Glioma Clinical Trials

• 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 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 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.

• 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 limit of normal (ULN)

• Renal function as follows:

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

⁃ 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

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

⁃ 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 at least 6 months 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. Acceptable methods of contraception are:

∙ Combined estrogen and progestin containing hormonal contraception associated with inhibition of ovulation given orally, intravaginally, or transdermally

‣ 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

‣ 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 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, must use a condom during intercourse and must agree to refrain from sperm donation, from registration on the study until 3 months after the last dose of treatment

⁃ 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 48 hours of starting the study drug(s)

⁃ Ability to adhere to the study visit schedule and all protocol requirements