DIPG – Diffuse Intrinsic Pontine Glioma

April 3, 2024

Sharing Insights: Enhancing DIPG (Brain Tumor) Care through Second Opinions

Overview

In this paper, we aim to communicate and share the insights garnered from MyChild’sCancer’s second opinion program (www.MyChildsCancer.org/our-services).

Through this program, we at MyChild’sCancer harness the expertise of a global network of specialists to offer second opinions for children with cancer facing complex circumstances.

We are a non-profit organization and our services are offered at no cost to the families we support.

Our objective in this paper is to share the knowledge compiled from world-renowned experts’ opinions on individual cases, to equip parents and doctors worldwide with information and tools to take proactive steps in managing the child’s condition and ideally improve treatment outcomes.

This review was prepared by Christina Katanov, a family coordinator at MyChild’sCancer, and was approved by the experts mentioned in it.

Disclaimer

The information provided in this review is intended for general informational purposes only. It is not intended to be a substitute for professional medical advice, diagnosis, or treatment.

Always seek the advice of your physician or other qualified healthcare provider with any questions you may have regarding a medical condition. Feel free to share this information page with them.

The inclusion of clinical trials in this review does not imply endorsement or recommendation by MyChild’sCancer. The decision to participate in a clinical trial should be made in consultation with your healthcare provider and after carefully considering the risks and potential benefits associated with the trial.

DIPG Case Study Compilation

Here, we present the background and treatment plan of four young children diagnosed with DIPG, ages 2-10 years old. We divided the information to 2 scenarios:

Case study: Management of children with DIPG following good response to radiotherapy.

Overview: Management of children with recurrent DIPG

The information and recommendations were given through a second opinion with the following experts that collaborate with the MyChild’sCancer organization;

Prof. Eric Bouffet, Professor of Pediatrics, Division of Hematology/Oncology, The Hospital for Sick Children, Toronto Canada

Prof. Stefan Rutkowski, Professor for Pediatric Hematology and Oncology, Director of Department of Pediatric Hematology and Oncology at UKE, Hamburg, Germany.

Case study:

Management of children with DIPG following good response to radiotherapy.

Relevant treatment history:

Biopsy: Tumor biopsy revealed the presence of a H3K27M mutation and an ACVR1 mutation which can be detected in approx. 25% of children with DIPG, and encodes ALK2.

Radiotherapy: Local conformal radiotherapy was given, followed by clinical improvement.

Experts opinion on future management for the patient

Clinical trials available for children with DIPG are experimental treatments, with unknown effects on tumor control and related side-effects. However, expert consensus is that a clinical trial option is reasonable with the aim of prolonging Recurrence-free survivorship (i.e. stability without recurrent tumor growth).

PNOC022: Combination of ONC201 and Paxalisib:

This trial investigates the combination of the Dopamine-receptor antagonist ONC201 (which has already shown activity signals against DIPG in prior single-agent trials), combined with the PI3K inhibitor – Paxalisib. PI3K is another relevant pathway activated in DIPG. Good preclinical evidence of this combination has been presented at ISPNO2022 (1).

Key inclusion criteria: Participants must be within 4-14 weeks of completion of radiation.

Key exclusion criteria: Participants who are currently receiving other anti-cancer agents.

Study locations: USA, Australia, Israel, New Zealand, Netherlands and Switzerland (Active, not recruiting).

Link: Combination Therapy for the Treatment of Diffuse Midline Gliomas

CAR-T Therapy:

Chimeric Antigen Receptor (CAR) T-cell therapy is a highly specialized and individualized treatment, in which patient’s T cells (a type of immune system cells) are engineered in the lab so they can find and destroy cancer cells.

A few pilot trials with CAR-T cells directed against various antigens expressed in DIPG (e.g. GD2, and B7-H3) are currently open, and some present partially encouraging interim results from patients with DIPG who experienced durable response for more than 1 year after relapse of irradiated DIPG. Although these favorable results have only been achieved in some of the few patients treated so far, they appear to be superior to the results obtained by other studies for DIPG (2).

CAR-T trials are mostly offered in the US, in particular in Seattle and Stanford. Until recently, these trials recruited only US residents only. Recently, the Seattle location has started accepting international patients as well.

Importantly, CAR-T trials are still highly experimental with limited clinical data on outcome and safety. Preliminary results have been considered “promising”, as some patients have shown clinical and radiological improvement with the injection of CAR-T cells in the ventricles. So far, improvements are not sustainable, and patients require repeated injections of the CAR-T cells to maintain remission.

This means that patients and families must stay locally for longer, which is a significant challenge especially for international patients. Additional potential barrier is the cost of treatment that ranges between 300,000 to 500,000 USD.

Key inclusion criteria: Diagnosis of DIPG or DMG at any time point following completion of standard therapy; CNS reservoir catheter, such as an Ommaya or Rickham catheter.

Study location: Seattle Children’s Hospital, Washington-USA (RECRUITING).

Link: Study of B7-H3, EGFR806, HER2, And IL13-Zetakine (Quad) CAR T Cell Locoregional Immunotherapy For Pediatric Diffuse Intrinsic Pontine Glioma

Key inclusion criteria: Diagnosis of DIPG or DMG at any time point following completion of standard therapy; CNS reservoir catheter, such as an Ommaya or Rickham catheter, present in the proper location for CNS-directed therapy delivered as specified for BrainChild-04

Study location: Seattle Children’s Hospital, Washington-USA (RECRUITING).
Link: Immunotherapy for Diffuse Intrinsic Pontine Glioma

Key inclusion criteria: Tissue diagnosis of H3K27M-mutated Diffuse Intrinsic Pontine Glioma (DIPG) with radiographically evident tumor restricted to the brainstem. Currently accepting US patients only.

Study location: Lucile Packard children’s hospital. Stanford, California, USA (RECRUITING).
Link: GD2 CAR T Cells in Diffuse Intrinsic Pontine Gliomas(DIPG) & Spinal Diffuse Midline Glioma(DMG)

Biomede 2.0:

This clinical trial, is taking place in France, evaluates the efficacy of ONC201(see 1) in comparison with everolimus (PARP-inhibitor), which has shown some activity in DIPG before.

Key Inclusion criteria: Eligible for a biopsy, or biopsy material available for the biomarker assessment.

Treatments will start on the first day of irradiation (+3 days max). Reirradiation is permitted according to local practice.

Key Exclusion criteria: Any other concomitant anti-cancer treatment not foreseen by this protocol is not allowed, except corticosteroids and Bevacizumab which are allowed at any dosage during the protocol.

Study location: Gustave Roussy, Cancer Campus, Grand Paris (RECRUITING).
Link: Biological Medicine for Diffuse Intrinsic Pontine Glioma (DIPG) Eradication 2.0 (BIOMEDE 2)

Temozolomide as per HIT-HGG 2007:

According to the recently reported results from this trial(3), temozolomide given during and after radiotherapy (as per the so-called Stupp regimen for adults with Glioblastoma) has some significant effect when compared to other more intensive chemotherapy regimens. However, the effect appears to be relatively modest and not long-lasting.

Vandetanib and Everolimus:

Regarding the ACVR1-mutation, there are currently no approved drugs available, and no open trials for drugs directed against this specific mutation.

In the meantime, one option is to use a combination of vandetanib and everolimus based on the preclinical work conducted in the UK by Chris Jones (4). So this strategy might become a therapeutic option in the future, but not for now.

In conclusion, the plan of the child’s local team to join the PNOC022 trial is a very suitable and good option.

In case the tumor progresses during or after PNOC022 treatment, it might be an option to include the child later in a CART-cell trial in North America or in Europe, or into any other promising trial.

Overview:

Management of children with recurrent DIPG

It is worth noting that so far nothing has shown better activity than radiotherapy alone and the pros and cons of additional treatment should be weighed carefully with the treating team.

Experts opinion on future management for the patient

Re-irradiation:

If the stabilization after the second radiation treatment is sustained, one option is to consider a third radiation treatment. Sickkids hospital reported their experience of third radiation treatment in 2017(5) and have since treated several patients with 3rd or even 4th radiation treatments.

Clinical trials:

CAR-T Therapy:

Phase I Study of Anti-GD2 Chimeric Antigen Receptor-Expressing T Cells in Pediatric and Young Adult Patients Affected by Relapsed/Refractory

Central Nervous System Tumors.

Key inclusion criteria: Positioning of an implantable intraventricular access device (CodmanHolterRickham reservoir, Integra LifeSciences, NJ, U.S.A) and a microdialysis probe (71 high cutoff microdialysis bolt catheter, M Dialysis AB, Stockholm Sweden).

Key exclusion criteria: Immunosuppressive agents less than or equal to 30 days.

Study location: Bambino Gesù Hospital and Research Institute, Rome, ITALY. (RECRUITING).

Link: GD2-CAR T Cells for Pediatric Brain Tumors

Chimeric Antigen Receptor (CAR)-T Cells to Target GD2 for Diffuse Midline Glioma.

Key inclusion criteria: Tissue diagnosis of H3K27M mutant Diffuse Midline Glioma; At least 6 weeks following completion of radiation therapy.

Study location: University College, London, UK (RECRUITING)

Link: CAR T Cells to Target GD2 for DMG (CARMIGO)

Phase 1 Study of B7-H3-Specific CAR-T Cell Locoregional Immunotherapy for Diffuse Intrinsic Pontine Glioma/Diffuse Midline Glioma and Recurrent or Refractory Pediatric Central Nervous System Tumors

Key inclusion criteria: Diagnosis of DIPG or DMG at any time point following completion of standard therapy; CNS reservoir catheter, such as an Ommaya or Rickham catheter.

Study location: Seattle Children’s Hospital, Washington-USA (RECRUITING).

Link: Study of B7-H3-Specific CAR T Cell Locoregional Immunotherapy for Diffuse Intrinsic Pontine Glioma

Phase 1 Study of B7-H3, EGFR806, HER2, And IL13-Zetakine (Quad) CAR-T Cell Locoregional Immunotherapy For Pediatric Diffuse Intrinsic Pontine Glioma, Diffuse Midline Glioma, And Recurrent Or Refractory Central Nervous System Tumors.

Study location: Seattle Children’s Hospital, Washington-USA (RECRUITING).

Link: Study of B7-H3, EGFR806, HER2, And IL13-Zetakine (Quad) CAR T Cell Locoregional Immunotherapy For Pediatric Diffuse Intrinsic Pontine Glioma

Phase 1 Clinical Trial of Autologous GD2 Chimeric Antigen Receptor (CAR)-T Cells (GD2CART) for Diffuse Intrinsic Pontine Gliomas (DIPG) and Spinal Diffuse Midline Glioma (DMG).

Key inclusion criteria: Currently accepting US patients only (it says “currently”, so it might be the case later on that non-US patients are allowed); upon progression.

Key exclusion criteria: Tumor involvement of cerebellar vermis or hemispheres (pontocerebellar peduncle involvement is allowed), thalamic lesions, or

supratentorial lesions.

Study location: Lucile Packard Children’s Hospital (LPCH), California-USA (RECRUITING).

Link: GD2 CAR T Cells in Diffuse Intrinsic Pontine Gliomas(DIPG) & Spinal Diffuse Midline Glioma(DMG)

Focused ultrasound:

Toronto has recently opened a trial of focused ultrasound to open the blood-brain barrier and facilitate the penetration of chemotherapy in the tumor. However, the access to international patients is currently very limited and even impossible currently.

If you wish to contact the international office and enquire about the possibilities, the email address is international.patientprogram@sickkids.ca

Key inclusion criteria: Age between 5 and 18 years. A patient was diagnosed with DIPG at least 4 weeks and not greater than 12 weeks from completion of radiation therapy.

Key exclusion criteria: Previous treatment with complete cumulative doses of Doxorubicin, daunorubicin, idarubicin, and/or other anthracyclines and anthracenedione.

Study location: USA and Toronto, Ontario, Canada (RECRUITING).

Link: Blood Brain Barrier (BBB) Disruption Using Exablate Focused Ultrasound With Doxorubicin for Treatment of Pediatric DIPG

Biopsy vs. CSF testing:

In most clinical trials one of the inclusion criteria is biopsy of the tumor to confirm the presence of H3K27M mutation, which is found in most DIPG tumors. Prof. Bouffet suggested an alternative to biopsies via CSF testing. However, this does not seem to be accepted for eligibility in the PNOC022 trial.

The timing of the test is important. If the response to radiotherapy is good, there may be very little cell-free DNA in the CSF and the result may come back as false negative.

A CSF study may be useful for parents, for the following reasons:

There are different types of H3K27M mutations, and the specific type of mutation may matter, as the mutation H3.1 is associated with a better response to treatment and a longer time of response. There is also another alteration, often combined with the H3.1 mutation, called ACVR1 mutation that is predicting better response to treatment and longer survival.
The other advantage or opportunity of this CSF testing is to identify potential mutations or alterations that could be targeted with specific medications.

Several sites are offering CSF testing:

Memorial Sloan Kettering Hospital in New York City which is offering this test for free (MSK-IMPACT).
SickKids Hospital in Toronto, Canada.

Disclaimer

The purpose of this information is to provide parents and caregivers an access to potentially life-saving information that cannot be easily gleaned from doctors or online searches. However, The information provided in this review is intended for general informational purposes only. It is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition.
The inclusion of clinical trials in this review does not imply endorsement or recommendation by MyChild’sCancer. The decision to participate in a clinical trial should be made in consultation with your healthcare provider and after carefully considering the risks and potential benefits associated with the trial.
By accessing and using this information, you agree to waive any and all claims against [Your Institution/Organization] arising out of or related to the use of the information provided herein.

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