Clinical Trial Results:
A study of pazopanib efficacy and safety in patients with advanced clear-cell renal cell carcinoma and ECOG Performance Status 2 (PaZ02)
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Summary
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EudraCT number |
2011-001211-31 |
Trial protocol |
GB |
Global end of trial date |
30 Jun 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
09 Oct 2020
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First version publication date |
09 Oct 2020
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
RG_10-177
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Additional study identifiers
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ISRCTN number |
ISRCTN38957238 | ||
US NCT number |
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WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
University of Birmingham
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Sponsor organisation address |
Edgbaston, Birmingham, United Kingdom, B15 2TT
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Public contact |
Dr Birgit Whitman, University of Birmingham, researchgovernance@contacts.bham.ac.uk
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Scientific contact |
Cancer Research UK Clinical Trials Unit (CRCTU) , University of Birmingham, crctu-generalenquiries@trials.bham.ac.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
10 Sep 2020
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
30 Jun 2019
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The main objective of our clinical trial is to find out whether treatment with a drug called pazopanib is beneficial and safe for patients with advanced renal cancer and poor clinical condition (‘poor performance status’). These patients are often deemed not fit for treatment because of their poor prognosis and because of their perceived inability to withstand the side effects of the therapy. The treatments currently available cause severe side effects in two thirds of the patients and may require frequent hospital visits. By contrast pazopanib has demonstrated a significant efficacy and is well tolerated therefore it may represent a valuable treatment option for renal cancer patients with poor performance status. To assess treatment efficacy we will study in what percentage of patients pazopanib is able to prevent further tumour growth for at least 6 months; to assess safety we will study the ratio of patients who develop severe, drug induced, toxicity.
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Protection of trial subjects |
This study was conducted in conformance with Good Clinical Practice standards and applicable regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research. Site staff received GCP and trial specific training prior to recruiting patients to the study. A Data Monitoring Committee reviewed patient safety data throughout the trial.
Additional measures were taken during the course of the study to monitor subject safety: (1) Medical history prior to registration to identify safety-related exclusion criteria, (2) Continuous assessment of adverse events and serious adverse events, (2) Haematology, biochemistry laboratory tests and urine dipstick test at regular intervals (2 weekly for the first 8 weeks, monthly thereafter during pazopanib treatment) (3) 8 weekly ECG with QTc measurement, (4) full review of body system through physical examination and vital signs assessment (2 weekly for the first 8 weeks, monthly thereafter during pazopanib treatment).
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Background therapy |
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Evidence for comparator |
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Actual start date of recruitment |
24 Aug 2012
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 75
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Worldwide total number of subjects |
75
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EEA total number of subjects |
75
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
21
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From 65 to 84 years |
53
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85 years and over |
1
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Recruitment
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Recruitment details |
26 UK sites took part in the study. The trial opened to recruitment in August 2012. The first participant was recruited into the trial on 21-Feb-2013. The recruitment rate was slower than anticipated and the trial reached its target of 75 patients in 42 months, with the last subject recruited on 12-Aug-2016. | ||||||||||||||
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Pre-assignment
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Screening details |
Formal screening logs were requested. A total of 255 patients were considered for the trial, of these 75 were recruited and 180 subjects excluded. Main reasons for exclusion: 121 patients did not meet all entry criteria; 25 declined to participate; 27 were excluded for other clinical reasons; no reason was given for 7 patients. | ||||||||||||||
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Period 1
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Period 1 title |
Overall period
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Is this the baseline period? |
Yes | ||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||
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Arms
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Arm title
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Pazopanib | ||||||||||||||
Arm description |
Patients who commenced Pazopanib treatment | ||||||||||||||
Arm type |
Experimental | ||||||||||||||
Investigational medicinal product name |
Pazopanib
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Investigational medicinal product code |
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Other name |
Votrient
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
800 mg OD, continuous dosing.
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Baseline characteristics reporting groups
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Reporting group title |
Overall period
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Pazopanib
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Reporting group description |
Patients who commenced Pazopanib treatment | ||
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End point title |
Tolerability [1] | ||||||
End point description |
Tolerability is defined as the proportion of patients who have not developed 'intolerable' adverse events within 183 days (6 months) from the date of registration.
Adverse events deemed 'Intolerable' must meet all the following criteria:
1. Grade 3 or 4 according to CTCAE version 4 AND
2. Rated as being possible, probably or definitely related to Pazopanib by the investigator AND
3. Result in either a Serious Adverse Event (SAE) OR discontinuation of pazopanib for a period greater than 21 days.
In cases where the adverse event meeting criteria 1 and 2 result in an SAE, the date of onset of the SAE is used as the date deemed intolerable. For those which result in pazopanib discontinuation, the first day that treatment was stopped is the intolerable date.
Patients who died prior to completing 6 months of treatment without having an event which meets the tolerability criteria are counted as tolerable and included in the denominator.
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End point type |
Primary
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End point timeframe |
183 days (6 months) from the date of registration
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This is a single arm phase II study looking at efficacy and toxicity. No statistical hypothesis testing was planned. |
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| No statistical analyses for this end point | |||||||
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End point title |
Efficacy [2] | ||||||
End point description |
Efficacy is the proportion of patients who are radiologically progression free and alive at 6 months.
Progression is defined in terms of RECIST 1.1 and it is also assumed that all deaths will be disease related and thus constitute progression. If multiple scans are done within the time frame the closest to day 183 will be used.
If no scan occurs within this time frame and the patient is alive and no prior progression has been reported then the following rules will be applied to determine whether the patient should be excluded from the analysis.
• In addition to the baseline scan if the patient has two scans (one before the time frame and one after) that show the same response this will be taken as the response at 6 months and used in the analysis
• If the patient does not have scan either side of the time frame or if the response on those scans differs then it is impossible to say with any certainty what the response was at 6 months and this patient will be excluded.
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End point type |
Primary
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End point timeframe |
The efficacy part of the primary outcome is reliant on recist data obtained from a scan at 6 months (183 days) post registration. A window of between 162 and 204 days is allowed for the scan to take place.
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This is a single arm phase II study looking at efficacy and toxicity. No statistical hypothesis testing was planned. |
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| No statistical analyses for this end point | |||||||
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End point title |
Response Rate | ||||||
End point description |
This is defined as the proportion of patients who achieve a Complete or Partial radiological response during the study.
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End point type |
Secondary
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End point timeframe |
Any point during the study
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| No statistical analyses for this end point | |||||||
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End point title |
Clinical Benefit Rate | ||||||
End point description |
The proportion of patients achieving Complete Response, Partial Response or Stable Disease during the study.
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End point type |
Secondary
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End point timeframe |
Any point during the study
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| No statistical analyses for this end point | |||||||
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End point title |
Progression free survival time | ||||||||
End point description |
Defined as the number of whole days from the date of registration until evidence of radiological disease progression or death from any cause. Patients who are alive and progression free will be censored at the date last known to be progression free.
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End point type |
Secondary
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End point timeframe |
Patients were followed for a minimum of 2 years post registration
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Attachments |
Untitled (Filename: PFS.pdf) |
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End point title |
Overall Survival time | ||||||||
End point description |
Defined as the number of whole days between the date of registration until death from any cause. Patients who are alive at the end of the study will be censored at the date last know to be alive.
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End point type |
Secondary
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End point timeframe |
Any time during the trial
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Attachments |
Untitled (Filename: OS.pdf) |
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| No statistical analyses for this end point | |||||||||
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End point title |
Treatment Duration | ||||||||
End point description |
Dose intensity is defined as the total dose of Pazopanib prescribed to each patients as a proportion of the planned protocol dose of 800mg per day for the 6 months during which time treatment tolerability was assessed.
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End point type |
Secondary
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End point timeframe |
Within 6 months of registration
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| No statistical analyses for this end point | |||||||||
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End point title |
Duration of Response | ||||||||
End point description |
Number of whole days from the date complete or partial response is determined by RECIST to the date of progression determined by RECIST.
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End point type |
Secondary
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End point timeframe |
Registration to end of follow up
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| No statistical analyses for this end point | |||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Details of all AEs grade as CTCAE grade 3 or higher were documented and reported from the date signed consent was given until 30 days after the last administration of trial pazopanib.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
CTCAE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
4.0
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Reporting groups
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Reporting group title |
Pazopanib
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 4% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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10 Feb 2012 |
Updated definition of Efficacy primary outcome measure: Proportion of patients who are progression free and alive at 6 months. |
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22 May 2012 |
Screening Bone scan, CT scan Head and CT scan Chest/Abdomen/Pelvis allowed within 4 weeks of registration (previously within 2 weeks). |
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13 Jul 2012 |
Change in protocol version numbering from 1.3 to 4 without changes in content. |
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04 Oct 2012 |
Table on page 21 amended to specify that informed consent must be obtained within 4 weeks of registration rather than 2. |
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30 Jan 2013 |
Bone Scan, CT Scan Head, and CT scan Chest/Abdo/Pelvis allowed within 6 weeks of registration (previously within 4 weeks) |
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30 May 2013 |
Addition of serum liver test monitoring at week 3 (ALT, AST and total bilirubin).
Bone scan and CT scan head now to be performed as clinically indicated (within 6 weeks prior to registration if being performed) rather than as mandatory at baseline.
Clarification that assessments conducted as standard of care do not require informed consent and
may be provided as screening data if conducted within the stipulated number of weeks prior to registration.
Clarification that scans can be performed up to 5 days prior to the treatment week visit.
Requirement for dynamic phase contrast enhanced CT scans removed, CT scans should be performed as per local practice. |
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04 Dec 2013 |
Term "Clinically relevant" changed to ‘intolerable event’ to avoid confusions.
Slight change in the definition of the primary endpoint. The wording ‘Adverse events which result in a decrease of the patient’s performance status’ has been removed from the definition of an ‘intolerable event’. The wording ‘lead to a drug discontinuation of greater than 3 weeks’ has been added to the definition of an intolerable event.
Addition to permitted concomitant medications to be used with caution w(PPIs, H2-H2-antagonists and antacids).
Update to the End of trial definition: The end of trial will be at the point when all patients have a minimum of 12 months follow-up from registration or until death.
Several typo corrections. |
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03 Nov 2016 |
Changes to trial personnel.
Trial Office telephone number updated.
Recruitment period extended until August 2016.
References to Novartis changed to GSK.
Change to drug supply to either clinical trial or commercial supply.
Inclusion of a 3 day window for treatment visit dates.
Change to scan schedule from 8 weekly for the duration of the trial to 12 weekly from week 52 onwards.
Revised toxicity management relating to Liver toxicities (specific Treatment Emergent Hepatotoxicity can result in the patient having to be dose reduced to 400mg without having a step of 600mg).
Blood sub-study removed.
Amended definition of Adverse Events to reflect change in collection of abnormal laboratory values.
Inclusion of updated TNM staging information |
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19 Jun 2017 |
Change to trial personnel and telephone contact number for urgent clinical queries.
Definition of Tolerability changed from ratio to proportion of patients who are free from grade 3-
grade 4 adverse events which are drug related and classified as an ‘intolerable event’.
References to primary and secondary endpoints changed to outcomes.
Removal of reference to Trial Steering Committee (TSC) throughout.
Amended trial duration: Change of follow up from 12 months after last dose of Pazopanib to until 31st December 2018 to allow for a minimum of 24 months follow up for all patients.
Clarification that all patients will be followed up until end of trial follow up period.
Amended End of trial definition to until all patients have been followed up until death or 31st December 2018, whichever is sooner (previously at the point when all patients have a minimum of 12 months follow up from registration or until death).
Secondary outcomes analysis timepoint changed from when all patients have a minimum of 12 months follow up to when all patients have completed follow up. |
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12 Feb 2018 |
Change to form of commercially supplied study drug and clarification of IMP supply. |
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01 Mar 2019 |
Change of Chief Investigator.
Change in Data Protection Regulations.
Update to Trial Management team details. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
