A Multi-Center, Randomized, Phase 2 Trial of Glioblastoma Immunotherapy Advancement with Nivolumab and Relatlimab (GIANT)
This multicenter phase 2 immunotherapy trial will evaluate the combination of two immune checkpoint inhibitors, nivolumab and relatlimab, in patients with newly diagnosed isocitrate dehydrogenase (IDH)-wild-type glioblastoma.
After surgery, tissue samples will be analyzed using 3D spatial mapping and advanced cell sequencing methods to help physicians understand how well the drugs penetrate tumor cells and activate each patient’s immune system.
Inclusion Criteria
- Signed informed consent approved by the 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 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, the 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 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.
- If adequate archival tissue, defined as at least 3 blocks, is readily available, there is clear
- Hematological function as follows:
- Absolute neutrophil count ≥ 1.5 x 109/L
- Platelet count ≥ 100 x 109/L
- Hemoglobin> 90 g/L
- Prothrombin time (PT) or partial thromboplastin time (PTT) < 1.5 x upper limit of normal
(ULN). Patients with a 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.
- Renal function as follows:
- Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 40 ml/min using the
Cockcroft-Gault formula.
- Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 40 ml/min using the
- Hepatic function as follows:
- 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
- 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
- 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) DNA test at Screening - Negative hepatitis C antibody (anti-HCV) test at Screening, or positive test followed by a negative
HCV 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) - Vasectomized 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.
- Progestin-only hormonal contraception associated with inhibition of ovulation given orally,
- 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 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 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/chest-feeding.
- 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.
Investigator(s)
