Trial of Glioblastoma Immunotherapy Advancement With Nivolumab and Relatlimab

Inclusion Criteria:

1. Signed informed consent approved by the IRB

2. Adults ≥ 18 years of age

3. 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 systemictherapy for their brain tumor

4. Patients who in the opinion of the treating neurosurgeon require resection

5. Patient is willing to undergo planned surgical procedures

6. Patient agrees to make biospecimens that will be prospectively collected (after dateof consent) available for research

7. Patients who have undergone a diagnostic biopsy or open surgical procedure prior toenrolling in this study:

• If adequate archival tissue, defined as at least 3 blocks, is readilyavailable, there is clear documentation of its availability, and the patientmust consents to provide that tissue, the patient does not need to undergoanother 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 eitherresidual enhancing disease requiring resection, or molecularly confirmed GBMwith a clear clinical indication for additional resection, as determined by thecountry PI (or delegate) and the designated trial surgeon.

• If archival tissue is insufficient, or if the patient previously underwent aneedle biopsy and there is no clear documentation of tissue availability, andthe patient wishes to enroll, the patient must agree to undergo a repeat biopsyas part of this study prior to Screening.

8. Hematological function as follows:

• Absolute neutrophil count ≥ 1.5 x 109/L

• Platelet count ≥ 100 x 109/L

• Haemoglobin > 90 g/L

• Prothrombin time (PT) or partial thromboplastin time (PTT) < 1.5 x upper limitof normal (ULN)

9. Renal function as follows:

• Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 40 ml/min usingthe Cockcroft-Gault formula (Appendix 1)

10. Hepatic function as follows:

• Total bilirubin ≤ 1.5 x ULN (Exception: Patient has known or suspectedGilbert's Syndrome for which additional lab testing of direct and/or indirectbilirubin 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

11. Eastern Co-operative Oncology Group (ECOG) performance status of 0-1 (Appendix 2)

12. Life expectancy of at least 12 months

13. Negative human immunodeficiency virus (HIV) test at Screening

14. Negative hepatitis B surface antigen (HbsAg) test at Screening or positive testfollowed by a negative hepatitis B virus (HBV) DNA test at Screening

15. Negative hepatitis C antibody (anti-HCV) test at Screening or positive test followedby a negative HCV RNA test at Screening

16. Able to undergo brain MRI with and without contrast

17. People of childbearing potential must agree to use a highly effective contraceptivemethod (with a failure rate of < 1%) during study treatment and for at least 6months following the last dose of study drug and agree not to donate eggs (ova,oocytes) for the purpose of reproduction for the same time period. Acceptablemethods of contraception are:

• Combined estrogen and progestin containing hormonal contraception associatedwith inhibition of ovulation given orally, intravaginally, or transdermally

• Progestin-only hormonal contraception associated with inhibition of ovulationgiven orally, by injection, or by implant

• Intrauterine device: Intrauterine hormone-releasing system

• Bilateral tubal occlusion

• Vasectomised partner

• Sexual abstinence: Considered a highly effective method only if defined asrefraining from heterosexual intercourse during an entire period of riskassociated with the study treatment. The reliability of sexual abstinence needswill be evaluated in relation to the duration of the study and to the usuallifestyle of the patient Note: People are considered post-menopausal and not ofchildbearing potential if they have had 12 months of natural (spontaneous)amenorrhea with an appropriate clinical profile (e.g. age appropriate historyof vasomotor symptoms) or have had surgical bilateral oophorectomy (with orwithout hysterectomy), total hysterectomy or tubal ligation at least 6 weeksago. In the case of oophorectomy alone, only when the reproductive status ofthe person has been confirmed by follow-up hormone level assessment are theyconsidered not of childbearing potential.

18. Sexually active patients that are able to produce a sperm, must use a condom duringintercourse and must agree to refrain from sperm donation, from registration on thestudy until 3 months after the last dose of treatment

19. People of childbearing potential must have a negative highly sensitive serumpregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionicgonadotropin) at the time of screening and within 48 hours of starting the studydrug(s)

20. Ability to adhere to the study visit schedule and all protocol requirements

Exclusion Criteria:

1. Tumors where a gross total resection is not considered feasible by the treatingneurosurgeon

2. Tumor involves cerebellum, brainstem, or deep basal ganglia

3. Patients who require urgent resection for mass effect, cerebral edema, orhydrocephalus in the opinion of the treating neurosurgeon

4. Patients with contraindications to MRI or unwilling to undergo MRI

5. History of CNS bleeding as defined by stroke within 6 months prior to registration

6. Contraindication to surgery

7. Treatment with immunosuppressive medications Note: Low-dose corticosteroids (≤ 2mg/day dexamethasone or equivalent) for tumor-associated edema is permitted.Patients who require corticosteroids > 2mg/day dexamethasone (or equivalent) foracute emergencies during the screening window will be eligible, if thecorticosteroid dosing reduces to ≤ 2 mg/day dexamethasone (or equivalent) at leastone day prior to the initial trial-mandated biopsy.

8. 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 antibodysyndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, ormultiple sclerosis

9. Active tuberculosis

10. 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 treatingphysician's assessment, there are no sequelae that would place the patient at ahigher risk of receiving trial treatment

11. Evidence of acute intracranial/intra-tumoral hemorrhage, which requires urgentintervention

12. Severe infection within 4 weeks prior to registration

13. Treatment with a live, attenuated vaccine within 4 weeks prior to registration, oranticipation of need for such a vaccine during study or within 5 months after finaldose of nivolumab and relatlimab

14. Patients with prior, unrelated malignancy requiring current active treatment withthe exception of cervical carcinoma in situ and adequately treated basal cell orsquamous cell carcinoma of the skin or other malignancies with no evidence ofdisease for 2 years or more

15. Major surgical procedure, other than for diagnosis, within 4 weeks prior toregistration

16. History of idiopathic pulmonary fibrosis, organising pneumonia (e.g., bronchiolitisobliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence ofactive pneumonitis Note: History of radiation pneumonitis in the radiation field (fibrosis) is permitted

17. Patient is pregnant or breastfeeding/chestfeeding

18. Prior allogeneic stem cell or solid organ transplantation

19. Known allergy or sensitivity nivolumab, relatlimab, temozolomide or their excipients

20. Patient has any kind of disorder that, in the opinion of the site PI, may compromisethe ability of the patient to give written informed consent and/or to comply withall required study procedures

21. Patients with a history of myocarditis

22. Patient has troponin T (TnT) or I (TnI) > 2 × ULN Note: Patients with TnT or TnIlevels between > 1 × to 2 × ULN will be eligible if repeat levels within 24 hoursare ≤ 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 hoursare not available, a repeat test should be conducted as soon as possible. If TnT orTnI repeat levels beyond 24 hours are < 2 × ULN, the patient must be evaluated by acardiologist. After cardiologist evaluation, the patient may be eligible if the sitePI assesses a favorable benefit/risk

23. Left ventricular ejection fraction (LVEF) < 50% by either echocardiogram (ECHO) ormultigated acquisition (MUGA) scan within 6 months prior to registration

24. History or evidence of any other clinically significant disorder, condition, ordisease (with the exception of those outlined above) that, in the opinion of thesite PI would pose a risk to patient safety or interfere with the study evaluation,procedures or completion