Axitinib (AG 013736) As Second Line Therapy For Metastatic Renal Cell Cancer

• ClinicalTrials.gov Identifier: NCT00678392
• Recruitment Status: Completed
• First Posted: May 15, 2008
• Results First Posted: March 27, 2012
• Last Update Posted: January 9, 2019
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: May 12, 2008
• First Posted Date: May 15, 2008
• Results First Submitted Date: February 25, 2012
• Results First Posted Date: March 27, 2012
• Last Update Posted Date: January 9, 2019
• Actual Study Start Date: September 3, 2008
• Actual Primary Completion Date: August 31, 2010 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 21, 2017)

Progression-Free Survival (PFS) [ Time Frame: From initiation of treatment up to follow-up period (up to 3 years) ]

PFS was defined as the time in months from start of study treatment to the first documentation of objective tumor progression of disease (PD) or to death due to any cause, whichever occurs first. PD was assessed by response evaluation criteria in solid tumors (RECIST) version 1.0. PD: >=20 percent (%) increase in the sum of the longest dimensions (LD) of the target lesions taking as a reference the smallest sum of the LD recorded since the start of treatment or unequivocal progression in non-target lesions or the appearance of 1 or more new lesions. Occurrence of a pleural effusion or ascites was also considered PD if demonstrated by cytological investigation and it was not previously documented. New bone lesions not previously documented were considered PD if confirmed by computed tomography/magnetic resonance imaging or X-ray.

• Original Primary Outcome Measures (submitted: May 12, 2008): Progression-Free Survival [ Time Frame: 3 years ]

Current Secondary Outcome Measures (submitted: February 21, 2017)

• Overall Survival (OS) [ Time Frame: From initiation of treatment up to follow-up period (up to 3 years) ]
  OS was defined as the duration from start of study treatment to date of death due to any cause. OS was calculated as (months) = (date of death minus the date of first dose of study medication plus 1) divided by 30.4. For participants who were alive, overall survival was censored on last date the participants were known to be alive.
• Objective Response Rate (ORR) [ Time Frame: From initiation of treatment up to follow-up period (up to 3 years) ]
  ORR = percentage of participants with confirmed complete response (CR) or confirmed partial response (PR) according to RECIST version 1.0 recorded from first dose of study treatment until PD or death due to any cause. CR: disappearance of all target, non target lesions and no appearance of new lesions, documented on 2 occasions separated by at least 4 weeks. PR: at least 30 % decrease in sum of LD of target lesions taking as reference baseline sum of LD, without progression of non target lesions, no appearance of new lesions. PD: >=20% increase in sum of LD of the target lesions taking as a reference smallest sum of LD recorded since the start of treatment or unequivocal progression in non-target lesions or appearance of 1 or more new lesions. Occurrence of pleural effusion or ascites if demonstrated by cytological investigation, not previously documented. New bone lesions not previously documented if confirmed by computed tomography/magnetic resonance imaging or X-ray.
• Duration of Response (DR) [ Time Frame: From initiation of treatment up to follow-up period (up to 3 years) ]
  DR: time from first documentation of objective tumor response (CR or PR), that was subsequently confirmed, to the first documentation of PD or to death due to any cause, whichever occurred first as per RECIST version 1.0, a) CR: disappearance of all target, non target lesions and no appearance of new lesions, documented on 2 occasions separated by at least 4 weeks, b) PR: at least 30 % decrease in sum of LD of target lesions taking as reference baseline sum of LD, without progression of non target lesions, no appearance of new lesions, c) PD: >=20% increase in sum of LD of the target lesions taking as a reference smallest sum of LD recorded since the start of treatment or unequivocal progression in non-target lesions or appearance of 1 or more new lesions. Occurrence of pleural effusion or ascites if demonstrated by cytological investigation, not previously documented. New bone lesions not previously documented if confirmed by computed tomography/magnetic resonance imaging or X-ray.
• Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: From initiation of treatment up to follow-up period (up to 3 years) ]
  An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life- threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pretreatment state. AEs included both serious and non-serious AEs.
• Percentage of Participants With Adverse Events (AEs) by Severity [ Time Frame: From initiation of treatment up to follow-up period (up to 3 years) ]
  An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Severity of the AEs was graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Grade 1= mild; Grade 2= moderate; Grade 3= severe; Grade 4= life-threatening or disabling; Grade 5= death related to AE.
• Percentage of Participants With Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: From initiation of treatment up to follow-up period (up to 3 years) ]
  An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life -threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both serious and non -serious AEs.
• Number of Participants With Clinically Significant Laboratory Abnormalities: Hematology [ Time Frame: From initiation of treatment up to follow-up period (up to 3 years) ]
  Hematology laboratory test included hemoglobin, platelet count, white blood cells count, neutrophils and lymphocytes. Abnormalities were assessed by CTCAE Grade Version 2 for severity: Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling.
• Number of Participants With Clinically Significant Laboratory Abnormalities: Biochemistry [ Time Frame: From initiation of treatment up to follow-up period (up to 3 years) ]
  Biochemistry laboratory test included parameters: alanine aminotransferase, alkaline phosphatase, amylase, aspartate aminotransferase, bicarbonate, bilirubin, creatinine, hypercalcemia, hyperglycemia, hyperkalemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia, hypophosphatemia and lipase. Abnormalities were assessed by CTCAE Grade Version 2 for severity: Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling.
• Number of Participants With Clinically Significant Laboratory Abnormalities: Urinalysis [ Time Frame: From initiation of treatment up to follow-up period (up to 3 years) ]
  Urinalysis included urine blood/ hemoglobin, glucose and protein. Abnormalities were assessed by CTCAE Grade Version 2 for severity: Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling.
• Functional Assessment of Cancer Therapy Kidney Symptom Index-15 (FKSI-15) Score [ Time Frame: Baseline (Predose on Cycle 1 Day 1) , Day 1 of each cycle until Cycle 21, End of treatment (Day 670) and Follow-up visit (Day 698) ]
  FKSI was used to assess quality of life (QoL) for those diagnosed with renal cell cancer and consisted of 15 items (lack of energy, side effects, pain, losing weight, bone pain, fatigue, enjoying life, short of breath, worsened condition, appetite, coughing, bothered by fevers, ability to work, hematuria and sleep). Each of the 15 items was answered on a 5-point Likert-type scale ranging from 0 to 4 (0= not at all, 1= a little bit, 2= somewhat, 3= quite a bit, 4= very much). Total FKSI score = sum of the 15 item scores; total range: 0 - 60; 0 (no symptoms) to 60 (very much); higher scores indicate greater presence of symptoms.
• Functional Assessment of Cancer Therapy Kidney Symptom Index-Disease Related Symptoms (FKSI-DRS) Score [ Time Frame: Baseline (Predose on Cycle 1 Day 1) , Day 1 of each cycle until Cycle 21, End of treatment (Day 670) and Follow-up visit (Day 698) ]
  FKSI-DRS was used to assess quality of life for those diagnosed with renal cell cancer and consisted of 9 items (lack of energy, pain, losing weight, bone pain, fatigue, short of breath, coughing, bothered by fevers, and hematuria). Each of the 9 items was answered on a 5-point Likert-type scale ranging from 0 to 4 (0= not at all, 1= a little bit, 2= somewhat, 3= quite a bit, 4= very much). Total FKSI-DRS score = sum of the 9 item scores; total range: 0 - 36; 0 (no symptoms) to 36 (very much); higher scores indicate greater presence of symptoms.
• Euro Quality of Life Questionnaire- 5 Dimension (EQ-5D): Health State Profile Utility Score [ Time Frame: Baseline (Predose on Cycle 1 Day 1) , Day 1 of each cycle until Cycle 21, End of treatment (Day 670) and Follow-up visit (Day 698) ]
  EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single utility or index score. Health state profile component assesses level of health for 5 domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each domain was rated on a 3-point response scale (1= no problems, 2= some/moderate problems and 3= extreme problems). Scoring formula developed by EuroQol Group assigned a utility value for each domain in the profile. Score were transformed and resulted in a total score range of 0 to 1, with higher scores indicating better health.
• Euro Quality of Life Questionnaire- 5 Dimension (EQ-5D): Visual Analog Scale (VAS) [ Time Frame: Baseline (Predose on Cycle 1 Day 1) , Day 1 of each cycle until Cycle 21, End of treatment (Day 670) and Follow-up visit (Day 698) ]
  EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single index value. VAS component: participants rated their current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health.

Original Secondary Outcome Measures (submitted: May 12, 2008)

• Compare Overall Survival [ Time Frame: 3 years ]
• Compare Response Rate [ Time Frame: 3 years ]
• Evaluate Safety and Tolerability on Axitinib [ Time Frame: 3 years ]
• Estimate the Duration of Response in Each Arm [ Time Frame: 3 years ]
• Compare the Kidney Specific Symptoms and Health Status [ Time Frame: 3 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Axitinib (AG 013736) As Second Line Therapy For Metastatic Renal Cell Cancer
• Official Title: AXITINIB (AG-013736) AS SECOND LINE THERAPY FOR METASTATIC RENAL CELL CANCER: AXIS TRIAL
• Brief Summary: The study is designed to demonstrate that axitinib (AG-013736) is superior to sorafenib in delaying tumor progression in patients with metastatic renal cell cancer after failure of one first line regimen.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Kidney Neoplasms

Intervention

• Drug: Axitinib (AG-013736)
  axitinib will be given at a starting dose of 5 mg twice daily [BID] with continuous dosing
• Drug: Sorafenib
  sorafenib will be given at a dose of 400 mg twice daily [BID] with continuous dosing

Study Arms

• Experimental: Axitinib
  Intervention: Drug: Axitinib (AG-013736)
• Active Comparator: Sorafenib
  Intervention: Drug: Sorafenib

Publications *

• Murphy DA, Rini BI, Escudier B, Motzer RJ, Wang P, Li S, Williams JA, Tarazi JC, Martini JF. Angiogenic and immunomodulatory biomarkers in axitinib-treated patients with advanced renal cell carcinoma. Future Oncol. 2020 Jun;16(17):1199-1210. doi: 10.2217/fon-2020-0212. Epub 2020 May 4.
• Bracarda S, Bamias A, Casper J, Negrier S, Sella A, Staehler M, Tarazi J, Felici A, Rosbrook B, Jardinaud-Lopez M, Escudier B. Is Axitinib Still a Valid Option for mRCC in the Second-Line Setting? Prognostic Factor Analyses From the AXIS Trial. Clin Genitourin Cancer. 2019 Jun;17(3):e689-e703. doi: 10.1016/j.clgc.2019.03.017. Epub 2019 Apr 1.
• de Velasco G, McKay RR, Lin X, Moreira RB, Simantov R, Choueiri TK. Comprehensive Analysis of Survival Outcomes in Non-Clear Cell Renal Cell Carcinoma Patients Treated in Clinical Trials. Clin Genitourin Cancer. 2017 Dec;15(6):652-660.e1. doi: 10.1016/j.clgc.2017.03.004. Epub 2017 Mar 21.
• Grunwald V, Lin X, Kalanovic D, Simantov R. Early Tumour Shrinkage: A Tool for the Detection of Early Clinical Activity in Metastatic Renal Cell Carcinoma. Eur Urol. 2016 Dec;70(6):1006-1015. doi: 10.1016/j.eururo.2016.05.010. Epub 2016 May 26.
• Grunwald V, McKay RR, Krajewski KM, Kalanovic D, Lin X, Perkins JJ, Simantov R, Choueiri TK. Depth of remission is a prognostic factor for survival in patients with metastatic renal cell carcinoma. Eur Urol. 2015 May;67(5):952-8. doi: 10.1016/j.eururo.2014.12.036. Epub 2015 Jan 7.
• Escudier B, Michaelson MD, Motzer RJ, Hutson TE, Clark JI, Lim HY, Porfiri E, Zalewski P, Kannourakis G, Staehler M, Tarazi J, Rosbrook B, Cisar L, Hariharan S, Kim S, Rini BI. Axitinib versus sorafenib in advanced renal cell carcinoma: subanalyses by prior therapy from a randomised phase III trial. Br J Cancer. 2014 Jun 10;110(12):2821-8. doi: 10.1038/bjc.2014.244. Epub 2014 May 13.
• Ueda T, Uemura H, Tomita Y, Tsukamoto T, Kanayama H, Shinohara N, Tarazi J, Chen C, Kim S, Ozono S, Naito S, Akaza H. Efficacy and safety of axitinib versus sorafenib in metastatic renal cell carcinoma: subgroup analysis of Japanese patients from the global randomized Phase 3 AXIS trial. Jpn J Clin Oncol. 2013 Jun;43(6):616-28. doi: 10.1093/jjco/hyt054. Epub 2013 Apr 28.
• Motzer RJ, Escudier B, Tomczak P, Hutson TE, Michaelson MD, Negrier S, Oudard S, Gore ME, Tarazi J, Hariharan S, Chen C, Rosbrook B, Kim S, Rini BI. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol. 2013 May;14(6):552-62. doi: 10.1016/S1470-2045(13)70093-7. Epub 2013 Apr 16. Erratum In: Lancet Oncol. 2013 Jun;14(7):e254.
• Cella D, Escudier B, Rini B, Chen C, Bhattacharyya H, Tarazi J, Rosbrook B, Kim S, Motzer R. Patient-reported outcomes for axitinib vs sorafenib in metastatic renal cell carcinoma: phase III (AXIS) trial. Br J Cancer. 2013 Apr 30;108(8):1571-8. doi: 10.1038/bjc.2013.145. Epub 2013 Apr 11.
• Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, Michaelson MD, Gorbunova VA, Gore ME, Rusakov IG, Negrier S, Ou YC, Castellano D, Lim HY, Uemura H, Tarazi J, Cella D, Chen C, Rosbrook B, Kim S, Motzer RJ. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011 Dec 3;378(9807):1931-9. doi: 10.1016/S0140-6736(11)61613-9. Epub 2011 Nov 4. Erratum In: Lancet. 2012 Nov 24;380(9856):1818.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 19, 2011): 723
• Original Estimated Enrollment (submitted: May 12, 2008): 540
• Actual Study Completion Date: February 25, 2016
• Actual Primary Completion Date: August 31, 2010 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Histologically or cytologically confirmed renal cell cancer with a component of clear cell subtype, with metastasis
• Evidence of measurable disease
• Must have failed one prior systemic first-line regimen for metastatic renal cell cancer

Exclusion Criteria:

• Prior treatment for metastatic renal cell cancer with more that one systemic first line therapy
• Major surgery less than 4 weeks or radiation less than 2 weeks of starting study drug

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Brazil, Canada, China, France, Germany, Greece, India, Ireland, Italy, Japan, Korea, Republic of, Poland, Russian Federation, Singapore, Slovakia, Spain, Sweden, Taiwan, United Kingdom, United States
• Removed Location Countries: Netherlands

Administrative Information

• NCT Number: NCT00678392
• Other Study ID Numbers: A4061032; AXIS TRIAL; 2008-001451-21 ( EudraCT Number ); AXIS ( Other Identifier: Alias Study Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
• URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

• Current Responsible Party: Pfizer
• Original Responsible Party: Director, Clinical Trial Disclosure Group, Pfizer, Inc.
• Current Study Sponsor: Pfizer
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

• PRS Account: Pfizer
• Verification Date: December 2018