Craniospinal Irradiation in Histone AlteRed Midline Glioma (CHARM)

Craniospinal Irradiation in Histone AlteRed Midline Glioma (CHARM) - A Phase II Open Label Prospective Study

Paediatric H3K27/H3G34 mutant diffuse midline gliomas are high grade gliomas that arise in midline structures/cerebral hemispheres and are known to have dismal outcomes. Standard treatment includes definitive radiation therapy to primary site along with concurrent temozolomide chemotherapy following histological confirmation with a biopsy. Studies have shown poorer outcomes in the paediatric age group compared to that of adults and an increased risk to fail/recur in the leptomeninges(covering of brain and spinal cord). The following study is planned in order to assess the benefit of craniospinal irradiation(delivering radiotherapy to brain, spinal cord and its covering membrane in this high risk population. Thereby the investigator aim to improve survival in newly diagnosed histone mutant pediatric midline gliomas in the upfront setting. Patterns of disease failure, treatment related toxicities and quality of life will also be assessed as a part of this study. If proven beneficial, this study will influence how patients with this diagnosis will be treated in the future.

Study Overview

• Status: Recruiting
• Conditions: Glioma
• Intervention / Treatment: Radiation: craniospinal irradiation

Detailed Description

Introduction: Paediatric H3K27/H3G34 mutant diffuse midline gliomas (DMGs) are aggressive high-grade gliomas predominantly affecting midline structures and cerebral hemispheres. Despite aggressive therapy including radiation and chemotherapy, these tumors carry a poor prognosis, particularly in children, with frequent recurrence and high risk of leptomeningeal spread. Current standard treatment involves definitive radiation therapy to the primary site and concurrent temozolomide chemotherapy following histological confirmation via biopsy. However, outcomes remain suboptimal, prompting exploration of more intensive therapeutic strategies.

Primary objective:

To study if the addition of craniospinal irradiation to standard practice improves outcomes in pediatric diffuse midline glioma.

Secondary objectives:

• Estimate median time to leptomeningeal dissemination and compare with historical control
• Study patterns of failure
• Early and late toxicities
• Study quality of life indices
• To estimate QTWiST (Quality of life without symptoms or toxicity)

Primary endpoint: Overall survival at 12 months

Secondary endpoints:

• Time to leptomeningeal dissemination in months
• Incidence of different failure patterns from clinico-radiological assessment
• Toxicity assessment with the NCI Common Terminology Criteria for Adverse Events version 5 (CTCAE v5) during CSI(weekly), at conclusion of radiotherapy , post completion of 6 cycles adjuvant temozolomide, and in subsequent follow-ups at 3, 6, 9 and 12 months.
• Quality of life indices using the EORTC QLQC- 30 and its BN -20 module at baseline, after completion of radiotherapy, post completion of 6 cycles adjuvant temozolomide and in subsequent follow-up visits at 3, 6, 9 and 12 months.
• Quality of life without symptoms or toxicity in three health states TOX (toxicity), TWIST (time without symptoms) and REL (relapse) at baseline, after completion of radiotherapy, post completion of 6 cycles adjuvant temozolomide and in subsequent follow-up visits at 3, 6, 9 and 12 months.

Study setting: The study will be conducted in the department of Radiation Oncology, Neuro Oncology Disease management group

• Study Type: Interventional
• Enrollment (Estimated): 32
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Abhishek Chatterjee, MD; Phone Number: 6015 2224177000; Email: chatterji08@gmail.com

Study Locations

• India
  • Mumbai, India
    • Recruiting
    • Tata Memorial Hospital
    • Contact: Abhishek Dr Chatterjee, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Newly diagnosed biopsy proven histone altered diffuse midline glioma
2. Age- ≥3 to <18 years at time of diagnosis
3. Karnofsky/Lansky Performance Score more than or equal to 70
4. Has provided written informed consent/ assent form
5. No prior therapy except debulking surgery or biopsy

Exclusion Criteria:

1. Recurrent or progressive disease
2. Clinical features or family history suggestive of Inherited Cancer Predisposition such as Constitutional Mismatch Repair Deficiency (CMMRD)
3. Previous history of malignancy
4. Not willing /unlikely to comply with proposed therapy and follow up

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Single arm; Craniospinal irradiation involves delivery of radiation therapy to the whole brain, spinal cord, nerve roots, the covering meninges(leptomeninges) and subarachnoid space and provides a viable means of mitigating leptomeningeal spread and possibly improving survival.	Radiation: craniospinal irradiation; Delivering radiotherapy to brain, spinal cord and its covering membrane.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival Outcomes	Overall survival- time in months between the date of diagnosis to date of death due to any cause	at 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Leptomeningeal Dissemination	Time to leptomeningeal dissemination (will be defined as time in months between completion of planned therapy to the date of confirmation of leptomeningeal metastasis)	at 12 months
Patterns of failure	Incidence of different patterns of failure from diagnosis ( the time point of measurement of the primary outcome - overall survival	at 12 months
Any treatment emergent acute toxicity recording	All treatment emergent acute toxicity- expected (nausea, vomiting, hematological, dermatitis and mucositis) and unexpected, will be recorded. Grading will be done for all using the Common Terminology Criteria for Adverse Events (CTCAE) Version 5	Baseline , week 1 , week 2 , week 3 , week 4 , week 5 ,week 6 , conclusion of RT
Quality of life indices	Objective scoring with European Organisation For Research And Treatment Of Cancer(EORTC) Quality of Life Questionnaire(QLQC-30), brain specific module (BN 20)	will be done at 3 months
QTWiST (Quality of life Without Symptoms or Toxicity) calculation	Objective score calculation using mean duration in each health state weighed by a utility coefficient; from QLQC 30- BN 20 scores and the time spent in serious toxicity and without relapse.	will be done at 3 months
Any treatment emergent late toxicity recording	All treatment emergent late toxicity- expected and unexpected, will be recorded after completion of chemotherapy. Grading will be done for all using the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.	After completion of 6 cycles of adjuvant chemotherapy, at 3months, 6months, 9months and 12months follow up

Collaborators and Investigators

• Sponsor: Tata Memorial Centre
• Investigators: Principal Investigator: Abhishek Chatterjee, MD, Tata Memorial Hospital

Study record dates

Study Major Dates

• Study Start (Actual): January 3, 2025
• Primary Completion (Estimated): November 8, 2028
• Study Completion (Estimated): November 8, 2028

Study Registration Dates

• First Submitted: October 30, 2024
• First Submitted That Met QC Criteria: December 2, 2024
• First Posted (Actual): December 6, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 16, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioma
• Other Study ID Numbers: 4481

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No