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Trial details imported from ClinicalTrials.gov

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

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

Registration number

NCT02233049

Ethics application status

Date submitted

29/08/2014

Date registered

8/09/2014

Date last updated

23/07/2018

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]

2014/2126

Secondary ID [2]

2014-001929-32

Universal Trial Number (UTN)

Trial acronym

BIOMEDE

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Condition category

Condition code

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Comparator / control treatment

Control group

Outcomes

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

Sex

Both males and females

Can healthy volunteers participate?

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

UNKNOWN

Data analysis

Reason for early stopping/withdrawal

Other reasons

Date of first participant enrolment

Anticipated

Actual

1/10/2014

Date of last participant enrolment

Anticipated

Actual

Date of last data collection

Anticipated

1/10/2018

Actual

Sample size

Target

250

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

Funding & Sponsors

Primary sponsor type

Other

Name

Gustave Roussy, Cancer Campus, Grand Paris

Address

Country

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/study/NCT02233049

Trial related presentations / publications

Public notes

 This record is viewable in the ANZCTR as it had previously listed Australia and/or New Zealand as a recruitment site, however these sites have since been removed

Contacts

Principal investigator

Name

Jacques GRILL, MD, PhD

Address

Gustave Roussy, Cancer Campus, Grand Paris

Country

Phone

Fax

Contact person for public queries

Name

Jacques GRILL, MD, PhD

Address

Country

Phone

0142116209

Fax

[email protected]

Contact person for scientific queries

No information has been provided regarding IPD availability

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

No documents have been uploaded by study researchers.

Results not provided in https://clinicaltrials.gov/study/NCT02233049

Additional trial details provided through ANZCTR

Accrual to date

Recruiting in Australia

Recruitment state(s)

NSW,QLD,SA,WA,VIC

Recruitment hospital [1]

The Children's Hospital at Westmead

Recruitment hospital [2]

Sydney Children's Hospital

Recruitment hospital [3]

Monash Children’s Hospital

Recruitment hospital [4]

Lady Cilento Children's Hospital

Recruitment hospital [5]

Womens and Childrens Hospital

Recruitment hospital [6]

The Royal Childrens Hospital

Recruitment hospital [7]

Perth Children's Hospital

Recruitment postcode(s) [1]

2145

Recruitment postcode(s) [2]

2031

Recruitment postcode(s) [3]

3168

Recruitment postcode(s) [4]

4101

Recruitment postcode(s) [5]

5006

Recruitment postcode(s) [6]

3052

Recruitment postcode(s) [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]

Sydney Children’s Hospitals Network Human Research Ethics Committee

Address [1]

Cnr Hainsworth Street and Hawkesbury Road, Westmead NSW 2145

Country [1]

Australia

Date submitted for ethics approval [1]

22/05/2017

Approval date [1]

19/07/2018

Ethics approval number [1]

HREC/17/SCHN/188

Public notes

Contacts

Principal investigator

Title

Name

Geoff McCowage

Address

Cnr Hainsworth Street & Hawkesbury Road Westmead NSW 2145

Country

Australia

Phone

+61 2 9845 0000

Fax

+61 2 9845 2171

[email protected]

Contact person for public queries

Title

Name

Anthony Jaworski

Address

Cnr Hainsworth Street & Hawkesbury Road Westmead NSW 2145

Country

Phone

+61 2 9845 2474

Fax

+61 2 9845 2171

[email protected]

Contact person for scientific queries

Title

Name

[email protected]

Address

Cnr Hainsworth Street & Hawkesbury Road Westmead NSW 2145

Country

Australia

Phone

+61 2 9845 0000

Fax

+61 2 9845 2171

[email protected]

Trial Review

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