Clinical trial NCT06325683: Anti-Lag-3 (Relatlimab) and Anti-PD-1 Blockade (Nivolumab) Versus Standard of Care (Lomustine) for the Treatment of Patients With Recurrent Glioblastoma
Official title: Randomized Phase II Trial of Anti-Lag-3 and Anti-PD-1 Blockade vs. SOC in Patients With Recurrent Glioblastoma
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE2
Conditions: Recurrent Glioblastoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2024-03-22
Enrollment: 184
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This phase II trial compares the safety, side effects and effectiveness of anti-lag-3 (relatlimab) 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. Relatlimab and nivolumab may be safe, tolerable, and/or effective compared to standard of care lomustine in treating patients with recurrent glioblastoma.

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. Additionally, patients undergo surgery or biopsy, magnetic resonance imaging (MRI), 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. Additionally, patients undergo surgery or biopsy, MRI, 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.

Eligibility criteria: 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, surgery, 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
* Calculated (calc.) creatinine clearance (CrCl): ≥ 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)

Primary outcomes:
measure: Overall survival (OS)
timeFrame: From randomization until death due to any cause, assessed at 30 months
measure: OS rate
timeFrame: From randomization until death due to any cause, assessed at 12 months
Secondary outcomes:
measure: Progression-free survival (PFS)
timeFrame: 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
measure: Radiographic response
timeFrame: Up to 5 years
measure: Incidence of adverse events (AEs)
timeFrame: Up to 5 years
Other outcomes:
Locations:
city: Auburn
country: United States
facility: Sutter Auburn Faith Hospital
state: California
city: Los Angeles
country: United States
facility: Kaiser Permanente Los Angeles Medical Center
state: California
city: Los Angeles
country: United States
facility: Cedars Sinai Medical Center
state: California
city: San Diego
country: United States
facility: Kaiser Permanente-San Diego Zion
state: California
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Trumbull
country: United States
facility: Smilow Cancer Hospital Care Center-Trumbull
state: Connecticut
city: Millville
country: United States
facility: Beebe South Coastal Health Campus
state: Delaware
city: Newark
country: United States
facility: Helen F Graham Cancer Center
state: Delaware
city: Newark
country: United States
facility: Medical Oncology Hematology Consultants PA
state: Delaware
city: Rehoboth Beach
country: United States
facility: Beebe Health Campus
state: Delaware
city: Boise
country: United States
facility: Saint Alphonsus Cancer Care Center-Boise
state: Idaho
city: Boise
country: United States
facility: Saint Luke's Cancer Institute - Boise
state: Idaho
city: Caldwell
country: United States
facility: Saint Alphonsus Cancer Care Center-Caldwell
state: Idaho
city: Coeur d'Alene
country: United States
facility: Kootenai Health - Coeur d'Alene
state: Idaho
city: Fruitland
country: United States
facility: Saint Luke's Cancer Institute - Fruitland
state: Idaho
city: Meridian
country: United States
facility: Saint Luke's Cancer Institute - Meridian
state: Idaho
city: Nampa
country: United States
facility: Saint Alphonsus Cancer Care Center-Nampa
state: Idaho
city: Nampa
country: United States
facility: Saint Luke's Cancer Institute - Nampa
state: Idaho
city: Post Falls
country: United States
facility: Kootenai Clinic Cancer Services - Post Falls
state: Idaho
city: Sandpoint
country: United States
facility: Kootenai Clinic Cancer Services - Sandpoint
state: Idaho
city: Bloomington
country: United States
facility: Illinois CancerCare-Bloomington
state: Illinois
city: Canton
country: United States
facility: Illinois CancerCare-Canton
state: Illinois
city: Carthage
country: United States
facility: Illinois CancerCare-Carthage
state: Illinois
city: Chicago
country: United States
facility: University of Illinois
state: Illinois
city: Decatur
country: United States
facility: Cancer Care Specialists of Illinois - Decatur
state: Illinois
city: Decatur
country: United States
facility: Decatur Memorial Hospital
state: Illinois
city: Dixon
country: United States
facility: Illinois CancerCare-Dixon
state: Illinois
city: Effingham
country: United States
facility: Crossroads Cancer Center
state: Illinois
city: Eureka
country: United States
facility: Illinois CancerCare-Eureka
state: Illinois
city: Evanston
country: United States
facility: NorthShore University HealthSystem-Evanston Hospital
state: Illinois
city: Galesburg
country: United States
facility: Illinois CancerCare-Galesburg
state: Illinois
city: Glenview
country: United States
facility: NorthShore University HealthSystem-Glenbrook Hospital
state: Illinois
city: Kewanee
country: United States
facility: Illinois CancerCare-Kewanee Clinic
state: Illinois
city: Macomb
country: United States
facility: Illinois CancerCare-Macomb
state: Illinois
city: Ottawa
country: United States
facility: Illinois CancerCare-Ottawa Clinic
state: Illinois
city: Pekin
country: United States
facility: Illinois CancerCare-Pekin
state: Illinois
city: Peoria
country: United States
facility: Illinois CancerCare-Peoria
state: Illinois
city: Peru
country: United States
facility: Illinois CancerCare-Peru
state: Illinois
city: Princeton
country: United States
facility: Illinois CancerCare-Princeton
state: Illinois
city: Shiloh
country: United States
facility: Memorial Hospital East
state: Illinois
city: Springfield
country: United States
facility: Southern Illinois University School of Medicine
state: Illinois
city: Springfield
country: United States
facility: Springfield Clinic
state: Illinois
city: Springfield
country: United States
facility: Springfield Memorial Hospital
state: Illinois
city: Washington
country: United States
facility: Illinois CancerCare - Washington
state: Illinois
city: Indianapolis
country: United States
facility: Franciscan Health Indianapolis
state: Indiana
city: Ames
country: United States
facility: Mary Greeley Medical Center
state: Iowa
city: Ames
country: United States
facility: McFarland Clinic - Ames
state: Iowa
city: Ankeny
country: United States
facility: UI Health Care Mission Cancer and Blood - Ankeny Clinic
state: Iowa
city: Boone
country: United States
facility: McFarland Clinic - Boone
state: Iowa
city: Carroll
country: United States
facility: Saint Anthony Regional Hospital
state: Iowa
city: Cedar Rapids
country: United States
facility: Mercy Hospital
state: Iowa
city: Cedar Rapids
country: United States
facility: Oncology Associates at Mercy Medical Center
state: Iowa
city: Clive
country: United States
facility: UI Health Care Mission Cancer and Blood - West Des Moines Clinic
state: Iowa
city: Des Moines
country: United States
facility: Iowa Methodist Medical Center
state: Iowa
city: Des Moines
country: United States
facility: UI Health Care Mission Cancer and Blood - Des Moines Clinic
state: Iowa
city: Des Moines
country: United States
facility: Broadlawns Medical Center
state: Iowa
city: Des Moines
country: United States
facility: UI Health Care Mission Cancer and Blood - Laurel Clinic
state: Iowa
city: Fort Dodge
country: United States
facility: McFarland Clinic - Trinity Cancer Center
state: Iowa
city: Fort Dodge
country: United States
facility: Trinity Regional Medical Center
state: Iowa
city: Iowa City
country: United States
facility: University of Iowa/Holden Comprehensive Cancer Center
state: Iowa
city: Jefferson
country: United States
facility: McFarland Clinic - Jefferson
state: Iowa
city: Marshalltown
country: United States
facility: McFarland Clinic - Marshalltown
state: Iowa
city: Lexington
country: United States
facility: University of Kentucky/Markey Cancer Center
state: Kentucky
city: South Portland
country: United States
facility: MaineHealth Cancer Care and IV Therapy - South Portland
state: Maine
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: Trinity Health Saint Joseph Mercy Hospital Ann Arbor
state: Michigan
city: Brighton
country: United States
facility: Trinity Health IHA Medical Group Hematology Oncology - Brighton
state: Michigan
city: Canton
country: United States
facility: Trinity Health IHA Medical Group Hematology Oncology - Canton
state: Michigan
city: Chelsea
country: United States
facility: Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital
state: Michigan
city: Flint
country: United States
facility: Cancer Hematology Centers - Flint
state: Michigan
city: Flint
country: United States
facility: Genesee Hematology Oncology PC
state: Michigan
city: Flint
country: United States
facility: Genesys Hurley Cancer Institute
state: Michigan
city: Flint
country: United States
facility: Hurley Medical Center
state: Michigan
city: Lansing
country: United States
facility: University of Michigan Health - Sparrow Lansing
state: Michigan
city: Livonia
country: United States
facility: Trinity Health Saint Mary Mercy Livonia Hospital
state: Michigan
city: Ypsilanti
country: United States
facility: Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus
state: Michigan
city: Brainerd
country: United States
facility: Essentia Health Saint Joseph's Medical Center
state: Minnesota
city: Deer River
country: United States
facility: Essentia Health - Deer River Clinic
state: Minnesota
city: Duluth
country: United States
facility: Essentia Health Cancer Center
state: Minnesota
city: Hibbing
country: United States
facility: Essentia Health Hibbing Clinic
state: Minnesota
city: Sandstone
country: United States
facility: Essentia Health Sandstone
state: Minnesota
city: Virginia
country: United States
facility: Essentia Health Virginia Clinic
state: Minnesota
city: Cape Girardeau
country: United States
facility: Saint Francis Medical Center
state: Missouri
city: Creve Coeur
country: United States
facility: Siteman Cancer Center at West County Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Saint Louis
country: United States
facility: Siteman Cancer Center-South County
state: Missouri
city: Saint Louis
country: United States
facility: Siteman Cancer Center at Christian Hospital
state: Missouri
city: Saint Peters
country: United States
facility: Siteman Cancer Center at Saint Peters Hospital
state: Missouri
city: Billings
country: United States
facility: Billings Clinic Cancer Center
state: Montana
city: Bozeman
country: United States
facility: Bozeman Health Deaconess Hospital
state: Montana
city: Great Falls
country: United States
facility: Benefis Sletten Cancer Institute
state: Montana
city: Missoula
country: United States
facility: Community Medical Center
state: Montana
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Morristown
country: United States
facility: Morristown Medical Center
state: New Jersey
city: Summit
country: United States
facility: Overlook Hospital
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Medical Center-Einstein Campus
state: New York
city: Glens Falls
country: United States
facility: Glens Falls Hospital
state: New York
city: New York
country: United States
facility: NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
state: New York
city: Pinehurst
country: United States
facility: FirstHealth of the Carolinas-Moore Regional Hospital
state: North Carolina
city: Fargo
country: United States
facility: Essentia Health Cancer Center-South University Clinic
state: North Dakota
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Ontario
country: United States
facility: Saint Alphonsus Cancer Care Center-Ontario
state: Oregon
city: Portland
country: United States
facility: Providence Portland Medical Center
state: Oregon
city: Portland
country: United States
facility: Providence Saint Vincent Medical Center
state: Oregon
city: Allentown
country: United States
facility: Lehigh Valley Hospital-Cedar Crest
state: Pennsylvania
city: Bethlehem
country: United States
facility: Lehigh Valley Hospital - Muhlenberg
state: Pennsylvania
city: East Stroudsburg
country: United States
facility: Pocono Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Wexford
country: United States
facility: Wexford Health and Wellness Pavilion
state: Pennsylvania
city: Burlington
country: United States
facility: University of Vermont Medical Center
state: Vermont
city: Burlington
country: United States
facility: University of Vermont and State Agricultural College
state: Vermont
city: Fairfax
country: United States
facility: Inova Schar Cancer Institute
state: Virginia
city: Ashland
country: United States
facility: Duluth Clinic Ashland
state: Wisconsin
city: Madison
country: United States
facility: University of Wisconsin Carbone Cancer Center - Eastpark Medical Center
state: Wisconsin
city: Madison
country: United States
facility: University of Wisconsin Carbone Cancer Center - University Hospital
state: Wisconsin
Study officials:
affiliation: Alliance for Clinical Trials in Oncology
name: Michael Lim
role: PRINCIPAL_INVESTIGATOR
References: