A Pilot Study Investigating Upfront Adaptive Immunotherapy Approach in Children, Adolescent and Young Adult (CAYA) Patients With Replication-Repair Deficient (RRD) High-Grade Gliomas (HGG)

NCT06519682 | Recruiting DMC

• 1 other identifier: U-R-Immune Glioma (CA209-1245)
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

This is open label, multicentre, single arm, pilot study of upfront nivolumab in patients with RRD-glioblastoma with favorable immune/genomic biomarkers. The purpose of the study is to use upfront immune checkpoint inhibitor (ICI) to delay/avoid radiation for patients with RRD-glioblastoma with favorable clinical (Gross total resection (GTR) or near total resection (NTR)) and biological (RRD, hypermutation, immune activation) biomarkers. At progression, patients will be undergoing surgery/biopsy and will get a combination of radiation + ICI followed by maintenance ICI. This model will allow us to additionally study the evolution tumor in response to ICI. The study will have two domains.

Conditions

High Grade Glioma; Replication Repair Deficient

Outcome Measures

Primary Outcomes (1)

• To evaluate Radiation-free survival (RFS) from start of immunotherapy

  Radiation-free survival defined as time from start of immunotherapy to date of onset of radiation for progression/recurrence as determined by the iRANO criteria.

  2 years

Secondary Outcomes (4)

• To evaluate overall survival (OS)

  5 years

• To evaluate progression free survival (post first progression)

  2 years

• To evaluate clinical benefit rate (CBR)

  2 years

• Quality of life as measured by a validated PedsQL, generic module and PROMIS.

  2 years

Study Arms (2)

Domain 1 - Upfront ICI

ACTIVE COMPARATOR

Initially 12 eligible patients will be enrolled for upfront ICI. At 12 week assessment if \>6 patients have response (NO radiation for recurrence/progression), an additional 6 patients will be enrolled for upfront ICI. All patients will be assessed at 12 weeks from the start of ICI. If 6 or fewer patients have response (NO radiation for progression/recurrence), no more patients will be recruited to this domain.

Drug: Nivolumab

Domain 2 - Radiation + ICI → maintenance ICI

ACTIVE COMPARATOR

All the patients experiencing tumor progression on domain 1 will be eligible for domain 2 and will receive a combination of radiation and nivolumab followed by maintenance nivolumab for 2 years. To be eligible for domain 2 post recurrence patients will need surgery/biopsy at recurrence. If 6 RRD-glioblastoma will recur/progress at 12 weeks on domain 1 then 8 additional eligible patients may be directly enrolled in domain 2.

Drug: Nivolumab; Radiation: Radiation

Interventions

Nivolumab DRUG

All patients will be administered Nivolumab with or without radiation

Domain 1 - Upfront ICI; Domain 2 - Radiation + ICI → maintenance ICI

Radiation RADIATION

Radiation

Domain 2 - Radiation + ICI → maintenance ICI

Eligibility Criteria

• Age: 12 Months - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Age: Patients must be ≥12 months and ≤25 years of age at the time of signing informed consent/assent.
• Diagnosis: Patients must have a histologically confirmed diagnosis of glioblastoma.
• Proof of RRD: By tumor immunohistochemistry showing functional loss of mismatch repair gene expression (MLH1, MSH2, MSH6, PMS2), or based on prior germline testing confirming congenital mismatch repair deficiency (CMMRD) or Lynch syndrome. To be done locally. Results have to be available within four weeks of last surgery.
• Tumor Tissue Specimen: Provide a tumor tissue specimen for molecular profiling, including TMB analysis. Any tumor sequencing data if available at time of enrolment will be recorded for relevant pathogenic variants in the mismatch repair and polymerase-proofreading genes to suggest RRD. A specimen from the time of relapse/ progression while on the study is required as well, when applicable.
• Favorable immune markers: High PD1 and CD8 positivity as detailed in the lab manual. To be done locally. Results have to be available within 4 weeks of last surgery.
• Surgical and disease status: Patients should have had Gross total resection (GTR)/Near Total Resection (NTR) as confirmed by the post-surgery scan. Patients are allowed a second look surgery to achieve NTR/GTR provided no tumor directed systemic or radiation therapy has been administered before this second surgery. Patients should be able to start therapy within 4 weeks of last surgery.
• Allowable Prior Therapy: 3.1.7.1 Patients must have recovered from the acute toxic effects of all prior anti-cancer therapies (with the exception of alopecia and lymphopenia). Previous treatment with nivolumab and/or other anti- PD-1/PD-L1 inhibitors for other prior tumors (other than high-grade glioma) will be permitted.
• Prior Therapy: No prior therapy except surgery will be permitted for high grade glioma. If the patient was previously diagnosed and treated for another tumor (other than high grade glioma), the patients must have completed that treatment and have no active disease in order to be enrolled in this trial The following time periods apply for prior therapy for other tumors:
• Cytotoxic chemotherapy: At least 21 days prior to initiation of protocol therapy from the last dose of cytotoxic or myelosuppressive chemotherapy; at least 42 days if prior nitrosourea (such as lomustine, CCNU).
• Hematopoietic growth factors: At least 7 days prior to initiation of protocol therapy from the last dose of short-acting growth factor; at least 14 days for long-acting.
• Anti-cancer agents not known to be myelosuppressive: At least 7 days prior to initiation of protocol therapy from the last dose.
• Interleukins, interferons, and cytokines (other than hematopoietic growth factors): At least 21 days prior to initiation of protocol therapy from the last dose.
• Antibodies: At least 21 days prior to initiation of protocol therapy from the last dose and toxicity related to prior antibody therapy must be recovered to Grade ≤1.
• Radiotherapy: At least 14 days prior to initiation of protocol therapy from local radiotherapy; at least 150 days from total body irradiation (TBI), craniospinal radiotherapy, or radiation to
• ≥50% of the pelvis; at least 42 days from other substantial bone marrow radiation.

You may not qualify if:

• Concomitant Medications:
• Corticosteroids: Patients requiring systemic corticosteroids or other forms of immunosuppressive therapy within 7 days prior to initiation of protocol therapy are not eligible.
• Following initiation of protocol therapy, systemic corticosteroids or other forms of immunosuppressive therapy are permitted if administered for the treatment of toxicity, tumor flare, or pseudo-progression and can be tapered. In most cases protocol therapy must be held until the dose is tapered to 10 mg/day prednisone or equivalent. The Protocol Principal Investigator must be consulted prior to resuming treatment.
• Physiologic corticosteroids up to 5 mg/day prednisone or equivalent are permitted.
• Topical, ocular, intra-articular, intra-nasal, and inhaled corticosteroids are permitted.
• Patients with CNS tumors receiving steroids must be able to discontinue these at least 7 days prior to initiation of protocol therapy.
• Anti-cancer agents: Patients who are currently receiving other anti-cancer agents are not eligible.
• Other investigational agents: Patients who are currently receiving or have received any other investigational agent within 14 days prior to initiation of protocol therapy are not eligible.
• CNS Tumor Bulk: Patients with CNS tumors with any of the following characteristics on imaging are not eligible:
• Tumor with any evidence of uncal herniation or mass effect leading to severe midline shift
• Tumor that in the opinion of the local investigator, shows significant mass effect after initial surgery or after second-look surgery.
• Uncontrolled Intercurrent Illness: Patients with uncontrolled intercurrent illness including, but not limited to, ongoing active infection, symptomatic congestive heart failure (New York Heart Association Class III or IV), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements are not eligible.
• Pregnant and/or Breastfeeding: The study agents have the potential for teratogenic or abortifacient effects. Females of reproductive potential must have a negative serum pregnancy test within 72 hours prior to initiation of protocol therapy. Additional pregnancy tests (serum or urine) should be obtained during study participation in accordance with local standards and guidelines.
• Males or females of reproductive potential may not participate unless they have agreed to use an effective method of contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of treatment, and as follows:
• ●Females receiving nivolumab must continue an effective method of contraception for a period of 5 months after the last dose of nivolumab.

Sponsors & Collaborators

• Daniel Morgenstern: lead
• Canadian Institutes of Health Research (CIHR): collaborator
• Anti Cancer Fund: collaborator

Study Sites (1)

Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

RECRUITING

MeSH Terms

Conditions

Glioma

Interventions

Nivolumab; Radiation

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Physical Phenomena

Study Officials

• Daniel Morgenstern, MD

  The Hospital for Sick Children

  STUDY DIRECTOR

Central Study Contacts

Nirav Thacker, MD

CONTACT

613-737-7600; Nthacker@cheo.on.ca

Aiman Siddiqi

CONTACT

416-813-7654; aiman.siddiqi@sickkids.ca

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Senior Medical Officer

Study Record Dates

• First Submitted: July 16, 2024
• First Posted: July 25, 2024
• Study Start: December 6, 2024
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): August 1, 2029
• Last Updated: August 29, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)