Anti-Lag-3 (Relatlinib) and Anti-PD-1 Blockade (Nivolumab) Versus Standard of Care (Lomustine) for the Treatment of Patients With Recurrent Glioblastoma

Randomized Phase II Trial of Anti-Lag-3 and Anti-PD-1 Blockade vs. SOC in Patients With Recurrent Glioblastoma

This phase II trial compares the safety, side effects and effectiveness of anti-lag-3 (relatlinib) and anti-PD-1 blockade (nivolumab) to standard of care lomustine for the treatment of patients with glioblastoma that has come back after a period of improvement (recurrent). Relatlimab and nivolumab are monoclonal antibodies that may interfere with the ability of tumor cells to grow and spread. Lomustine is a chemotherapy drug and in a class of medications called alkylating agents. It damages the cell's deoxyribonucleic acid (DNA) and may kill cancer cells. Relatlinib and nivolumab may be safe, tolerable, and/or effective compared to standard of care lomustine in treating patients with recurrent glioblastoma.

Study Overview

• Status: Not yet recruiting
• Conditions: Recurrent Glioblastoma
• Intervention / Treatment: Biological: Nivolumab; Procedure: Magnetic Resonance Imaging; Procedure: Biospecimen Collection; Procedure: Surgical Procedure; Biological: Relatlimab; Procedure: Biopsy; Drug: Lomustine

Detailed Description

PRIMARY OBJECTIVE:

I. To compare the restricted mean survival time (RMST) for overall survival (OS) between patients receiving the combination of relatlimab (BMS-986016) and nivolumab versus patients receiving standard of care chloroethylcyclohexylnitrosourea (CCNU) (lomustine).

SECONDARY OBJECTIVES:

I. To compare the 12-month OS rates between patients receiving the combination of relatlimab (BMS-986016) and nivolumab versus patients receiving standard of care CCNU (lomustine).

II. To compare the restricted mean survival times for progression-free survival (PFS) between patients receiving the combination of relatlimab (BMS-986016) and nivolumab versus patients receiving standard of care CCNU (lomustine).

III. To compare the radiographic response rate between patients receiving the combination of relatlimab (BMS-986016) and nivolumab versus patients receiving standard of care CCNU (lomustine).

IV. To compare the safety/adverse event rate between patients receiving the combination of relatlimab (BMS-986016) and nivolumab versus patients receiving standard of care CCNU (lomustine).

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive nivolumab intravenously (IV) over 30 minutes followed by relatlimab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo magnetic resonance imaging (MRI) at baseline and every 8 weeks until progression and then at least 8 weeks after objective response. Additionally patients undergo surgery or biopsy and blood sample collection throughout study.

ARM II: Patients receive lomustine orally (PO) on day 1 of each cycle. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI every 9 weeks until progression and then at least 6 weeks after objective response. Additionally patients undergo surgery or biopsy and blood sample collection throughout study.

After completion of study treatment, patients are followed up every 6 months for up to 5 years from time of randomization.

• Study Type: Interventional
• Enrollment (Estimated): 178
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Histologically-proven glioblastoma (World Health Organization [WHO] 2021 criteria)
• Progressive or recurrent disease per Response Assessment in Neuro-Oncology (RANO) criteria
• No IDH mutation (IDH1 R132H negative by immunohistochemistry [IHC] or sequencing)
• Patients must be in first recurrence of glioblastoma following radiation therapy and temozolomide
• No prior therapies except radiation, temozolomide, Tumor Treating Fields (TTFields), and/or Gliadel wafers (placed during the first surgery at diagnosis of glioblastoma multiforme [GBM]). Prior radiation therapy, TTFields, or placement of Gliadel wafers must be completed at least 12 weeks prior to registration. Prior temozolomide must be completed at least 3 weeks prior to registration
• No prior use of nivolumab or other anti-PD1 agents
• Patients must be neurologically stable off corticosteroids for at least 5 days prior to registration
• Age: ≥ 18 years
• Karnofsky Performance Status: ≥ 60% (i.e. patient must be able to care for themselves with occasional help from others)
• Absolute lymphocyte count (ALC): ≥ 1000/mm^3
• Absolute neutrophil count (ANC): ≥ 1500/mm^3
• Platelet count: ≥ 100,000/mm^3
• Hemoglobin: ≥ 9.0 g/dL
• Activated partial thromboplastin time (APTT) or partial thromboplastin time (PTT): ≤ 1.5 x upper limit of normal (ULN)
• Total bilirubin: < 2.0 x ULN (Except for patients with Gilbert's syndrome, who must have direct bilirubin < 2.0 x ULN)
• Aspartate aminotransferase (AST) / alanine aminotransferase (ALT): < 3.0 x ULN
• Creatinine: ≤ 1.0 x ULN (For patients with creatinine > 1.0 x ULN, calculated creatinine clearance must be ≥ 50 mL/min/1.73m^2)
• Thyroid-stimulating hormone (TSH): within normal limits (WNL) (Supplementation is acceptable to achieve a TSH WNL. In patients with abnormal TSH, if Free T4 is normal and patient is clinically euthyroid, patient is eligible)
• Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown and an agent that has known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test done within 14 days prior to registration is required
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• No active brain metastases or leptomeningeal disease
• HIV: HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months prior to registration are eligible for this trial
• Hepatitis B: For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Hepatitis C: Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• No known medical condition causing an inability to swallow oral formulations of agents
• No current symptomatic pulmonary disease
• No autoimmune disorders that require systemic treatment (except hyperthyroidism or diabetes mellitus)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (nivolumab, relatlimab); Patients receive nivolumab IV over 30 minutes followed by relatlimab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI at baseline and every 8 weeks until progression and then at least 8 weeks after objective response. Additionally patients undergo surgery or biopsy and blood sample collection throughout study.	Biological: Nivolumab; Given IV; Other Names: BMS-936558; MDX-1106; NIVO; ONO-4538; Opdivo; CMAB819; Nivolumab Biosimilar CMAB819; ABP 206; Nivolumab Biosimilar ABP 206; BCD-263; Nivolumab Biosimilar BCD-263; Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Surgical Procedure; Undergo surgery; Other Names: Operation; Surgery; Surgery Type; Surgical; Surgical Intervention; Surgical Interventions; Surgical Procedures; Type of Surgery; Surgery, NOS; Biological: Relatlimab; Given IV; Other Names: BMS-986016; BMS986016; Immunoglobulin G4, Anti-(human Lymphocyte Activation Gene-3 Protein) (Human Heavy Chain), Disulfide with Human Light Chain, Dimer; Procedure: Biopsy; Undergo biopsy; Other Names: Bx; BIOPSY_TYPE
Active Comparator: Arm II (lomustine); Patients receive lomustine PO on day 1 of each cycle. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI every 9 weeks until progression and then at least 6 weeks after objective response. Additionally patients undergo surgery or biopsy and blood sample collection throughout study.	Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Surgical Procedure; Undergo surgery; Other Names: Operation; Surgery; Surgery Type; Surgical; Surgical Intervention; Surgical Interventions; Surgical Procedures; Type of Surgery; Surgery, NOS; Procedure: Biopsy; Undergo biopsy; Other Names: Bx; BIOPSY_TYPE; Drug: Lomustine; Given PO; Other Names: CCNU; CeeNU; Gleostine; 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea; 1-Nitrosourea, 1-(2-chloroethyl)-3-cyclohexyl-; Belustin; Belustine; Cecenu; Chloroethylcyclohexylnitrosourea; Citostal; Lomeblastin; Lomustinum; Lucostin; Lucostine; N-(2-Chloroethyl)-N'-cyclohexyl-N-nitrosourea; Prava; RB-1509; WR-139017

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	The comparison of OS between the arms will be made with respect to restricted mean survival time (RMST) at 30 months. The RMST difference between arms will be determined as a point estimate with a corresponding 90% confidence interval (CI).	From randomization until death due to any cause, assessed at 30 months
OS rate	The OS rate between the 2 arms will be compared using a chi-square test. The point estimate and corresponding 90% CI will be generated for the difference in proportion.	From randomization until death due to any cause, assessed at 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS)		From randomization until confirmed disease progression as assessed by the treating physician or death due to any cause, whichever occurs first, assessed up to 5 years
Radiographic response	Radiographic response will be assessed using Immunotherapy Response Assessment in Neuro-Oncology criteria. Patients with a complete response or partial response will be deemed a radiographic response. Patients with no follow-up imaging assessment will be deemed as a non-response. The proportion of patients with a radiographic response will be compared between the treatment arms with a Fisher's exact test.	Up to 5 years
Incidence of adverse events (AEs)	AEs will be assessed using Common Terminology Criteria for Adverse Events version 5.0. AEs will be summarized with frequencies and relative frequencies. The maximum grade for an AE will be recorded for each patient. The number (percent) of patients that experience each observed AE will be summarized by the treatment a patient received. The proportion of patients who experience a grade 3+, a grade 4+, and grade 5 AEs will be summarized by number and percent for each treatment arm. The primary summary will be for AEs regardless of attribution to treatment. An analogous summary will be performed for AEs deemed at least possibly related to treatment.	Up to 5 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Michael Lim, Alliance for Clinical Trials in Oncology

Study record dates

Study Major Dates

• Study Start (Estimated): June 21, 2024
• Primary Completion (Estimated): July 15, 2028
• Study Completion (Estimated): July 15, 2028

Study Registration Dates

• First Submitted: March 20, 2024
• First Submitted That Met QC Criteria: March 20, 2024
• First Posted (Actual): March 22, 2024

Study Record Updates

• Last Update Posted (Actual): March 22, 2024
• Last Update Submitted That Met QC Criteria: March 20, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Disease Attributes; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Recurrence; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab; Immunoglobulins; Immunoglobulin G; Lomustine; Relatlimab
• Other Study ID Numbers: NCI-2024-01995 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U10CA180821 (U.S. NIH Grant/Contract); A072201 (Other Identifier: CTEP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No