Clinical Trial Results:
Phase II pilot, prospective, open label, multicenter Clinical Trial, to evaluate the safety and efficacy of PF299804, a pan-HER irreversible inhibitor, in patients with recurrent glioblastoma with EGFR amplification or presence of EGFRvIII mutation

Trial information Top of page
Trial identification
Sponsor protocol code	GEINO-11
Additional study identifiers
ISRCTN number	-
US NCT number	NCT01520870
WHO universal trial number (UTN)	-
Sponsors
Sponsor organisation name	Grupo Español de Investigacion en NeuroOncología (GEINO)
Sponsor organisation address	C/ Balmes 243 5º 1º, Barcelona, Spain, 08006
Public contact	Pau Doñate, MFAR Clinical Research, investigacion@mfar.net
Scientific contact	Pau Doñate, MFAR Clinical Research, investigacion@mfar.net
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)	No
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Results analysis stage
Analysis stage	Final
Date of interim/final analysis	01 Jun 2017
Is this the analysis of the primary completion data?	Yes
Primary completion date	09 Mar 2017
Global end of trial reached?	Yes
Global end of trial date	09 Mar 2017
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	To assess progression-free survival (PFS) at six months (PFS6m) in patients with recurrent glioblastoma with EGFR amplification or presence of EGFRvIII mutation.
Protection of trial subjects	The protocol included measures to ensure the integrity and safety of all patients and the protection of their data according to the local regulations
Background therapy	-
Evidence for comparator	-
Actual start date of recruitment	28 Feb 2012
Long term follow-up planned	No
Independent data monitoring committee (IDMC) involvement?	No
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	Spain: 49
Worldwide total number of subjects	49
EEA total number of subjects	49
Number of subjects enrolled per age group
In utero	0
Preterm newborn - gestational age < 37 wk	0
Newborns (0-27 days)	0
Infants and toddlers (28 days-23 months)	0
Children (2-11 years)	0
Adolescents (12-17 years)	0
Adults (18-64 years)	29
From 65 to 84 years	20
85 years and over	0

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	Patients with first recurrence were enrolled in 2 cohorts. Cohort A included patients with EGFR gene amplification without EGFRvIII mutation. Cohort B included patients with EGFR gene amplification and EGFRvIII mutation.
Pre-assignment
Screening details	Patients over 18 years of age who had central review histologically confirmed recurrent GB with EGFR amplification (determined by fluorescence in situ hybridization [FISH] assay), also confirmed by central molecular pathology review, were eligible for the study.
Period 1
Period 1 title	Overall study (overall period)
Is this the baseline period?	Yes
Allocation method	Not applicable
Blinding used	Not blinded
Arms
Are arms mutually exclusive	Yes
Arm title	Cohort A
Arm description	patients with EGFR gene amplification without EGFRvIII mutation. Dacomitinib was administered (45 mg/day) until disease progression/unacceptable adverse events (AEs).
Arm type	Experimental
Investigational medicinal product name	Dacomintinib
Investigational medicinal product code
Other name
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	daily dose of 45mg orally
Arm title	Cohort B
Arm description	Patients with EGFR gene amplification and EGFRvIII mutation. Dacomitinib was administered (45 mg/day) until disease progression/unacceptable adverse events (AEs).
Arm type	Experimental
Investigational medicinal product name	Dacomintinib
Investigational medicinal product code
Other name
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	daily dose of 45mg orally
Number of subjects in period 1 Cohort A Cohort B Started 30 19 Completed 30 17 Not completed 0 2      Consent withdrawn by subject - 2

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	Cohort A
Reporting group description	patients with EGFR gene amplification without EGFRvIII mutation. Dacomitinib was administered (45 mg/day) until disease progression/unacceptable adverse events (AEs).
Reporting group title	Cohort B
Reporting group description	Patients with EGFR gene amplification and EGFRvIII mutation. Dacomitinib was administered (45 mg/day) until disease progression/unacceptable adverse events (AEs).
Reporting group values Cohort A Cohort B Total Number of subjects 30 19 49 Age categorical Units: Subjects     In utero 0     Preterm newborn infants (gestational age < 37 wks) 0     Newborns (0-27 days) 0     Infants and toddlers (28 days-23 months) 0     Children (2-11 years) 0     Adolescents (12-17 years) 0     Adults (18-64 years) 0     From 65-84 years 0     85 years and over 0 Age continuous Units: years     median (full range (min-max)) 62.5 (41 to 81) 52 (39 to 72) - Gender categorical Units: Subjects     Female 10 7 17     Male 20 12 32 ECOG performance status Units: Subjects     score 0 3 2 5     score 1 19 13 32     score 2 8 4 12 MGMT methylation Units: Subjects     unmethylated 7 10 17     Methylated 9 1 10     not determined 14 8 22 IDH mutations Units: Subjects     IDH1 mutant 2 0 2     IDH2 mutant 0 0 0     IDH1/2 not mutated 19 15 34     not determined 9 4 13

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	Cohort A
Reporting group description	patients with EGFR gene amplification without EGFRvIII mutation. Dacomitinib was administered (45 mg/day) until disease progression/unacceptable adverse events (AEs).
Reporting group title	Cohort B
Reporting group description	Patients with EGFR gene amplification and EGFRvIII mutation. Dacomitinib was administered (45 mg/day) until disease progression/unacceptable adverse events (AEs).

End points Top of page

Primary: Progression-free survival (PFS) Top of page
End point title	Progression-free survival (PFS) [1]
End point description
End point type	Primary
End point timeframe	Throughout the study period, 4 years. MRI was performed every 12 weeks to assess response to treatment according to RANO criteria.
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 was a single arm open-label phase II trial. All patients received the same treatment despite they were allocated in two arms according to their mutational status. No comparison between arms was planned.
End point values Cohort A Cohort B Number of subjects analysed 30 17 [2] Units: Months     median (confidence interval 95%) 2.7 (2.3 to 3.2) 2.6 (1.8 to 3.4)
Notes [2] - 2 patients were not evaluable due to consent withdrawal
No statistical analyses for this end point

Primary: Progression-free survival (PFS) Top of page

Secondary: Best Objective Response Top of page
End point title	Best Objective Response
End point description
End point type	Secondary
End point timeframe	Throughout the study, 4 years. MRI was performed every 12 weeks to assess response to treatment according to RANO criteria.
End point values Cohort A Cohort B Number of subjects analysed 30 19 Units: Patients     Complete response 1 0     Partial response 1 1     Stable disease 8 4     Progressive disease 17 13     not evaluable 3 1
No statistical analyses for this end point

Secondary: Best Objective Response Top of page

Secondary: Overall survival (OS) Top of page
End point title	Overall survival (OS)
End point description
End point type	Secondary
End point timeframe	Throughout the study period, 4 years
End point values Cohort A Cohort B Number of subjects analysed 30 17 [3] Units: Months     median (confidence interval 95%) 7.8 (5.6 to 10.1) 6.7 (4.3 to 9.1)
Notes [3] - 2 patients were not evaluable due to consent withdrawal
No statistical analyses for this end point

Secondary: Overall survival (OS) Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	Throughout the study, 4 years
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	NCI CTCAE
Dictionary version	4.0
Reporting groups
Reporting group title	Safety population
Reporting group description	All patients enrolled in the study and that received at least one dose of study treatment
Serious adverse events Safety population Total subjects affected by serious adverse events      subjects affected / exposed 16 / 49 (32.65%)      number of deaths (all causes) 43      number of deaths resulting from adverse events 0 General disorders and administration site conditions Asthenia      subjects affected / exposed 2 / 49 (4.08%)      occurrences causally related to treatment / all 2 / 2      deaths causally related to treatment / all 0 / 0 Gastrointestinal disorders Diarrhoea      subjects affected / exposed 3 / 49 (6.12%)      occurrences causally related to treatment / all 3 / 3      deaths causally related to treatment / all 0 / 0 Skin and subcutaneous tissue disorders Rash      subjects affected / exposed 11 / 49 (22.45%)      occurrences causally related to treatment / all 11 / 11      deaths causally related to treatment / all 0 / 0
Frequency threshold for reporting non-serious adverse events: 5%
Non-serious adverse events Safety population Total subjects affected by non serious adverse events      subjects affected / exposed 47 / 49 (95.92%) General disorders and administration site conditions Asthenia      subjects affected / exposed 11 / 49 (22.45%)      occurrences all number 11 Gastrointestinal disorders Diarrhoea      subjects affected / exposed 33 / 49 (67.35%)      occurrences all number 33 Vomiting      subjects affected / exposed 4 / 49 (8.16%)      occurrences all number 4 Skin and subcutaneous tissue disorders Rash      subjects affected / exposed 40 / 49 (81.63%)      occurrences all number 40

Adverse events Top of page

More information Top of page
Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? Yes
Date	Amendment
01 Oct 2013	Change of sites
01 Dec 2013	Inclusion of a retrospective biological sample substudy
Interruptions (globally)
Were there any global interruptions to the trial? No
Limitations and caveats
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
Important limitations of our study are the small sample size and the nonrandomized design, which preclude drawing firm conclusions.

More information Top of page