Nivolumab with or without Relatlimab given Prior to Surgery and Temozolomide and Radiation Therapy for the Treatment of IDH Wildtype Newly Diagnosed Glioblastoma
This phase II trial tests how well nivolumab, administered alone or in combination with relatlimab, given prior to surgery to remove the brain tumor, followed by nivolumab and relatlimab given after surgery, in combination with standard radiation therapy with or without temozolomide, then followed by nivolumab and relatlimab with or without temozolomide works in treating patients with isocitrate dehydrogenase (IDH) wildtype newly diagnosed glioblastoma (ndGBM). Nivolumab and relatlimab are a type of monoclonal antibody and a type of immune checkpoint inhibitor. The combination of nivolumab and relatlimab binds to the proteins PD-1 and LAG-3, which are found on T cells (a type of immune cell). Blocking these proteins may help the immune system kill tumor cells. The combination of nivolumab and relatlimab may work better than either drug alone. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Temozolomide (TMZ) is in a class of medications called alkylating agents. It works by damaging the cell's Deoxyribonucleic acid (DNA) and may kill tumor cells and slow down or stop tumor growth. Giving nivolumab with or without relatlimab prior to surgery and temozolomide and radiation therapy may work better in treating patients with IDH wildtype newly diagnosed glioblastoma.
Inclusion Criteria
- Signed informed consent approved by the Institutional Review Board (IRB)
- Adults ≥ 18 years of age
- Patients with either: * A newly suspected diagnosis of GBM based on MRI * A previous diagnosis of GBM and who have not received prior RT or systemic therapy for their brain tumor
- Patients who in the opinion of the treating neurosurgeon require resection
- Patient is willing to undergo planned surgical procedures
- Patient agrees to make biospecimens that will be prospectively collected (after date of consent) available for research
- Patients who have undergone a diagnostic biopsy or open surgical procedure prior to enrolling in this study: * If adequate archival tissue, defined as at least 3 blocks, is readily available, there is clear documentation of its availability, and the patient must consents to provide that tissue, the patient does not need to undergo another biopsy prior to, or on study, in order to be eligible for this trial. * If archival tissue is sufficient as described above, patient must have either residual enhancing disease requiring resection, or molecularly confirmed GBM with a clear clinical indication for additional resection, as determined by the country principal investigator (PI) (or delegate) and the designated trial surgeon. * If archival tissue is insufficient, or if the patient previously underwent a needle biopsy and there is no clear documentation of tissue availability, and the patient wishes to enroll, the patient must agree to undergo a repeat biopsy as part of this study prior to screening
- Absolute neutrophil count ≥ 1.5 x 10^9/L
- Platelet count ≥ 100 x 10^9/L
- Hemoglobin > 90 g/L
- Prothrombin time (PT) or partial thromboplastin time (PTT) < 1.5 x upper limit of normal (ULN). Patients with prior history of thrombosis/embolism are allowed to be on anticoagulation, understanding that anticoagulation will be held in the perioperative period per the neurosurgical team’s recommendations. Low molecular weight heparin is preferred. Warfarin and similar anticoagulants in the vitamin K antagonist (VKA) class are not allowed
- Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 40 ml/min using the Cockcroft-Gault formula
- Total bilirubin ≤ 1.5 x ULN (Exception: Patient has known or suspected Gilbert’s Syndrome for which additional lab testing of direct and/or indirect bilirubin supports this diagnosis. In these instances, a total bilirubin of ≤ 3.0 x ULN is acceptable)
- Alkaline phosphatase (ALP) ≤ 2.5 x ULN
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN
- Serum albumin ≥ 25 g/L
- Eastern Co-operative Oncology Group (ECOG) performance status of 0-1
- Life expectancy of at least 12 months
- Negative human immunodeficiency virus (HIV) test at screening
- Negative hepatitis B surface antigen (HbsAg) test at screening, or positive test followed by a negative hepatitis B virus (HBV) deoxyribonucleic acid (DNA) test at screening
- Negative hepatitis C antibody (anti-HCV) test at screening, or positive test followed by a negative HCV ribonucleic acid (RNA) test at screening
- Able to undergo brain MRI with and without contrast
- People of childbearing potential must agree to use a highly effective contraceptive method (with a failure rate of < 1%) during study treatment and for either 6 months following the last dose of TMZ or 5 months after the last dose of study drug, and agree not to donate eggs (ova, oocytes) for the purpose of reproduction for the same time period. Acceptable methods of contraception are: * Progestin-only hormonal contraception associated with inhibition of ovulation given orally, by injection, or by implant * Intrauterine device: Intrauterine hormone-releasing system * Bilateral tubal occlusion * Double-barrier contraception methods can be utilized and may include the use of a condom with an occlusive cap (such as a diaphragm or cervical cap) * Vasectomised partner * Sexual abstinence: Considered a highly effective method only if defined as refraining from heterosexual intercourse during an entire period of risk associated with the study treatment. The reliability of sexual abstinence needs will be evaluated in relation to the duration of the study and to the usual lifestyle of the patient * Note: People are considered post-menopausal and not of childbearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 6 weeks ago. In the case of unilateral oophorectomy alone, only when the reproductive status of the person has been confirmed by follow-up hormone level assessment are they considered not of childbearing potential
- Sexually active patients that are able to produce a sperm, and their partners, must agree to use 1 highly effective method of contraception as outlined in inclusion criteria #17 during study treatment and, if the patient receives TMZ, for 3 months after their last dose of TMZ, and agree to avoid impregnating a parter and donating sperm for the same time period
- People of childbearing potential must have a negative highly sensitive serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) at the time of screening and within 24 hours of starting the study drug(s)
- Ability to adhere to the study visit schedule and all protocol requirements
Exclusion Criteria
- Tumors where a gross total resection is not considered feasible by the treating neurosurgeon
- Tumor involves cerebellum, brainstem, or deep basal ganglia
- Patients who require urgent resection for mass effect, cerebral edema, or hydrocephalus in the opinion of the treating neurosurgeon
- Patients with contraindications to MRI or unwilling to undergo MRI
- History of central nervous system (CNS) bleeding as defined by stroke within 6 months prior to registration
- Contraindication to surgery
- Treatment with immunosuppressive medications * Note: Low-dose corticosteroids (≤ 2 mg/day dexamethasone or equivalent) for tumor-associated edema is permitted. Patients who require corticosteroids > 2mg/day dexamethasone (or equivalent) for acute emergencies during the screening window will be eligible, if the corticosteroid dosing reduces to ≤ 2 mg/day dexamethasone (or equivalent) at least one day prior to diagnostic biopsy
- Active autoimmune disease or immune deficiency including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis
- Active tuberculosis
- Patient has had a previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection either suspected or confirmed within 4 weeks prior to screening. Acute symptoms must have resolved and based on treating physician’s assessment, there are no sequelae that would place the patient at a higher risk of receiving trial treatment
- Evidence of acute intracranial/intra-tumoral hemorrhage, which requires urgent intervention
- Severe infection within 4 weeks prior to registration
- Treatment with a live, attenuated vaccine within 4 weeks prior to registration, or anticipation of need for such a vaccine during study or within 5 months after final dose of nivolumab and relatlimab
- Patients with prior, unrelated malignancy requiring current active treatment with the exception of cervical carcinoma in situ and adequately treated basal cell or squamous cell carcinoma of the skin or other malignancies with no evidence of disease for 2 years or more
- Major surgical procedure, other than for diagnosis, within 4 weeks prior to registration
- History of idiopathic pulmonary fibrosis, organising pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis * Note: History of radiation pneumonitis in the radiation field (fibrosis) is permitted
- Patient is pregnant or breastfeeding/chestfeeding
- Prior allogeneic stem cell or solid organ transplantation
- Known allergy or sensitivity nivolumab, relatlimab, temozolomide or their excipients
- Patient has any kind of disorder that, in the opinion of the site PI or delegate, may compromise the ability of the patient to give written informed consent and/or to comply with all required study procedures
- Patients with a history of myocarditis
- Patient has troponin T (TnT) or I (TnI) > 2 × ULN * Note: Patients with TnT or TnI levels between > 1 × to 2 × ULN will be eligible if repeat levels within 24 hours are ≤ 1 × ULN. If TnT or TnI levels are between > 1 × to 2 × ULN within 24 hours, the patient must be evaluated by a cardiologist. When repeat levels within 24 hours are not available, a repeat test should be conducted as soon as possible. If TnT or TnI repeat levels beyond 24 hours are < 2 × ULN, the patient must be evaluated by a cardiologist. After cardiologist evaluation, the patient may be eligible if the site PI or delegate assesses a favorable benefit/risk
- Left ventricular ejection fraction (LVEF) < 50% by either echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 6 months prior to registration
- History or evidence of any other clinically significant disorder, condition, or disease (with the exception of those outlined above) that, in the opinion of the site PI or delegate would pose a risk to patient safety or interfere with the study evaluation, procedures or completion
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT06816927.
Locations matching your search criteria
United States
North Carolina
Durham
PRIMARY OBJECTIVES:
I. To assess the safety of concurrently administering nivolumab, relatlimab, radiation therapy (RT), with or without TMZ during part 1 of the adjuvant treatment phase in ndGBM patients, with a specific go-no go focus on MGMT methylated patients receiving TMZ. (Stage 1 – Safety Lead-In)
II. To assess the feasibility of undertaking a peri-operative study involving administration of nivolumab with or without relatlimab in patients with ndGBM. (Stage 2 – Randomized Phase 2)
III. To establish the biological activity of nivolumab administered with or without relatlimab in patients with ndGBM, by demonstrating the presence of tumor infiltrating lymphocytes (TILs) in the resected tumor
SECONDARY OBJECTIVES:
I. To describe the toxicity of nivolumab administered with or without relatlimab during the neoadjuvant phase in patients with ndGBM following tumor biopsy, and prior to surgical resection of their tumor.
II. To assess the safety of planned craniotomy and tumor resection performed after biopsy and neoadjuvant treatment with nivolumab administered with or without relatlimab in patients with ndGBM.
III. To determine the toxicity of nivolumab administered with relatlimab during the adjuvant phase, following surgical resection of their tumor in patients with ndGBM.
IV. To estimate the radiological response rate of nivolumab administered with or without relatlimab in ndGBM
V. To describe survival of patients who have been assigned (as in the stage 1 safety lead-in) or randomized (stage 2) to receive neoadjuvant nivolumab administered with or without relatlimab.
EXPLORATORY OBJECTIVES:
I. To assess the pharmacokinetics (PK) of nivolumab administered with or without relatlimab during the neoadjuvant phase following biopsy, and prior to tumor resection for patients with ndGBM.
II. To assess the impact of nivolumab administered with or without relatlimab on the operability of GBM.
III. To assess the peripheral immune response to nivolumab administered with or without relatlimab.
IV. To assess the microbiome changes in response to nivolumab administered with or without relatlimab.
V. To assess the potential mechanisms of response and resistance to nivolumab administered with or without relatlimab.
VI. To compare neoantigen profile and tumor mutational burden (TMB) between biopsy and resection.
VII. To describe cell-free DNA (cfDNA) levels in plasma and cerebrospinal fluid (CSF), and perform single-cell ribonucleic acid (RNA) (scRNA) sequencing of CSF.
VIII. To describe cell populations in skull bone marrow from samples collected during biopsy (baseline), tumor resection, and future craniotomies, if clinically indicated.
IX. To describe neurological function during nivolumab treatment, administered with or without relatlimab as measured by the Neurologic Assessment in Neuro-Oncology (NANO) scale.
X. To assess patient experience and acceptability of undertaking a perioperative clinical trial in glioblastoma (GBM).
OUTLINE:
STAGE I: Patients receive neoadjuvant nivolumab and relatlimab intravenously (IV) over 30 minutes on day 1 of cycle 1. Within 14 days, patients then undergo surgical resection of their tumor. During Part I adjuvant therapy, patients receive nivolumab and relatlimab IV over 30 minutes on day 1 and 29 and may receive TMZ orally (PO) on days 1-42 of cycle 2. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients also undergo RT once daily, 5 days per week for 6 weeks. During Part II adjuvant therapy, patients receive nivolumab and relatlimab IV over 30 minutes on day 1 of cycles 3-14 and may receive TMZ PO on days 1-5 for cycles 3-8. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
STAGE II: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive nivolumab IV over 30 minutes on day 1 of cycle 1. Within 14 days, patients then undergo surgical resection of their tumor. Patients then undergo Part I and II adjuvant therapy as described in Stage I.
ARM II: Patients receive nivolumab and relatlimab IV over 30 minutes on day 1 of cycle 1. Within 14 days, patients then undergo surgical resection of their tumor. Patients then undergo Part I and II adjuvant therapy as described in Stage I.
In both stages, patients also undergo tissue biopsy and Ommaya reservoir placement on study. Additionally, patients undergo echocardiogram (ECHO) or multigated acquisition (MUGA) scan during screening, magnetic resonance imaging (MRI), blood, urine, skull bone fragment, saliva and CSF sample collection throughout the study.
After completion of study treatment, patients are followed up on day 135 and then every 12 weeks for up to 2 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationDuke University Medical Center
Principal InvestigatorMustafa Khasraw
- Primary IDPRO00116940
- Secondary IDsNCI-2026-00237
- ClinicalTrials.gov IDNCT06816927