, the analysis to evaluate the association between baseline SNPs in angiogenesis-related genes and response was not be done.
  • Tumor Tissue Banking [ Time Frame: Baseline ]
    To bank tumor tissue (formalin-fixed, paraffin-embedded tumor blocks) for retrospective examination of the molecular pathophysiologic mediators of tumorigenesis and progression such as phospho-protein expression of MAPK signaling network intermediates in endothelial cells. Banking of tumor tissue is optional but strongly encouraged. Note: None of the 3 patients submitted tumor tissues so the analysis won't be performed.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 21, 2012)
  • Response Rate [ Time Frame: 36 months ]
    To determine the overall response rate to the aforementioned TKI therapeutic in recurrent disease associated with post-adjuvant TKI therapy.
  • Biospecimen Banking for IL-8 and VEGF-A [ Time Frame: 24 months ]
    To bank biospecimens for the retrospective determination of whether baseline or changes in cytokine levels of IL-8 and VEGF-A predict response to treatment in this setting. Banking of plasma and serum is optional but strongly encouraged.
  • Biospecimen Banking for SNPs Analysis [ Time Frame: 24 months ]
    To bank biospecimens for the retrospective determination of whether baseline single nucleotide polymorphisms (SNPs) in angiogenesis-related genes predict response to treatment (candidate gene approach). Banking of PBMC is optional but strongly encouraged.
  • Bank Tumor Tissue [ Time Frame: 24 months ]
    To bank tumor tissue (formalin-fixed, paraffin-embedded tumor blocks) for retrospective examination of the molecular pathophysiologic mediators of tumorigenesis and progression such as phospho-protein expression of MAPK signaling network intermediates in endothelial cells. Banking of tumor tissue is optional but strongly encouraged.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE NEXT: Subsequent Exposure to Tyrosine Kinase Inhibition at Recurrence After Adjuvant Therapy in Renal Cell Carcinoma
Official Title  ICMJE NEXT: Subsequent Exposure to Tyrosine Kinase Inhibition (TKI) at Recurrence After Adjuvant Therapy in Renal Cell Carcinoma (RCC)
Brief Summary

The purpose of this study is to see how well the study drug, axitinib, helps control renal (kidney) cancer that has come back (recurrent) or spread (metastatic). Patients must have already been treated as a participant in a clinical trial with sunitinib, sorafenib, pazopanib or placebo (sugar pill) after their initial surgery.

This study will examine the effect of adjuvant tyrosine kinase inhibition (TKI) therapy (sorafenib, sunitinib or pazopanib) on subsequent exposure to TKI with axitinib in the first-line recurrent or metastatic setting.

Detailed Description

Approximately 64,770 cases of cancer involving the kidney and renal pelvis were diagnosed in the United States in 2012 and 13,570 deaths occurred from these tumors. The rate of Renal Cell Carcinoma (RCC) has increased by 2% per year for the past 65 years. The reason for this increase in unknown but smoking and obesity are risk factors for the development of RCC. Early stage disease is typically treated with resection with definitive intent with partial or radical nephrectomy. Patients with metastatic disease are often treated with systemic therapy with palliative intent. Systemic therapeutic options include so-called targeted therapies, and less often chemotherapy and immunomodulatory therapies (interferon alpha and interleukin-2).

The Food and Drug Administration (FDA) has approved six targeted agents for the treatment of advanced and metastatic renal cell carcinoma that fall into two general classes - vascular endothelial growth factor (VEGF) inhibitors and inhibitors of mammalian target of rapamycin (mTOR). On the basis of several randomized phase III studies, vascular endothelial growth factor receptor-2 (VEGFR2) inhibitor therapy has become the generally preferred treatment for recurrent and metastatic ccRCC (clear cell Renal Cell Carcinoma) in the first-line setting. Treatment of ccRCC with VEGF-inhibition in the first-line metastatic setting, is associated with a progression-free survival of approximately 11 months. Vascular endothelial growth factor (VEGF) inhibitor therapy in the second-line remains active, but to a lesser degree - progression-free survival (PFS) has been reported to be between 5 and 7 months.

Adjuvant treatment of high-risk, early-stage ccRCC with VEGFR2 TKI therapy following definitive resection has become an area of active investigation. The ASSURE trial (ECOG 2805) recently completed accrual, and other adjuvant trials - i.) SORCE (sorafenib for 3 or 1 year versus placebo), ii.) S-Trac (sunitinib versus placebo) - are in accrual.

Axitinib (AG-013736, Pfizer Inc.), a receptor-tyrosine kinase inhibitor that is selective for VEGFR1, 2, and 3, is an important new agent for use in metastatic RCC. Axitinib has been examined extensively in RCC, and it has been shown to be safe, well-tolerated, and highly active. On January 27, 2012, the FDA approved axitinib for the treatment of advanced RCC after failure of one prior systemic therapy.

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: Axitinib
Axitinib 5 mg orally with food every 12 hours. One cycle=28 days.
Other Names:
  • AG-013736
  • Tyrosine Kinase Inhibitor (TKI)
Study Arms  ICMJE Experimental: Axitinib
Axitinib will be given orally and will continue until progression of disease.
Intervention: Drug: Axitinib
Publications *

*   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 Terminated
Actual Enrollment  ICMJE
 (submitted: March 1, 2016)
3
Original Estimated Enrollment  ICMJE
 (submitted: July 21, 2012)
105
Actual Study Completion Date  ICMJE March 2016
Actual Primary Completion Date January 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Locally recurrent or metastatic RCC requiring systemic therapy following treatment (tx) with sorafenib, sunitinib, pazopanib, or placebo on an adjuvant study
  • Required to have primary or recurrence tumor samples containing clear cell variant RCC with <50% of any other histology
  • Recurrence must occur ≥ 3 months following end of exposure to the adjuvant intervention
  • Received ≥ 3 six week cycles of prior adjuvant tx with sorafenib, sunitinib, pazopanib or placebo in the adjuvant setting on a clinical trial, or recurrence >3 months of tx on an adjuvant placebo arm
  • Required to have measurable recurrent or metastatic disease that is not curable by standard radiation therapy or surgery
  • Male or female, ≥ 18 years old
  • ECOG PS 0 or 1
  • Blood pressure (B/P) must be controlled at time of enrollment. Tx with antihypertensive medication(s) is allowed. Controlled B/P is defined as in clinic measurement of systolic B/P ≤ 140 mm Hg AND diastolic B/P ≤ 90 mm Hg. If B/P is uncontrolled at time of planned enrollment, tx or optimization with antihypertensive medication(s) may be initiated in order to control B/P. Patient may be considered for enrollment when this has happened.
  • Women must not be pregnant or breastfeeding
  • Men and women who are of reproductive potential must be willing to employ an effective method of birth control/contraception
  • Willingness and ability to comply with scheduled visits, tx plans, laboratory tests, and other study procedures
  • Ability to understand and willingness to sign an IRB-approved informed consent
  • Adequate organ function as evidenced by the following, obtained within 28 days prior to registration:

    • Absolute neutrophil count (ANC) ≥ 1250 cells/mm³
    • Platelet count ≥ 75,000 cells/mm³
    • Hemoglobin ≥ 9.0 g/dL
    • Total direct serum bilirubin ≤ 1.5x upper limit of normal (ULN)
    • ALT and AST ≤ 2.5 x ULN unless there are liver metastases in which case AST and ALT ≤ 5.0 x ULN
    • Serum creatinine <1.5 x ULN or calculated creatinine clearance ≥ 45 mL/min
    • Urine protein <2+ by urine dipstick
  • Resolution of all previous tx-related toxicity to ≤ grade 1 or back to baseline
  • No major surgery <4 weeks or radiation therapy <2 weeks of starting study tx. Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided there is at least one measurable lesion that has not been irradiated.
  • No clinically significant gastrointestinal abnormalities
  • No current use or anticipated need for tx with drugs that are known potent CYP3A4 inhibitors
  • No current or anticipated need for tx with drugs that are known CYP3A4 or CYP1A2 inducers
  • No current requirement of anticoagulant therapy with oral vitamin K antagonists
  • No untreated brain metastases, spinal cord compression, or carcinomatous meningitis. Patients must be off oral (systemic) steroids prior to registration. Inhalational steroids, e.g., for asthma, emphysema are permissible.
  • No serious uncontrolled medical disorder or active infection that would impair their ability to receive study tx
  • None of the following conditions within the 6 months prior to study drug: myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, deep vein thrombosis or pulmonary embolism
  • No known HIV or AIDS-related illness
  • No other active malignancy
  • No dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of the protocol
  • No other severe acute/chronic medical or psychiatric condition or lab abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study
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 United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01649180
Other Study ID Numbers  ICMJE PrE0801
WS1512227 ( Other Grant/Funding Number: Pfizer )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: Data is proprietary.
Responsible Party PrECOG, LLC.
Study Sponsor  ICMJE PrECOG, LLC.
Collaborators  ICMJE Pfizer
Investigators  ICMJE
Study Chair: Stephen Keefe, MD University of Pennsylvania Health System
PRS Account PrECOG, LLC.
Verification Date April 2017

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