Clinical Trial Results:
Phase II, randomized, open-label study of the IGF-1R inhibitor AXL1717 compared to docetaxel in patients with previously treated, locally advanced, or metastatic squamous cell carcinoma or adenocarcinoma of the lung
Summary
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EudraCT number |
2011-002007-15 |
Trial protocol |
HU |
Global end of trial date |
11 Nov 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
04 May 2016
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First version publication date |
04 May 2016
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Other versions |
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 |
AXL-003
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01561456 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Axelar AB
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Sponsor organisation address |
Karolinska Institutet Science Park, Fogdevreten 2, Solna, Sweden, 171 65
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Public contact |
Ulrika Wennberg, Axelar AB, +48 70 722 6332, ulrika.wennberg@axelar.se
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Scientific contact |
Ulrika Wennberg, Axelar AB, +48 70 722 6332, ulrika.wennberg@axelar.se
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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 |
23 Dec 2014
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
01 Sep 2013
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Global end of trial reached? |
Yes
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Global end of trial date |
11 Nov 2014
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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 |
To compare the rate of progression-free survival (PFS) at 12 weeks between patients treated with AXL1717 (AXL) and patients treated with docetaxel (DCT) in the total study population and in the squamous cell carcinoma (SCC) and adenocarcinoma (AC) subtypes of non-small cell lung cancer (NSCLC).
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Protection of trial subjects |
Good Clinical Practice; informed consent required; maximum 4 treatment cycles in primary treatment period; extension treatment offered to patients with stable disease or better, only if initiated by investigator; disease progression monitored regularly according to RECIST through death or end of study.
Following 12 deaths early in the study, enrollment was suspended while the cases were reviewed. Recommended changes to the protocol were implemented as Amendment 2. The opinion of the Data Safety Monitoring Committee (DSMC) was that steroids should be avoided in neutropenic patients because steroids may stimulate the growth of microorganisms by causing immunosuppression, may mask fever and symptoms of infection, and do not stimulate host defense against microorganisms. Prophylactic antibiotics should be used in all Grade 4 neutropenic patients, irrespective of the presence of fever or other symptoms. Guidelines with respect to prophylactic antibiotic treatment of neutropenic patients were provided to all centers. Guidelines from ASCO were also issued with respect to use of hematologic growth factors for treating neutropenia in patients in the AXL group. Neutropenic patients should be followed daily. The DSMC recommended direct contact between the patient and the study center for all future cases involving events of fever and/or neutropenia.
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Background therapy |
None. | ||
Evidence for comparator |
Docetaxel is standard therapy for advanced NSCLC. | ||
Actual start date of recruitment |
15 Dec 2011
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
14 Months | ||
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 |
Belarus: 2
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Country: Number of subjects enrolled |
Russian Federation: 28
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Country: Number of subjects enrolled |
Ukraine: 50
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Country: Number of subjects enrolled |
Hungary: 14
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Country: Number of subjects enrolled |
Poland: 5
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Worldwide total number of subjects |
99
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EEA total number of subjects |
19
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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) |
85
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From 65 to 84 years |
14
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85 years and over |
0
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Recruitment
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Recruitment details |
The first patient randomized on 27Dec2011. The last patient randomized on 29Apr2013. The recruitment put on hold on 19Jul2012 (until Protocol Amendment approved in each country) -due to additional safety actions in order to decrease the numbers of neutropenia development. During the study the patients were observed at multifunctional hospitals. | |||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
138 screened; 37 screen failures due to: hematology (7), non-measurable disease (RECIST) (6), randomization on hold (5), CNS malignancy (4), ECOG status >2 (2), mixed histology of NSCLC (2), infection/other major disease (2), coexisting medical condition (1), history of cancer in 5 years (1), lack of suitability for participation (1), other (6). | |||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
overall trial (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | |||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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AXL1717 | |||||||||||||||||||||||||||||||||
Arm description |
Test Arm; The Per Protocol set consisted of 101 randomized patients, 2 of whom were not treated (patient 101-008 withdrew consent; patient 305-007 was mistakenly randomized despite the presence of an exclusion criterion), and therefore the full analysis set (FAS) (also used for safety) consisted of 99 treated patients (58 AXL, 41 DCT). | |||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Picropodophyllin
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Investigational medicinal product code |
AXL1717(H2O)
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Other name |
AXL1717, BVT.51004, BVT.51004G
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Pharmaceutical forms |
Oral suspension
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Routes of administration |
Oral use
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Dosage and administration details |
300 mg or 400 mg BID (twice daily)
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Arm title
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Docetaxel | |||||||||||||||||||||||||||||||||
Arm description |
Active comparator | |||||||||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Docetaxel
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Standard 75 mg/m2 in 100 mL of normal saline solution with IV infusion over 60 minutes
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Baseline characteristics reporting groups
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Reporting group title |
AXL1717
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Reporting group description |
Test Arm; The Per Protocol set consisted of 101 randomized patients, 2 of whom were not treated (patient 101-008 withdrew consent; patient 305-007 was mistakenly randomized despite the presence of an exclusion criterion), and therefore the full analysis set (FAS) (also used for safety) consisted of 99 treated patients (58 AXL, 41 DCT). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Docetaxel
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Reporting group description |
Active comparator | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
AXL1717
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Reporting group description |
Test Arm; The Per Protocol set consisted of 101 randomized patients, 2 of whom were not treated (patient 101-008 withdrew consent; patient 305-007 was mistakenly randomized despite the presence of an exclusion criterion), and therefore the full analysis set (FAS) (also used for safety) consisted of 99 treated patients (58 AXL, 41 DCT). | ||
Reporting group title |
Docetaxel
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Reporting group description |
Active comparator |
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End point title |
Rate of PFS - by squamous cell carcinoma (SCC) subtype | |||||||||||||||
End point description |
The primary efficacy parameter in this study was the assessment of tumor response as evaluated by RECIST 1.1. The PFS rate was defined as the proportion of surviving, non-progressing patients at 12 weeks. Only patients with a tumor assessment performed during the protocol-defined window for the 12-week assessment were included in the analysis of the primary endpoint. To objective was to compare the rate of PFS at 12 weeks between patients treated with AXL1717 and patients treated with docetaxel in the total study population and in the squamous cell carcinoma (SCC) and adenocarcinoma (AC) subtypes of NSCLC.
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End point type |
Primary
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End point timeframe |
12 weeks following first dose of study drug
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Statistical analysis title |
The PFS rate - SCC subtype | |||||||||||||||
Statistical analysis description |
The PFS rate is defined as the proportion of surviving, non-progressing patients at 12 weeks. Only patients with a tumor assessment performed during the protocol-defined window for the 12-week assessment were included in the analysis of the primary endpoint.
The PFS rate and associated 95% confidence interval are presented for each treatment group. Difference in PFS rates between treatment groups are presented along with the exact 95% CI.
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Comparison groups |
AXL1717 v Docetaxel
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Number of subjects included in analysis |
50
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
= 0.213 | |||||||||||||||
Method |
Fisher exact | |||||||||||||||
Parameter type |
Risk difference (RD) | |||||||||||||||
Point estimate |
-17.4
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
-43.6 | |||||||||||||||
upper limit |
10.6 |
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End point title |
Rate of PFS - adenocarcinoma (AC) subtype | |||||||||||||||
End point description |
The primary efficacy parameter in this study was the assessment of tumor response as evaluated by RECIST 1.1. The PFS rate was defined as the proportion of surviving, non-progressing patients at 12 weeks. Only patients with a tumor assessment performed during the protocol-defined window for the 12-week assessment were included in the analysis of the primary endpoint. To objective was to compare the rate of PFS at 12 weeks between patients treated with AXL1717 and patients treated with docetaxel in the total study population and in the squamous cell carcinoma (SCC) and adenocarcinoma (AC) subtypes of NSCLC.
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End point type |
Primary
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End point timeframe |
12 weeks following first dose of study drug
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Statistical analysis title |
The PFS rate - AC subtype | |||||||||||||||
Statistical analysis description |
The PFS rate is defined as the proportion of surviving, non-progressing patients at 12 weeks. Only patients with a tumor assessment performed during the protocol-defined window for the 12-week assessment were included in the analysis of the primary endpoint.
The PFS rate and associated 95% confidence interval are presented for each treatment group. Difference in PFS rates between treatment groups are presented along with the exact 95% CI.
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Comparison groups |
Docetaxel v AXL1717
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Number of subjects included in analysis |
50
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
= 0.555 | |||||||||||||||
Method |
Fisher exact | |||||||||||||||
Parameter type |
Risk difference (RD) | |||||||||||||||
Point estimate |
-9
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
-36.7 | |||||||||||||||
upper limit |
19.2 |
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End point title |
Rate of PFS | |||||||||||||||
End point description |
The primary efficacy parameter in this study was the assessment of tumor response as evaluated by RECIST 1.1. The PFS rate was defined as the proportion of surviving, non-progressing patients at 12 weeks. Only patients with a tumor assessment performed during the protocol-defined window for the 12-week assessment were included in the analysis of the primary endpoint. To objective was to compare the rate of PFS at 12 weeks between patients treated with AXL1717 and patients treated with docetaxel in the total study population and in the squamous cell carcinoma (SCC) and adenocarcinoma (AC) subtypes of NSCLC.
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End point type |
Primary
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End point timeframe |
12 weeks following first dose of study drug
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Statistical analysis title |
The PFS rate at 12 weeks following first drug dose | |||||||||||||||
Statistical analysis description |
The PFS rate is defined as the proportion of surviving, non-progressing patients at 12 weeks. Only patients with a tumor assessment performed during the protocol-defined window for the 12-week assessment were included in the analysis of the primary endpoint.
The PFS rate and associated 95% confidence interval are presented for each treatment group. Difference in PFS rates between treatment groups are presented along with the exact 95% CI.
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Comparison groups |
AXL1717 v Docetaxel
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Number of subjects included in analysis |
99
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
= 0.191 | |||||||||||||||
Method |
Fisher exact | |||||||||||||||
Parameter type |
Risk difference (RD) | |||||||||||||||
Point estimate |
-13.2
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
-32.4 | |||||||||||||||
upper limit |
6.8 |
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End point title |
Survival rates | ||||||||||||||||||
End point description |
The survival rate was defined as the percentage of patients in the study who had survived for a period of time from randomization. The 12-week and 1-year survival rates and associated 95% CIs were planned for each treatment group. Differences in survival rates between treatment groups were to be presented along with the exact 95% CIs.
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End point type |
Secondary
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End point timeframe |
12 weeks and 1 year
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No statistical analyses for this end point |
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End point title |
Survival rates – SCC subtype | ||||||||||||||||||
End point description |
The survival rate was defined as the percentage of patients in the study who had survived for a period of time from randomization. The 12-week and 1-year survival rates and associated 95% CIs were planned for each treatment group. Differences in survival rates between treatment groups were to be presented along with the exact 95% CIs.
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End point type |
Secondary
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End point timeframe |
12 weeks and 1 year
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No statistical analyses for this end point |
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End point title |
Survival rates – AC subtype | ||||||||||||||||||
End point description |
The survival rate was defined as the percentage of patients in the study who had survived for a period of time from randomization. The 12-week and 1-year survival rates and associated 95% CIs were planned for each treatment group. Differences in survival rates between treatment groups were to be presented along with the exact 95% CIs.
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End point type |
Secondary
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End point timeframe |
12 weeks and 1 year
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No statistical analyses for this end point |
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End point title |
Overall survival | |||||||||||||||
End point description |
Overall survival was defined as the time from randomization to death from any cause. Patients who were lost to follow-up were censored at the date last known alive. Patients who were alive on the date of the data cut-off were censored at that date.
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End point type |
Secondary
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End point timeframe |
Through cutoff date of analyses.
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Attachments |
Untitled (Filename: Graphical Representation.pdf) |
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Statistical analysis title |
Kaplan-Meier estimate of median OS | |||||||||||||||
Statistical analysis description |
Overall survival was defined as the time from randomization to death from any cause. Patients who were lost to follow-up were censored at the date last known alive. Patients who were alive on the date of the data cut-off were censored at that date.
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Comparison groups |
Docetaxel v AXL1717
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Number of subjects included in analysis |
99
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
= 0.907 | |||||||||||||||
Method |
Logrank | |||||||||||||||
Confidence interval |
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End point title |
Overall survival – SCC subtype | |||||||||||||||
End point description |
Overall survival was defined as the time from randomization to death from any cause. Patients who were lost to follow-up were censored at the date last known alive. Patients who were alive on the date of the data cut-off were censored at that date.
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End point type |
Secondary
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End point timeframe |
Through cutoff date of analyses.
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Statistical analysis title |
Kaplan-Meier estimate of median OS – SCC subtype | |||||||||||||||
Statistical analysis description |
Overall survival was defined as the time from randomization to death from any cause. Patients who were lost to follow-up were censored at the date last known alive. Patients who were alive on the date of the data cut-off were censored at that date.
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Comparison groups |
AXL1717 v Docetaxel
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Number of subjects included in analysis |
50
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Analysis specification |
Pre-specified
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Analysis type |
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P-value |
= 0.626 | |||||||||||||||
Method |
Logrank | |||||||||||||||
Confidence interval |
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End point title |
Overall survival – AC subtype | |||||||||||||||
End point description |
Overall survival was defined as the time from randomization to death from any cause. Patients who were lost to follow-up were censored at the date last known alive. Patients who were alive on the date of the data cut-off were censored at that date.
Kaplan-Meier estimate of median OS, weeks [95% CI] for AC Subtype:
AXL1717 - 57.3 [ 18.0, NA]
Docetaxel - 24.8 [15.0, NA]
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End point type |
Secondary
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End point timeframe |
Through cutoff date of analyses.
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Notes [1] - AC subtype of NSCLC covers 29 subjects from AXL1717 group [2] - AC subtype of NSCLC covers 20 subjects from Decetaxel group |
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Statistical analysis title |
Kaplan-Meier estimate of median OS – AC subtype | |||||||||||||||
Statistical analysis description |
Overall survival was defined as the time from randomization to death from any cause. Patients who were lost to follow-up were censored at the date last known alive. Patients who were alive on the date of the data cut-off were censored at that date.
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Comparison groups |
AXL1717 v Docetaxel
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Number of subjects included in analysis |
49
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
= 0.745 | |||||||||||||||
Method |
Logrank | |||||||||||||||
Confidence interval |
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End point title |
Kaplan-Meier estimate of median PFS | |||||||||||||||
End point description |
Using the same definition as for the primary endpoint, PFS was defined as the time from randomization to the first observation of disease progression according to the RECIST criteria or death due to any cause.
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End point type |
Secondary
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End point timeframe |
Through cutoff date of analyses.
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Attachments |
Untitled (Filename: Graphical Representation_2.pdf) |
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Notes [3] - AC subtype of NSCLC covers 29 subjects from AXL1717 group [4] - AC subtype of NSCLC covers 20 subjects from Decetaxel group |
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Statistical analysis title |
Kaplan-Meier estimate of median PFS | |||||||||||||||
Statistical analysis description |
PFS was defined as the time from randomization to the first observation of disease progression according to the RECIST criteria or death due to any cause.
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Comparison groups |
AXL1717 v Docetaxel
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Number of subjects included in analysis |
49
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
= 0.615 | |||||||||||||||
Method |
Logrank | |||||||||||||||
Confidence interval |
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End point title |
Kaplan-Meier estimate of median PFS – SCC subtype | |||||||||||||||
End point description |
Using the same definition as for the primary endpoint, PFS was defined as the time from randomization to the first observation of disease progression according to the RECIST criteria or death due to any cause.
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End point type |
Secondary
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End point timeframe |
Through cutoff date of analyses.
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Attachments |
Untitled (Filename: Graphical Representation_3.pdf) |
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Statistical analysis title |
Kaplan-Meier estimate of median PFS – SCC subtype | |||||||||||||||
Comparison groups |
Docetaxel v AXL1717
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Number of subjects included in analysis |
50
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
= 0.082 | |||||||||||||||
Method |
Logrank | |||||||||||||||
Confidence interval |
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End point title |
Kaplan-Meier estimate of median PFS – AC subtype | |||||||||||||||
End point description |
Using the same definition as for the primary endpoint, PFS was defined as the time from randomization to the first observation of disease progression according to the RECIST criteria or death due to any cause.
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End point type |
Secondary
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End point timeframe |
Through cutoff date of analyses.
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Attachments |
Untitled (Filename: Graphical Representation_4.pdf) |
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Statistical analysis title |
Kaplan-Meier estimate of median PFS – AC subtype | |||||||||||||||
Statistical analysis description |
PFS was defined as the time from randomization to the first observation of disease progression according to the RECIST criteria or death due to any cause.
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Comparison groups |
AXL1717 v Docetaxel
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Number of subjects included in analysis |
49
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
= 0.615 | |||||||||||||||
Method |
Logrank | |||||||||||||||
Confidence interval |
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End point title |
Tumor response – combined local/central reader | |||||||||||||||||||||||||||||||||
End point description |
A secondary endpoint of the study was to compare the rate of CR, PR, SD, PD, disease control (CR + PR + SD), and objective response (CR + PR) at 12 weeks between the AXL and DCT groups in the total study population and in the SCC and AC subtypes. Results are presented combining the RECIST tumor response assessments of central readers and local readers.
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End point type |
Secondary
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End point timeframe |
12 weeks
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Statistical analysis title |
Tumor response – Combined Local/Central reader | |||||||||||||||||||||||||||||||||
Statistical analysis description |
Tumor response after four cycles will be summarized descriptively using response categories based on RECIST criteria: PD, SD, PR, CR, or Not Evaluable (NE). Separate analysis will be performed for Central reader and for Local reader data.
The rates for disease control and objective response will be calculated based on the best tumor response during four cycles.
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Comparison groups |
AXL1717 v Docetaxel
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Number of subjects included in analysis |
99
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||||||||||||||||||||
P-value |
= 0.063 | |||||||||||||||||||||||||||||||||
Method |
Fisher exact | |||||||||||||||||||||||||||||||||
Confidence interval |
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End point title |
Tumor response – combined local/central reader | ||||||||||||||||||
End point description |
A secondary endpoint of the study was to compare the rate of CR, PR, SD, PD, disease control (CR + PR + SD), and objective response (CR + PR) at 12 weeks between the AXL and DCT groups in the total study population and in the SCC and AC subtypes. Results are presented combining the RECIST tumor response assessments of central readers and local readers.
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End point type |
Secondary
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End point timeframe |
12 weeks.
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Statistical analysis title |
Tumor response – Combined Local/Central reader | ||||||||||||||||||
Statistical analysis description |
Tumor response after four cycles will be summarized descriptively using response categories based on RECIST criteria: PD, SD, PR, CR, or Not Evaluable (NE). Separate analysis will be performed for Central reader and for Local reader data.
The rates for disease control and objective response will be calculated based on the best tumor response during four cycles.
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Comparison groups |
AXL1717 v Docetaxel
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Number of subjects included in analysis |
99
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||
P-value |
= 0.063 | ||||||||||||||||||
Method |
Fisher exact | ||||||||||||||||||
Confidence interval |
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End point title |
Time to progression | |||||||||||||||
End point description |
Time to progression was defined as the time from randomization to the first observation of disease progression according to the RECIST criteria or death due to progression.
A patient who stopped treatment with the study drug and received alternative therapy prior to documentation of disease progression was censored on the date that the alternative therapy started. If a patient had not progressed, TTP was censored on the date of the last tumor assessment.
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End point type |
Secondary
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End point timeframe |
Through cutoff date of analyses.
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Attachments |
Untitled (Filename: Graphical Representation_5.pdf) |
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Statistical analysis title |
Time to progression | |||||||||||||||
Statistical analysis description |
Time to progression (TTP) is defined as the time from randomization to the first observation of disease progression according to the RECIST criteria or death due to progression.
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Comparison groups |
AXL1717 v Docetaxel
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Number of subjects included in analysis |
99
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
= 0.662 | |||||||||||||||
Method |
Logrank | |||||||||||||||
Confidence interval |
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End point title |
Time to treatment failure | |||||||||||||||
End point description |
Time to treatment failure was defined as the time from randomization to the first observation of discontinuation of treatment, PD, or death.
A patient who stopped treatment with the study drug and received alternative therapy prior to documentation of disease progression was censored on the date that the alternative therapy started. If a patient had not progressed, TTF was censored on the date of the last tumor assessment.
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End point type |
Secondary
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End point timeframe |
Through cutoff date of analyses.
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Statistical analysis title |
Time to treatment failure | |||||||||||||||
Statistical analysis description |
TTF is defined as the time from randomization to the first observation of discontinuation of treatment, PD or death.
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Comparison groups |
Docetaxel v AXL1717
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Number of subjects included in analysis |
99
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Analysis specification |
Pre-specified
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Analysis type |
other | |||||||||||||||
P-value |
= 0.129 | |||||||||||||||
Method |
Logrank | |||||||||||||||
Confidence interval |
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Adverse events information
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Timeframe for reporting adverse events |
Signing of informed consent through no later than 30 days after last date of study drug exposure.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
15,0
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Reporting groups
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Reporting group title |
AXL1717
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Reporting group description |
subjects who received AXL1717 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Docetaxel
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Reporting group description |
Subjects who received docetaxel | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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03 May 2012 |
Protocol Amendment 1 addressed safety concerns. A summary of changes included:
Added:
-additional biomarker evaluation
-clarification of inclusion criteria related to radiation therapy
-clarification to the exclusion criteria for men who are capable of fathering a child
-that AXL patients could be treated with WBC growth factors while in the study. Per Amendment 1, WBC growth factors could be used in the management of patients in the AXL group, according to ASCO guidelines. Investigators were encouraged to use G-CSF for treatment of nonfebrile Grade 3 neutropenia. Upon development of febrile neutropenia or nonfebrile Grade 4 neutropenia, G-CSF use was required in the AXL group
-an additional biopsy procedure and evaluation
-Appendix 2 to clarify the procedures for both AXL treatment groups
-additional safety testing to evaluate the need for dose delays or adjustments
-Appendix 9 to include TNM classification
-Appendix 10 for clarification of BSA calculation used for DCT dose calculation
-Appendix 11 for clarification of list of the CYP3A4 substrate with narrow therapeutic index and CYP2C9 inhibitors
Clarified
-parameters for WBC with or without differential counts to evaluate safety related to dose delays or interruptions
-AXL dose interruptions/adjustment procedures
-DCT dose procedures & dose interruption procedures
-protocol procedures for toxicity criteria for patient withdrawal
-patient withdrawal procedures
-local standard of care among clinical sites
-end of study procedures
-protocol procedures for exploratory assessments, AEs, clinical laboratory, and biomarker evaluations
Included a list of medications that were to be avoided
Provided an alternate treatment schedule based on safety
Patients receiving DCT were to be premedicated with corticosteroids to account for local standard of care among clinical sites
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07 Oct 2012 |
Protocol Amendment 2 addressed safety concerns and implemented clarifications throughout the protocol. Changes included:
• Clinical update summarizing recruitment, which was temporarily stopped on 19 July 2012 due to safety concerns, as noted above; dose-limiting events; and fatalities.
• Implemented a revised treatment regimen based on safety recommendation from the DSMC. The starting dose of AXL was reduced to 300 mg for the first 28 days; then, depending on ANC levels measured during the first 28 days, subsequent doses could be increased to 400 mg BID, remain at 300 mg BID, or be temporarily interrupted and, when ANC levels recovered to an acceptable level, be resumed at the same dose or 1 dose level lower.
• Revised the exclusion criteria based on safety recommendations from the DSMC. SCC patients with involvement of major vessels (diagnosis as confirmed by a radiologist) were excluded.
• Updated and provided additional safety data and information.
• Clarified storage and handling procedures for AXL.
• Implementation of procedural changes based on safety recommendations from the DSMC.
• Appendix 7 clarified guidelines for the use of WBC growth factors.
• Appendix 12 was added as a safety recommendation from the DSMB to provide standard recommendations and procedures for the management of patients who developed neutropenia while treated with AXL. Appendix 12 included guidelines for use of WBC growth factors in the treatment of patients in the AXL group.
After implementation of the amended protocol, 1 patient died due to an SAE of clinically suspected pneumonia with neutropenic sepsis. The DSMC investigated the case in detail and decided to recommend to permanently abandon the 400 mg BID dose for the remainder of the study. The 300 mg BID dose of AXL was thus instituted as the recommended Phase II dose for continuous treatment. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? Yes | |||||||
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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. | |||||||
Following implementation of Protocol Amendment 2, the Sponsor curtailed enrollment in the study from a planned 140 treated patients to the 99 patients described in this report. |