Study of Relatlimab and Nivolumab (Opdualag) in Replication Repair Deficient HGG and DIPG

Feasibility and Phase 2a Study of Relatlimab and Nivolumab (Opdualag™) in Adolescent and Young Adult Patients Newly Diagnosed With Replication Repair Deficient High-Grade Glioma (HGG), Including Diffuse Intrinsic Pontine Glioma (DIPG)

The goal of this study is to further evaluate feasibility and tolerability of Opdualag for patients with replication repair deficient HGG, including DIPG.

Study Overview

• Status: Not yet recruiting
• Conditions: High Grade Glioma; WHO Grade 3 Glioma; Diffuse Intrinsic Pontine Glioma; WHO Grade 4 Glioma; Replication Repair Deficient
• Intervention / Treatment: Drug: Opdualag

Detailed Description

This is a multicenter, international study of post-radiotherapy (RT) fixed dose combination of nivolumab and relatlimab (Opdualag) to treat adolescent and young adult patients newly diagnosed with replication repair deficient (RRD) HGG and DIPG. The objectives of the study are to further evaluate feasibility and tolerability of Opdualag after RT, and to further characterize the safety and toxicity of Opdualag for patients with RRD HGG. We will also assess the progression free survival and overall survival distribution in patients.

Protocol maintenance therapy of Opdualag must begin no later than 56 days post-completion of RT. The earliest patients can begin protocol treatment is 28 calendar days post-completion of RT. Each cycle will be 28 days in duration and treatment can continue up to a total of 26 cycles. Opdualag will be given intravenously once every 4 weeks.

• Study Type: Interventional
• Enrollment (Estimated): 12
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Kelsey Troyer, PhD; Phone Number: 6147223284; Email: kelsey.troyer@nationwidechildrens.org

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Patients must be ≥12 years and ≤39 years of age at the time of enrollment on TarGeT-SCR.
• Within the United States, patients must weight ≥ 40 kg at the time of enrollment. For all other countries, patients must weight ≥ 30 kg at the time of enrollment.

Diagnosis:

• Patients with newly-diagnosed HGG, including DIPG, are eligible. All patients mut have histologic confirmation from diagnostic biopsy or resection. The diagnosis of HGG, including DIPG must have been confirmed through TarGeT-SCR.
• All HGGs must be WHO Grade 3 or 4. Note: WHO Grade 2 gliomas with pontine epicenter and diffuse involvement of at least 2/3 of the pons are eligible.

Disease Status:

• Patients must be newly diagnosed.
• Measurable disease is not required.
• Patients with primary spinal tumors are eligible.
• Patients should have no evidence of herniation or impending herniation, and no mass effect leading to severe midline shift.
• Patients with prior malignancy are eligible.
• Metastatic disease is excluded.
• Disseminated or multifocal disease: discussion with Study Chairs is required. Patients with multifocal disease who received upfront CSI are not eligible.

Demonstration of DNA replication repair deficiency (RRD) by fulfilling at least 2 of the following criteria:

• Tumor mutational burden greater than or equal to 5 mutations/megabase (Intermediate and high TMB)
• Genetic diagnosis of germline Constitutional Mismatch Repair Deficiency (CMMRD), Lynch Syndrome, or Polymerase-Proofreading Deficiency (PPD)
• Validated functional genomic assay (e.g. LOGIC) confirming mismatch repair (MMR) deficiency
• Immunohistochemistry (IHC) demonstrating loss of protein expression of any of the 4 MMR genes

Performance Level: Karnofsky ≥ 50 for patients > 16 years of age and Lansky ≥ 50 for patients ≤ 16 years of age

Prior Therapy for HGG:

• Surgery, RT, and/or dexamethasone are permissible. Temozolomide administration is highly discouraged with concurrent RT, but permissible. Anti-VEGF treatment used for vasogenic edema or steroid weaning is permitted. No other prior anticancer therapy for HGG will be allowed. Anti-VEGF use is well-established to not impact outcomes in HGG and is not considered as oncologic treatment but rather as a supportive measure to minimize steroid use in this setting. Discussion with Study Chairs is highly recommended.
• RT requirements: Patients must have received photon or proton focal RT and administered at a standard dose, including:
• 54 Gy in 30 fractions for DIPG
• 54-59.4 Gy in 30-33 fractions for other HGG
• 45-54 Gy for primary spinal cord HGG Note: Variances in RT dose within 10% of standard doses listed above are acceptable.
• Timing between diagnosis and start of RT: Patients must have started RT < 42 calendar days from initial diagnosis.
• Timing post-RT: The earliest patent can begin protocl treatment is 28 days post-completion of RT. It is recommended treatment should begin within 25 days, however patients must start treatment on TarGeT-F no later than 8 weeks post-completion of RT.

Organ Function Requirements:

• ANC ≥ 1000/mm3
• Platelet count ≥ 100,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment).
• Hemoglobin > 8g/dL (may be transfused)

• Creatinine clearance or radioisotope GFR≥ 70 mL/min/1.73 m2 OR serum creatinine based on age/gender as follows:

  10 to < 13 years: 1.2 mg/dL for males and females 13 to < 16 years: 1.5 mg/dL for males and 1.4 mg/dL for females

  • 16 years: 1.7 mg/dL for males and 1.4 mg/dL for females
• AST/ALT < 3 times the ULN. For the purpose of this study, the ULN for ALT and AST is 45 U/L.
• Ejection fraction greater than or equal to 50% as measured by echocardiogram or multiple-gated acquisition
• QTc ≤ 480 msec (by Bazett formula)
• Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled.
• TSH within institutional guidelines for normal range.

Exclusion Criteria:

• Pregnant or breastfeeding patients are excluded.
• Patients with uncontrolled infection.
• Patients with bone marrow failure syndrome.
• Participants who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study.
• Inflammatory bowel disease
• Moderate to severe pulmonary conditions defined by need for medical intervention and/or limiting activities of daily living or shortness of breath with limited exertion.
• Personal history of pneumonitis.
• Cardiac conditions.
• Patients with a history of severe or life-threatening adverse dermatologic reactions such as SJS or toxic epidermal necrolysis, or other severe reactions that have been associated with prior immune checkpoint inhibitor therapy.
• Active tuberculosis
• Active autoimmune disease requiring systemic treatment in the past 2 years
• Chronic HBV infections with active disease
• Personal known history of HPC who have not completed curative antiviral treatment
• Personal known history of HIV
• Receipt of any organ transplantation
• Treated with other malignancy within 1 year prior to enrollment with the exception of the following: curatively treated basal cell carcinoma, squamous cell carcinoma of the skin, and in situ cervical cancer.
• Receipt of a live or live-attenuated vaccine within 4 weeks prior to enrollment
• Previous treatment with relatlimab
• Patients with ongoing or clinically significant illness, medical or psychiatric conditions that, in the investigator's opinion, could affect the safety of the participant, or could impair assessment of the study's results are not eligible.

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: Opdualag Maintenance Therapy; Post-RT Opdualag Maintenance Therapy	Drug: Opdualag; Fixed dose combination of relatlimab and nivolumab (Opdualag)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with Adverse Events, Immune Related Adverse Events, and Dose Modifying Toxicities as assessed by CTCAE v6	Assess the feasibility of fixed dose combination of nivolumab and relatlimab as adjuvant therapy following radiation therapy in patients with newly diagnosed replication repair deficiency HGG. Adverse event data will be summarized in tables which will incorporate grade, attribution, and dose delays.	4 years
Number of participants that complete the first 3 cycles of maintenance therapy without experiencing dose modifying toxicities	Assess the tolerability of fixed dose combination of nivolumab and relatlimab (Opdualag) as adjuvant therapy following radiation therapy in patients with newly diagnosed replication repair deficient HGG by quantifying the number of participants that complete at least the first 3 cycles of maintenance therapy without experiencing dose modifying toxicities that require permanent discontinuation of Opdualag therapy.	4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival in HGG	Estimate PFS distribution for patients with newly diagnosed RRD-HGG who received Opdualag following RT compared to molecularly stratified and matched historical controls	Day 1 of treatment until date of Progressive Disease or death due to any cause or date of last follow-up, assessed up to 5 years
Overall Survival in HGG	Estimate overall survival distribution for patients with newly diagnosed RRD-HGG who receive Opdualag following RT compared to molecularly stratified and matched historical controls.	Day 1 of treatment until date of death due to any cause or date of last follow-up, assessed up to 5 years
Correlations between genomic tumor alterations with radiographic response	Explore longitudinal associations of genomic, transcriptomic, epigenetic, and/or immunologic alterations of tumor at diagnosis, recurrence, or autopsy with radiographic response and advanced neuro-imaging measures. Incidence of significant genomic/transcriptomic/epigenetic and/or immunologic alterations found by sequencing and proteomics will be correlated with percent of patients that achieve radiographic responses using RAPNO guidelines.	Diagnosis until date of death due to any cause or date of last follow-up, assessed up to 5 years
Evaluate health-related quality of life outcomes using PROMIS questionnaire	Using PROMIS questionnaire, evaluate health-related quality of life outcomes of patients newly diagnosed with RRD-HGG from diagnosis through the end of treatment.	From diagnosis through the end of treatment with Opdualag, usually 2 years per patient

Collaborators and Investigators

• Sponsor: Nationwide Children's Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2027
• Primary Completion (Estimated): March 1, 2033
• Study Completion (Estimated): March 1, 2038

Study Registration Dates

• First Submitted: May 29, 2026
• First Submitted That Met QC Criteria: June 8, 2026
• First Posted (Actual): June 12, 2026

Study Record Updates

• Last Update Posted (Actual): June 12, 2026
• Last Update Submitted That Met QC Criteria: June 8, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nervous System Neoplasms; Central Nervous System Neoplasms; Brain Neoplasms; Brain Stem Neoplasms; Infratentorial Neoplasms; Diffuse Intrinsic Pontine Glioma; Glioma; Opdualag
• Other Study ID Numbers: CONNECT TarGeT-F

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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