Clinical Trial Results:
Phase I/II open label, dose escalation trial to determine the MTD, safety, PK and efficacy of afatinib
monotherapy in children aged ≥1 year to <18 years with recurrent/refractory neuroectodermal tumours, rhabdomyosarcoma and/or other solid tumours with known ErbB pathway deregulation regardless of tumour histology
Summary
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EudraCT number |
2014-002123-10 |
Trial protocol |
ES DE GB AT FR DK IT NL IE |
Global end of trial date |
05 Aug 2020
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Results information
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Results version number |
v1 |
This version publication date |
22 Feb 2021
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First version publication date |
22 Feb 2021
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Other versions |
v2 |
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 |
1200.120
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02372006 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Boehringer Ingelheim
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Sponsor organisation address |
Binger Str. 173, Ingelheim am Rhein, Germany, 55216
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Public contact |
Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
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Scientific contact |
Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-001596-PIP02-17 | ||
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 |
14 Oct 2020
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
05 Aug 2020
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Global end of trial reached? |
Yes
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Global end of trial date |
05 Aug 2020
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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 objective of the Phase I dose finding part was to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics of afatinib in paediatric patients across all applicable tumour entities.
The objective of the MTD expansion cohorts/Phase II part was to assess anti-tumour activity, safety, and pharmacokinetics of afatinib in a larger number of patients.
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Protection of trial subjects |
Prior to the initiation of any trial-related procedure, all patients´ parents/legally accepted
representatives were informed about the trial verbally and in writing by the investigator. The
parents/legally accepted representatives were allowed sufficient time to consider participation
in the trial and to ask questions concerning the details of the trial. Because a high rate of screening failures was expected for the MTD expansion
cohorts/Phase II part, a pre-screening informed consent was allowed to be used to enable
collection and testing of tumour tissue for ErbB deregulations. Upon confirmation of
positivity for selection biomarkers and before proceeding with trial procedures, the informed
consent/assent for trial entry had to be signed. The patient’s parents/legally accepted representatives and (where applicable) the patient were
informed that they were free to withdraw their consent at any time during the trial without
penalty or prejudice. They were informed that the patient’s personal trial-related data would
be considered confidential and used by BI in accordance with the local data protection laws.
The level of disclosure was explained to the parents/legally accepted representatives. The 397 enrolled participants in age category of "In Utero" was actually with age missing.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
22 May 2015
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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 |
Australia: 6
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Country: Number of subjects enrolled |
Austria: 12
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Country: Number of subjects enrolled |
Canada: 33
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Country: Number of subjects enrolled |
Denmark: 39
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Country: Number of subjects enrolled |
France: 102
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Country: Number of subjects enrolled |
Germany: 8
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Country: Number of subjects enrolled |
Italy: 71
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Country: Number of subjects enrolled |
Netherlands: 4
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Country: Number of subjects enrolled |
Spain: 44
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Country: Number of subjects enrolled |
United States: 51
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Country: Number of subjects enrolled |
United Kingdom: 193
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Worldwide total number of subjects |
563
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EEA total number of subjects |
280
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Number of subjects enrolled per age group |
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In utero |
397
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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) |
96
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Adolescents (12-17 years) |
68
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Adults (18-64 years) |
2
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Phase I/II open label, dose escalation trial to determine the MTD, safety, PK and efficacy of afatinib monotherapy in children aged ≥1 year to <18 years with recurrent/refractory neuroectodermal tumours, rhabdomyosarcoma and/or other solid tumours with known ErbB pathway deregulation regardless of tumour histology. | ||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all patients as required. | ||||||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||||||||
Blinding implementation details |
This study is open label
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Dose finding - level 0 | ||||||||||||||||||||||||||||||||||||
Arm description |
Afatinib, dose level 0. (Once daily at 80% of the recommended adult dose per m2 body surface area using allometric scaling): Oral solid single-unit film-coated tablets for pediatric patients who are able to swallow them. Oral liquid formulation for patients who cannot swallow the film-coated tablets, or for doses which cannot be achieved by the film-coated tablets, or for pediatric patients who did not accept the film-coated tablets. Therapy with afatinib continued as long as the individual patient benefited from the therapy, did not develop secondary malignancy, and did not meet one of the criteria requiring withdrawal from treatment. Afatinib in film-coated tablet form can be given in tablets of 20, 30, 40 and 50 milligram (mg). The tablet dose is related to the free base equivalent to afatinib. The dose of afatinib as capsule and solvent for oral solution is given as a 200 mg capsule to be dissolved in aqueous solvent (2 capsules per 100 milliliter (ml) solvent) i.e. 4 mg per ml. | ||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Afatinib
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Film-coated tablet, Capsule, Powder and solvent for oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
Once daily at 80% of the recommended adult dose per m2 body surface area [BSA] using allometric scaling: Oral solid single-unit film-coated tablets for pediatric patients who are able to swallow them. Oral liquid formulation for patients who cannot swallow the film-coated tablets, or for doses which cannot be achieved by the film-coated tablets, or for pediatric patients who did not accept the film-coated tablets. Therapy continued as long as the individual patient benefited from the therapy, did not develop secondary malignancy, and did not meet one of the criteria requiring withdrawal from treatment. Afatinib in film-coated tablet from can be given in tablets of 20, 30, 40 and 50 mg. The dose in film-coated tablets is related to the free base equivalent to afatinib. The dose of afatinib as capsule and solvent for oral solution is given as a 200 mg capsule to be dissolved in aqueous solvent (2 capsules per 100 milliliter solvent) i.e. 4 milligram per milliliter.
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Arm title
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Dose finding - level 1 | ||||||||||||||||||||||||||||||||||||
Arm description |
Afatinib, dose level 1. (Once daily at 100% of the recommended adult dose per m2 body surface area using allometric scaling): Oral solid single-unit film-coated tablets for pediatric patients who are able to swallow them. Oral liquid formulation for patients who cannot swallow the film-coated tablets, or for doses which cannot be achieved by the film-coated tablets, or for pediatric patients who did not accept the film-coated tablets. Therapy with afatinib continued as long as the individual patient benefited from the therapy, did not develop secondary malignancy, and did not meet one of the criteria requiring withdrawal from treatment. Afatinib in film-coated tablet form can be given in tablets of 20, 30, 40 and 50 milligram (mg). The tablet dose is related to the free base equivalent to afatinib. The dose of afatinib as capsule and solvent for oral solution is given as a 200 mg capsule to be dissolved in aqueous solvent (2 capsules per 100 milliliter (ml) solvent) i.e. 4 mg per ml. | ||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Afatinib
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Film-coated tablet, Capsule, Powder and solvent for oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
Once daily at 100% of the recommended adult dose per m2 body surface area [BSA] using allometric scaling: Oral solid single-unit film-coated tablets for pediatric patients who are able to swallow them. Oral liquid formulation for patients who cannot swallow the film-coated tablets, or for doses which cannot be achieved by the film-coated tablets, or for pediatric patients who did not accept the film-coated tablets. Therapy continued as long as the individual patient benefited from the therapy, did not develop secondary malignancy, and did not meet one of the criteria requiring withdrawal from treatment. Afatinib in film-coated tablet from can be given in tablets of 20, 30, 40 and 50 mg. The dose in film-coated tablets is related to the free base equivalent to afatinib. The dose of afatinib as capsule and solvent for oral solution is given as a 200 mg capsule to be dissolved in aqueous solvent (2 capsules per 100 milliliter solvent) i.e. 4 milligram per milliliter.
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Arm title
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Maximum tolerated dose (MTD) expansion cohort - level 0 | ||||||||||||||||||||||||||||||||||||
Arm description |
Afatinib, dose level 0. (Once daily at 80% of the recommended adult dose per m2 body surface area using allometric scaling): Oral solid single-unit film-coated tablets for pediatric patients who are able to swallow them. Oral liquid formulation for patients who cannot swallow the film-coated tablets, or for doses which cannot be achieved by the film-coated tablets, or for pediatric patients who did not accept the film-coated tablets. Therapy with afatinib continued as long as the individual patient benefited from the therapy, did not develop secondary malignancy, and did not meet one of the criteria requiring withdrawal from treatment. Afatinib in film-coated tablet form can be given in tablets of 20, 30, 40 and 50 milligram (mg). The tablet dose is related to the free base equivalent to afatinib. The dose of afatinib as capsule and solvent for oral solution is given as a 200 mg capsule to be dissolved in aqueous solvent (2 capsules per 100 milliliter (ml) solvent) i.e. 4 mg per ml. | ||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Afatinib
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Film-coated tablet, Capsule, Powder and solvent for oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
Once daily at 80% of the recommended adult dose per m2 body surface area [BSA] using allometric scaling: Oral solid single-unit film-coated tablets for pediatric patients who are able to swallow them. Oral liquid formulation for patients who cannot swallow the film-coated tablets, or for doses which cannot be achieved by the film-coated tablets, or for pediatric patients who did not accept the film-coated tablets. Therapy continued as long as the individual patient benefited from the therapy, did not develop secondary malignancy, and did not meet one of the criteria requiring withdrawal from treatment. Afatinib in film-coated tablet from can be given in tablets of 20, 30, 40 and 50 mg. The dose in film-coated tablets is related to the free base equivalent to afatinib. The dose of afatinib as capsule and solvent for oral solution is given as a 200 mg capsule to be dissolved in aqueous solvent (2 capsules per 100 milliliter solvent) i.e. 4 milligram per milliliter.
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Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one dose of the trial medication. |
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Baseline characteristics reporting groups
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Reporting group title |
Dose finding - level 0
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Reporting group description |
Afatinib, dose level 0. (Once daily at 80% of the recommended adult dose per m2 body surface area using allometric scaling): Oral solid single-unit film-coated tablets for pediatric patients who are able to swallow them. Oral liquid formulation for patients who cannot swallow the film-coated tablets, or for doses which cannot be achieved by the film-coated tablets, or for pediatric patients who did not accept the film-coated tablets. Therapy with afatinib continued as long as the individual patient benefited from the therapy, did not develop secondary malignancy, and did not meet one of the criteria requiring withdrawal from treatment. Afatinib in film-coated tablet form can be given in tablets of 20, 30, 40 and 50 milligram (mg). The tablet dose is related to the free base equivalent to afatinib. The dose of afatinib as capsule and solvent for oral solution is given as a 200 mg capsule to be dissolved in aqueous solvent (2 capsules per 100 milliliter (ml) solvent) i.e. 4 mg per ml. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Dose finding - level 1
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Reporting group description |
Afatinib, dose level 1. (Once daily at 100% of the recommended adult dose per m2 body surface area using allometric scaling): Oral solid single-unit film-coated tablets for pediatric patients who are able to swallow them. Oral liquid formulation for patients who cannot swallow the film-coated tablets, or for doses which cannot be achieved by the film-coated tablets, or for pediatric patients who did not accept the film-coated tablets. Therapy with afatinib continued as long as the individual patient benefited from the therapy, did not develop secondary malignancy, and did not meet one of the criteria requiring withdrawal from treatment. Afatinib in film-coated tablet form can be given in tablets of 20, 30, 40 and 50 milligram (mg). The tablet dose is related to the free base equivalent to afatinib. The dose of afatinib as capsule and solvent for oral solution is given as a 200 mg capsule to be dissolved in aqueous solvent (2 capsules per 100 milliliter (ml) solvent) i.e. 4 mg per ml. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Maximum tolerated dose (MTD) expansion cohort - level 0
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Reporting group description |
Afatinib, dose level 0. (Once daily at 80% of the recommended adult dose per m2 body surface area using allometric scaling): Oral solid single-unit film-coated tablets for pediatric patients who are able to swallow them. Oral liquid formulation for patients who cannot swallow the film-coated tablets, or for doses which cannot be achieved by the film-coated tablets, or for pediatric patients who did not accept the film-coated tablets. Therapy with afatinib continued as long as the individual patient benefited from the therapy, did not develop secondary malignancy, and did not meet one of the criteria requiring withdrawal from treatment. Afatinib in film-coated tablet form can be given in tablets of 20, 30, 40 and 50 milligram (mg). The tablet dose is related to the free base equivalent to afatinib. The dose of afatinib as capsule and solvent for oral solution is given as a 200 mg capsule to be dissolved in aqueous solvent (2 capsules per 100 milliliter (ml) solvent) i.e. 4 mg per ml. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Dose finding - level 0
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Reporting group description |
Afatinib, dose level 0. (Once daily at 80% of the recommended adult dose per m2 body surface area using allometric scaling): Oral solid single-unit film-coated tablets for pediatric patients who are able to swallow them. Oral liquid formulation for patients who cannot swallow the film-coated tablets, or for doses which cannot be achieved by the film-coated tablets, or for pediatric patients who did not accept the film-coated tablets. Therapy with afatinib continued as long as the individual patient benefited from the therapy, did not develop secondary malignancy, and did not meet one of the criteria requiring withdrawal from treatment. Afatinib in film-coated tablet form can be given in tablets of 20, 30, 40 and 50 milligram (mg). The tablet dose is related to the free base equivalent to afatinib. The dose of afatinib as capsule and solvent for oral solution is given as a 200 mg capsule to be dissolved in aqueous solvent (2 capsules per 100 milliliter (ml) solvent) i.e. 4 mg per ml. | ||
Reporting group title |
Dose finding - level 1
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Reporting group description |
Afatinib, dose level 1. (Once daily at 100% of the recommended adult dose per m2 body surface area using allometric scaling): Oral solid single-unit film-coated tablets for pediatric patients who are able to swallow them. Oral liquid formulation for patients who cannot swallow the film-coated tablets, or for doses which cannot be achieved by the film-coated tablets, or for pediatric patients who did not accept the film-coated tablets. Therapy with afatinib continued as long as the individual patient benefited from the therapy, did not develop secondary malignancy, and did not meet one of the criteria requiring withdrawal from treatment. Afatinib in film-coated tablet form can be given in tablets of 20, 30, 40 and 50 milligram (mg). The tablet dose is related to the free base equivalent to afatinib. The dose of afatinib as capsule and solvent for oral solution is given as a 200 mg capsule to be dissolved in aqueous solvent (2 capsules per 100 milliliter (ml) solvent) i.e. 4 mg per ml. | ||
Reporting group title |
Maximum tolerated dose (MTD) expansion cohort - level 0
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Reporting group description |
Afatinib, dose level 0. (Once daily at 80% of the recommended adult dose per m2 body surface area using allometric scaling): Oral solid single-unit film-coated tablets for pediatric patients who are able to swallow them. Oral liquid formulation for patients who cannot swallow the film-coated tablets, or for doses which cannot be achieved by the film-coated tablets, or for pediatric patients who did not accept the film-coated tablets. Therapy with afatinib continued as long as the individual patient benefited from the therapy, did not develop secondary malignancy, and did not meet one of the criteria requiring withdrawal from treatment. Afatinib in film-coated tablet form can be given in tablets of 20, 30, 40 and 50 milligram (mg). The tablet dose is related to the free base equivalent to afatinib. The dose of afatinib as capsule and solvent for oral solution is given as a 200 mg capsule to be dissolved in aqueous solvent (2 capsules per 100 milliliter (ml) solvent) i.e. 4 mg per ml. |
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End point title |
Area under the curve over dosing interval τ at steady state (AUCτ, ss) - Dose finding part [1] [2] | ||||||||||||
End point description |
Area under the curve over dosing interval τ at steady state (AUCτ,ss) was reported. Pharmacokinetics (PK) analysis set (PKS): This patient set included all patients in the TS who provided at least one PK endpoint that was not excluded due to a protocol
deviation relevant to the evaluation of PK or due to PK non-evaluability.
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End point type |
Primary
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End point timeframe |
Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration at steady state on Day 8.
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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 endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested. [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported. |
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No statistical analyses for this end point |
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End point title |
Maximum measured concentration of the analyte in plasma at steady state (Cmax,ss) - Dose finding part [3] [4] | ||||||||||||
End point description |
Maximum measured concentration of the analyte in plasma at steady state (Cmax,ss) - Dose finding part was reported. Pharmacokinetics (PK) analysis set (PKS): This patient set included all patients in the TS who provided at least one PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Only participants with non-missing results were included in the analysis.
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End point type |
Primary
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End point timeframe |
Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration at steady state on Day 8.
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Notes [3] - 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 endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested. [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported. |
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No statistical analyses for this end point |
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End point title |
Number of participants with objective response - maximum tolerated dose (MTD) expansion cohort [5] [6] | ||||||
End point description |
Number of participants with objective response in maximum tolerated dose (MTD) expansion cohort was reported. The objective response was defined as a best overall response of complete response or partial response based on investigator’s assessment according to the institutional response evaluation criteria for the given tumour type, assessed every 8 weeks until progression. Treated set (TS): This patient set included all patients enrolled in the trial who were documented to have taken at least one dose of study medication.
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End point type |
Primary
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End point timeframe |
Assessed every 8 weeks until progression of disease, up to 336 days.
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Notes [5] - 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 endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested. [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported. |
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No statistical analyses for this end point |
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End point title |
Number of participants with Dose Limiting Toxicity adverse events - Dose finding part [7] [8] | |||||||||
End point description |
Number of participants with Dose Limiting Toxicity adverse events in Dose finding part was reported. Treated set (TS) This patient set included all patients enrolled in the trial who were documented to have taken at least one dose of study medication.
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End point type |
Primary
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End point timeframe |
During the first course (28 days) of treatment.
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Notes [7] - 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 endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested. [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported. |
||||||||||
|
||||||||||
No statistical analyses for this end point |
|
||||||||||
End point title |
Number of participants with objective response - Dose finding part [9] | |||||||||
End point description |
Number of participants with objective response in Dose finding part was reported. The objective response was defined as a best overall response of complete response or partial response based on investigator’s assessment according to the institutional response evaluation criteria for the given tumour type, assessed every 8 weeks until progression. Treated set (TS): This patient set included all patients enrolled in the trial who were documented to have taken at least one dose of study medication.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Assessed every 8 weeks until progression of disease, up to 336 days.
|
|||||||||
Notes [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported. |
||||||||||
|
||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 24 hours (AUC0-24) - Dose finding part [10] | ||||||||||||
End point description |
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 24 hours (AUC0-24) for Dose finding part was reported. Pharmacokinetics (PK) analysis set (PKS): This patient set included all patients in the TS who provided at least one PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Only participants with non-missing results were included in the analysis.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration on Day 1.
|
||||||||||||
Notes [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Maximum measured concentration (Cmax) - Dose finding part/maximum tolerated dose (MTD) expansion cohort | ||||||||||||||||
End point description |
Maximum measured concentration (Cmax) for Dose finding part/maximum tolerated dose expansion cohort was reported. Pharmacokinetics (PK) analysis set (PKS): This patient set included all patients in the TS who provided at least one PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Only participants with non-missing results were included in the analysis.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration on Day 1.
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Time from (last) dosing to the maximum measured concentration (tmax) - Dose finding part/maximum tolerated dose (MTD) expansion cohort | ||||||||||||||||
End point description |
Times from (last) dosing to the maximum measured concentration (tmax) for Dose finding oart/maximum tolerated dose (MTD) expansion cohort was reported. Pharmacokinetics (PK) analysis set (PKS): This patient set included all patients in the TS who provided at least one PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Only participants with non-missing results were included in the analysis.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration on Day 1.
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Time from (last) dosing to the maximum measured concentration at steady state (tmax,ss) - Dose finding part/maximum tolerated dose (MTD) expansion cohort | ||||||||||||||||
End point description |
Time from (last) dosing to the maximum measured concentration at steady state (tmax,ss) for Dose finding part/maximum tolerated dose (MTD) expansion cohort was reported. Pharmacokinetics (PK) analysis set (PKS): This patient set included all patients in the TS who provided at least one PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Only participants with non-missing results were included in the analysis.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration at steady state on Day 8.
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Progression free survival - maximum tolerated dose (MTD) expansion cohort [11] | ||||||||
End point description |
Progression free survival for maximum tolerated dose (MTD) expansion cohort was reported. Progression free survival (PFS) was defined as the duration from the date of first treatment until the date of the first documented progression or death due to any cause. If a patient did not have an event, PFS was censored at the date of last adequate tumour assessment. Median PFS was estimated by Kaplan-Meier. Treated set (TS) This patient set included all patients enrolled in the trial who were documented to have taken at least one dose of study medication.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From the first treatment until date of first progression or death, up to 336 days.
|
||||||||
Notes [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Accumulation (or effective) half-life - Dose finding part/maximum tolerated dose (MTD) expansion cohort | ||||||||||||||||
End point description |
Accumulation (or effective) half-life for Dose finding part/maximum tolerated dose (MTD) expansion cohort was reported. Pharmacokinetics (PK) analysis set (PKS): This patient set included all patients in the TS who provided at least one PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Only participants with non-missing results were included in the analysis.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration at steady state on Day 8.
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Duration of objective response - maximum tolerated dose (MTD) expansion cohort [12] | ||||||||
End point description |
Duration of objective response for maximum tolerated dose (MTD) expansion cohort was reported. Treated set (TS) This patient set included all patients enrolled in the trial who were documented to have taken at least one dose of study medication.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From first documented response until the earliest of disease progression or death, up to 336 days.
|
||||||||
Notes [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Area under the curve over dosing interval τ at steady state (AUCτ, ss) - maximum tolerated dose (MTD) expansion cohort [13] | ||||||||
End point description |
Area under the curve over dosing interval τ at steady state (AUCτ, ss) for maximum tolerated dose (MTD) expansion cohort was reported. Pharmacokinetics (PK) analysis set (PKS): This patient set included all patients in the TS who provided at least one PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Only participants with non-missing results were included in the analysis.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration at steady state on Day 8.
|
||||||||
Notes [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Maximum measured concentration of the analyte in plasma at steady state (Cmax,ss) - maximum tolerated dose (MTD) expansion cohort [14] | ||||||||
End point description |
Maximum measured concentration of the analyte in plasma at steady state (Cmax,ss) for maximum tolerated dose (MTD) expansion cohort was reported. Pharmacokinetics (PK) analysis set (PKS): This patient set included all patients in the TS who provided at least one PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Only participants with non-missing results were included in the analysis.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration at steady state on Day 8.
|
||||||||
Notes [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
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Timeframe for reporting adverse events |
From the first drug administration until end of study period, up to 336 days.
|
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Adverse event reporting additional description |
Treated set (TS) This patient set included all patients enrolled in the trial who were documented to have taken at least one dose of study medication.
|
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.0
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Reporting groups
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Reporting group title |
Dose finding Level 0
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Reporting group description |
Afatinib, dose level 0. (Once daily at 80% of the recommended adult dose per m2 body surface area using allometric scaling): Oral solid single-unit film-coated tablets for pediatric patients who are able to swallow them. Oral liquid formulation for patients who cannot swallow the film-coated tablets, or for doses which cannot be achieved by the film-coated tablets, or for pediatric patients who did not accept the film-coated tablets. Therapy with afatinib continued as long as the individual patient benefited from the therapy, did not develop secondary malignancy, and did not meet one of the criteria requiring withdrawal from treatment. Afatinib in film-coated tablet form can be given in tablets of 20, 30, 40 and 50 milligram (mg). The tablet dose is related to the free base equivalent to afatinib. The dose of afatinib as capsule and solvent for oral solution is given as a 200 mg capsule to be dissolved in aqueous solvent (2 capsules per 100 milliliter (ml) solvent) i.e. 4 mg per ml. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Maximum tolerated dose (MTD) expansion cohort - level 0
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Reporting group description |
Afatinib, dose level 0. (Once daily at 80% of the recommended adult dose per m2 body surface area using allometric scaling): Oral solid single-unit film-coated tablets for pediatric patients who are able to swallow them. Oral liquid formulation for patients who cannot swallow the film-coated tablets, or for doses which cannot be achieved by the film-coated tablets, or for pediatric patients who did not accept the film-coated tablets. Therapy with afatinib continued as long as the individual patient benefited from the therapy, did not develop secondary malignancy, and did not meet one of the criteria requiring withdrawal from treatment. Afatinib in film-coated tablet form can be given in tablets of 20, 30, 40 and 50 milligram (mg). The tablet dose is related to the free base equivalent to afatinib. The dose of afatinib as capsule and solvent for oral solution is given as a 200 mg capsule to be dissolved in aqueous solvent (2 capsules per 100 milliliter (ml) solvent) i.e. 4 mg per ml. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Dose finding Level 1
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Reporting group description |
Afatinib, dose level 1. (Once daily at 100% of the recommended adult dose per m2 body surface area using allometric scaling): Oral solid single-unit film-coated tablets for pediatric patients who are able to swallow them. Oral liquid formulation for patients who cannot swallow the film-coated tablets, or for doses which cannot be achieved by the film-coated tablets, or for pediatric patients who did not accept the film-coated tablets. Therapy with afatinib continued as long as the individual patient benefited from the therapy, did not develop secondary malignancy, and did not meet one of the criteria requiring withdrawal from treatment. Afatinib in film-coated tablet form can be given in tablets of 20, 30, 40 and 50 milligram (mg). The tablet dose is related to the free base equivalent to afatinib. The dose of afatinib as capsule and solvent for oral solution is given as a 200 mg capsule to be dissolved in aqueous solvent (2 capsules per 100 milliliter (ml) solvent) i.e. 4 mg per ml. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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04 May 2015 |
Addition of optional cerebrospinal fluid PK sampling: Assess afatinib penetration into the cerebrospinal fluid /
Implemented only after approval of the IRB/IEC/
Competent Authorities.
Addition of details on handling of
strong P-gp inhibitors/ inducers: Assure that MTD determination was not affected by the
use of strong P-gp inhibitors or inducers /
Implemented without IRB/IEC/Competent Authority
approval as changes involved logistical or
administrative aspects only. |
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18 Aug 2016 |
Clarifications, e.g. regarding the
possible use of a pre-screening
informed consent for the
collection and testing of tumour
tissue sample and collection of
tumour images during the
screening period. |
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02 Jun 2017 |
Change from Phase I trial to
adaptive Phase I/II design,
clarification of pre-screening
informed consent use and
alternative PK samplings. To comply with the Written Request received from
FDA and to follow the contraception guidance per ICH
M3 (R2)2 and HMA CTFG /
Implemented only after approval of the IRB/IEC/
Competent Authorities |
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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 |