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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02233049


Additional trial details provided through ANZCTR are available at the end of this record.


Registration number
NCT02233049
Ethics application status
Date submitted
1/06/2016
Date registered
5/09/2014
Date last updated
8/06/2016

Titles & IDs
Public title
Biological Medicine for Diffuse Intrinsic Pontine Glioma (DIPG) Eradication
Scientific title
Biological Medicine for Diffuse Intrinsic Pontine Glioma (DIPG) Eradication
Secondary ID [1] 0 0
2014/2126
Secondary ID [2] 0 0
2014-001929-32
Universal Trial Number (UTN)
Trial acronym
BIOMEDE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Diffuse Intrinsic Pontine Glioma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Erlotinib
Treatment: Drugs - Everolimus
Treatment: Drugs - Dasatinib

Experimental: R1: erlotinib versus dasatinib - EGFR+ only Tarceva® (erlotinib): 25 mg and 100 mg tablets. The prescribed dose is 125 mg/m²/day orally, once daily. Sprycel® (dasatinib): 20 mg and 50 mg tablets. The prescribed dose is 85 mg/m²/dose, orally, twice daily, i.e. 170 mg/m2/day.

Experimental: R2: everolimus versus dasatinib - PTEN-loss only Votubia® (everolimus): 2.5 mg tablets. The prescribed dose is 5 mg/m²/day, orally, once daily. Sprycel® (dasatinib): 20 mg and 50 mg tablets. The prescribed dose is 85 mg/m²/dose, orally, twice daily, i.e. 170 mg/m2/day.

Experimental: R3: erlotinib versus everolimus versus dasatinib - EGFR+ and PTEN-loss or inconclusive biopsy Tarceva® (erlotinib): 25 mg and 100 mg tablets. The prescribed dose is 125 mg/m²/day orally, once daily. Votubia® (everolimus): 2.5 mg tablets. The prescribed dose is 5 mg/m²/day, orally, once daily. Sprycel® (dasatinib): 20 mg and 50 mg tablets. The prescribed dose is 85 mg/m²/dose, orally, twice daily, i.e. 170 mg/m2/day.

Experimental: Cohort Dasatinib - Neither EGFR overexpression nor loss of PTEN expression Sprycel® (dasatinib): 20 mg and 50 mg tablets. The prescribed dose is 85 mg/m²/dose, orally, twice daily, i.e. 170 mg/m2/day


Treatment: Drugs: Erlotinib


Treatment: Drugs: Everolimus


Treatment: Drugs: Dasatinib


Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Overall Survival
Timepoint [1] 0 0
Assessed up two years after randomization

Eligibility
Key inclusion criteria
Eligibility criteria for the BIOMEDE study (pre-screening for the randomised subtrials)

- Diagnosis of DIPG (clinical and radiological, or histological in case the biopsy was
performed before study entry)

- DIPG at diagnosis: no prior chemotherapy for the present cancer;no prior cerebral
radiation therapy

- NB : Metastatic disease allowed. Patient with metastatic disease are eligible for the
study (including the randomised trial if diagnosis of DIPG confirmed). In this
situation, radiotherapy will have to start within three weeks after the biopsy while
targerted treatment will start at the end of the irradiation.

- Age > 6 months and < 25 years. For children below the age of 3 years, inclusion in the
study and medical decisions should be discussed with the coordinating investigator.

- Eligible for a biopsy, or biopsy performed for diagnostic purpose and material
available for the biomarker assessment

- Eligible for cerebral radiotherapy

- Patient covered by an health insurance if national requirement

- Written informed consent given by patient and/or parents/legal representative for
biomarkers assessment and registration in the study.

Non eligibility criteria for the study

- Massive intratumour bleeding

- Any other concomitant anti-cancer treatment not foreseen by this protocol

- Any other cancer during the last 5 years

- Uncontrolled intercurrent illness or active infection

- Any other co-morbid condition that in the investigator's opinion would impair study
participation

- Unable for medical follow-up (geographic, social or mental reasons)

- Patient not fulfilling one of the previous eligibility criteria.

- Patient previously treated with irradiation on the brainstem for another neoplasm

- Patient with congenital galactose intolerance, Lapp lactase deficiency or
glucose-galactose malabsorption.

- Patient not covered by a social security agreement accepted in the treating country if
national requirement

- Pregnant or breast feeding women

- NB: A patient with known hypersensitivity for one the drug or its excipients could
still participate to the study and receive one of the other drug(s)

Common eligibility criteria for the BIOMEDE randomised subtrials

- Eligibility criteria for the study (see above)

- Confirmed histological diagnosis of diffuse intrinsic pontine glioma (grade II, III,
IV WHO), confirmed by central pathology review (including the assessment of the loss
of H3K27me3 by immunohistochemistry or the presence of a mutation in the histone H3
variant genes).

Patients without classical clinical and radiological diagnostic criteria who fulfil the
histological and biological criteria of DIPG are eligible for the trial.

Pilocytic astrocytoma and gangliogliomas are not eligible.

- Life expectancy > 12 weeks after the start of study treatment

- Karnofsky performance status scale or Lansky Play Scale > 50%. The PS should not take
the neurologic deficit per se into account. NB: Children and young adults with a worse
performance status due to glioma-related motor paresis can be included.

- Absolute neutrophil count > 1.5 x 109/l, Platelets > 100 x 109/l

- Total bilirubin < 1,5 x ULN, AST and ALT< 2,5 x ULN

- Serum creatinine < 1,5 X ULN for age. If serum creatinine > 1,5 ULN, creatinine
clearance must be > 70 ml/min/1,73 m² (EDTA radioisotope GFR or 24 hours urines
collection)

- Normal coagulation tests: prothrombin rate (prothrombin time = PT), TCA (PTT),
fibrinogen

- No current organ toxicity > grade 2 according to the NCI-CTCAE version 4.0 especially
cardiovascular, pulmonary or renal disease (,including but not limited to: congenital
long QT syndrome, nephrotic syndrome, glomerulopathy, uncontrolled high blood pressure
despite adequate treatment, interstitial lung disease, pulmonary arterial
hypertension). In case of known or possible cardiac disease, a cardiological advice
will be required prior to the inclusion in the randomized trial as a preexisting
cardiopathy represents a contra-indication to dasatinib.

- Effective contraception for patients (male and female) of reproductive potential
during their entire participation in the study and during 6 months after the end of
treatment

- Negative pregnancy test (serum beta-HCG) evaluated in the last week in females of
reproductive potential

- Written informed consent given by patient and/or parents/legal representative for
treatment and randomization

Eligibility criteria for the subtrials Eligibility criteria for the different subtrials
will be mainly based on biomarkers assessment as detailed in the table above. In addition,
contra-indication and precautions for use to specific drugs will be considered.
Minimum age
6 Months
Maximum age
25 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 0 0
France
State/province [1] 0 0
Val de Marne

Funding & Sponsors
Primary sponsor type
Other
Name
Gustave Roussy, Cancer Campus, Grand Paris
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Innovative Therapies For Children with Cancer Consortium
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Diffuse Intrinsic Pontine Gliomas (DIPG) appear almost exclusively in children and
adolescents, representing 15 to 20% of posterior fossa tumours. Even if it is one of the most
common malignant brain tumours, there are only 30 to 40 new cases per year in France. Their
clinical presentation is stereotyped with a short clinical history and a unique MRI
appearance that was usually considered as sufficient to establish the diagnosis. The
prognosis of DIPG is always unfavourable; median overall survival is 9 to 10 months in
general and most patients will die within two years after diagnosis (Kaplan 1996,Hargrave
2006). Malignant gliomas infiltrating the brainstem represent the greatest challenge of
paediatric oncology; despite numerous collaborative studies performed, patients' survival has
not significantly increased in thirty years (Hargrave 2009). There is no validated prognostic
factor. There is currently no validated treatment except radiotherapy.

Several targeted agents have been tested in DIPG (Pollack 2007 Haas-Kogan 2008, Geoerger,
2011), without knowing whether the target was present in the tumour. A critical review of the
paradigms of these trials tells us that there are long term survivors in these studies that
is to say patients who may have benefited from the tested therapy, but they are few. So far,
the new therapies that have been tried were evaluated one after the other in search of a
treatment that would be effective for all patients, measuring the treatment effect on median
survival. They were all rejected as ineffective. However the investigators can challenge the
endpoint to evaluate efficacy in these trials as the existence of long term survivors (> 18
months, for example) and their number should not been ignored, especially if targeted
therapies are considered. The investigators propose a paradigm shift in the choice of
treatment; the issue raised would be to give to each patient the treatment associated with
the highest likelihood of efficacy based on the specific biological tumour profile.

The development of targeted therapies for malignant gliomas infiltrating the brainstem has
been hampered by the absence of biological data. It is therefore crucial to better understand
the biology of these tumours. Despite the safety of the biopsy in brainstem tumours, most
teams of paediatric neurosurgery limit the use of stereotactic biopsy only for clinically or
radiologically unusual forms. Until recently, there has been no systematic genetic study at
diagnosis to date and the few available data were confounded by the inclusion of autopsies or
clinically and radiologically unusual cases (Louis, 1993; Gilbertson 2003; Okada, 2008;
Zarghooni 2010; Broniscer, 2010; Wu, 2012 and Schwartzentruber, 2012).

French teams gathered in the French Society of Paediatric Oncology and the European
consortium "Innovative Therapies in Children with Cancer (ITCC)" decided a few years ago to
perform biopsies of these tumours for diagnostic confirmation and to ensure the presence of
certain therapeutic targets prior to a possible inclusion in a trial evaluating a targeted
therapy (Geoerger, 2009; Geoerger, 2010). Part of this experiment was reported by the team of
the Necker Hospital in Paris, confirming the low rate of complications of stereotactic biopsy
procedure (Roujeau, 2007). The biopsy specimen analysis allowed practicing
immunohistochemical, genomic (CGHarray), gene expression (transcriptome) and direct
sequencing of candidate genes studies.

In this study, the majority of patients will receive a treatment assumed to specifically
target a biological abnormality identified on the biopsy. More importantly, patients will not
receive a drug for which the identified target is absent.

In this first step of the protocol, the patients will thus be allocated to one of the three
treatment groups as follows:

- If the tumor overexpresses EGFR without PTEN loss of expression, patients may receive
erlotinib or dasatinib allocated by randomization (R1 randomisation).

- If the tumor shows loss of PTEN expression without EGFR overexpression, patients may
receive everolimus or dasatinib allocated by randomisation (R2 randomisation).

- If the tumor shows both EGFR overexpression and loss of PTEN expression, patients may
receive erlotinib, everolimus or dasatinib by randomisation (R3 randomisation).

- If the tumor shows neither EGFR overexpression nor loss of PTEN expression (a very rare
situation in our experience), patients will receive dasatinib (no randomisation).

- If the biopsy assessment is not contributive, the treatment will be allocated by
randomisation between erlotinib, everolimus and dasatinib (R3 randomisation).
Trial website
https://clinicaltrials.gov/show/NCT02233049
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Jacques GRILL, MD, PhD
Address 0 0
Gustave Roussy, Cancer Campus, Grand Paris
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Jacques GRILL, MD, PhD
Address 0 0
Country 0 0
Phone 0 0
0142116209
Fax 0 0
Email 0 0
jacques.grill@gustaveroussy.fr
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT02233049

Additional trial details provided through ANZCTR
Accrual to date
Recruiting in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 1
The Children's Hospital at Westmead
Recruitment hospital [2] 2
Sydney Children's Hospital
Recruitment hospital [3] 3
Monash Children’s Hospital
Recruitment hospital [4] 4
Lady Cilento Children's Hospital
Recruitment hospital [5] 5
Womens and Childrens Hospital
Recruitment hospital [6] 6
The Royal Childrens Hospital
Recruitment hospital [7] 7
Perth Children's Hospital
Recruitment postcode(s) [1] 1
2145
Recruitment postcode(s) [2] 2
2031
Recruitment postcode(s) [3] 3
3168
Recruitment postcode(s) [4] 4
4101
Recruitment postcode(s) [5] 5
5006
Recruitment postcode(s) [6] 6
3052
Recruitment postcode(s) [7] 7
6009
Recruiting in New Zealand
Province(s)/district(s)
Auckland
Funding & Sponsors
Primary sponsor
Charities/Societies/Foundations
Primary sponsor name
Cure Brain Cancer Foundation
Primary sponsor address
L1 351 Crown St
Surry Hills NSW 2010
Primary sponsor country
Australia
Ethics approval
Ethics application status
Approved
Ethics committee name [1] 1
Sydney Children’s Hospitals Network Human Research Ethics Committee
Address [1] 1
Cnr Hainsworth Street and Hawkesbury Road, Westmead NSW 2145
Country [1] 1
Australia
Date submitted for ethics approval [1] 1
22/05/2017
Approval date [1] 1
19/07/2018
Ethics approval number [1] 1
HREC/17/SCHN/188
 
Public notes

Contacts
Principal investigator
Title 1 0
Dr
Name 1 0
Geoff McCowage
Address 1 0
Cnr Hainsworth Street & Hawkesbury Road Westmead NSW 2145
Country 1 0
Australia
Phone 1 0
+61 2 9845 0000
Fax 1 0
+61 2 9845 2171
Email 1 0
geoff.mccowage@health.nsw.gov.au
Contact person for public queries
Title 2 0
Mr
Name 2 0
Anthony Jaworski
Address 2 0
Cnr Hainsworth Street & Hawkesbury Road Westmead NSW 2145
Country 2 0
Phone 2 0
+61 2 9845 2474
Fax 2 0
+61 2 9845 2171
Email 2 0
anthony.jaworski@health.nsw.gov.au
Contact person for scientific queries
Title 3 0
Dr
Name 3 0
geoff.mccowage@health.nsw.gov.au
Address 3 0
Cnr Hainsworth Street & Hawkesbury Road Westmead NSW 2145
Country 3 0
Australia
Phone 3 0
+61 2 9845 0000
Fax 3 0
+61 2 9845 2171
Email 3 0
geoff.mccowage@health.nsw.gov.au