Gliomatosis Cerebri Clinical Trials

• Have HLA-A\*0201 genotype as determined by genomic testing performed locally;

• Have histologically confirmed World Health Organization (WHO) Grade 4 glioblastoma, other WHO grade 4 malignant glioma or molecular GBM (based on the 2021 WHO Classification) at first recurrence. Patients with gliosarcoma are NOT eligible;

• Be willing and able to provide written informed consent/assent for the trial;

• Be ≥ 18 years of age on day of signing informed consent;

• Have a Karnofsky performance status (KPS) ≥ 70 (Appendix A);

• Participants must be at least 4 weeks from start of last chemotherapy cycle (at least 6 weeks for nitrosoureas and at least 1 week for metronomic dosing) and at least 4 weeks or 5 half-lives (whichever is shorter) for any prior investigational agent. There is no minimal time from cessation of Optune TTF nor for prior cancer vaccine therapy.

• MRI within 14 days prior to registration. MRIs should include vascular imaging when possible. Corticosteroid dose must be stable or decreasing for at least 5 days prior to the scan. If steroids are added or the steroid dose is increased between the date of the screening MRI scan and the start of treatment, a new baseline MRI or CT is required;

• Patients must have fully completed initial radiation therapy with or without daily temozolomide including 60 Gy in 30 fractions, 59.4 Gy in 1.8 Gy per fraction or equivalent;

• At least 12 weeks from completion of radiotherapy +/- temozolomide. Patients \< 12 weeks from the completion of radiation therapy may be eligible if they have either of the following: 1) histopathologic confirmation of recurrent tumor; or 2) new contrast enhancing disease outside the primary radiation field. Participants who have received investigational therapies as a component of treatment for newly diagnosed GBM as long as remaining eligibility criteria are satisfied;

• Participants must have recovered to grade 0 or 1 or pre-treatment baseline from clinically significant toxic effects of prior therapy (exceptions include alopecia, laboratory values listed per inclusion criteria, and lymphopenia, which is common after therapy with temozolomide);

• Participants must meet the following organ and marrow function as defined below, all screening labs should be performed within 14 days of registration:

‣ Absolute neutrophil count (ANC) ≥1,500 /mcL

⁃ Platelets ≥100,000 / mcL

⁃ Hemoglobin ≥9 g/dL or ≥5.6 mmol/L (Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks)

⁃ Serum creatinine ≤ 1.5 X institutional ULN OR

⁃ Measured or calculated creatinine clearance (CrCl) ≥45 mL/min for participant with creatinine levels \> 1.5 X institutional ULN (CrCl should be calculated per institutional standard, GFR can also be used in place of creatinine or CrCl)

⁃ Serum total bilirubin ≤ 1.5 X institutional ULN OR

⁃ Direct bilirubin ≤ institutional ULN for participants with total bilirubin levels \> 1.5 X institutional ULN

⁃ AST (SGOT) and ALT (SGPT) ≤ 3.0 X institutional ULN OR ≤ 5 X institutional ULN for participants with Gilberts syndrome

⁃ International Normalized Ratio (INR) OR Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) ≤1.5 X institutional ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants

⁃ Resting baseline oxygen saturation by pulse oximetry ≥92% at rest

• Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, must have a negative urine or serum pregnancy within 72 hours prior to enrollment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required;

⁃ -Women in the following categories are not considered WOCBP:

⁃ Premenarchal

⁃ Premenopausal female with 1 of the following:

• Documented hysterectomy

∙ Documented bilateral salpingectomy

∙ Documented bilateral oophorectomy

∙ Note: Documentation can come from the site personnel's review of the participant's medical records, medical examination, or medical history interview.

⁃ Postmenopausal female

• A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.

⁃ ----A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, confirmation with two FSH measurements in the postmenopausal range is required.

∙ Females on HRT and whose menopausal status is in doubt will be required to use one of the non-hormonal highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status before study enrollment.

• Women of child-bearing potential (WOCBP; see definition above), must agree to use a highly effective method of contraception consistently and correctly as described below during study treatment and for 120 days after study treatment discontinuation or the initiation of other cancer therapy (whichever is shorter);

‣ Highly Effective Contraceptive Methods That Are User Dependent a (Failure rate of \< 1% per year when used consistently and correctly.)

⁃ Combined (estrogen- and progestogen- containing) hormonal contraception

• i. Oral

∙ ii. Intravaginal

∙ iii. Transdermal

∙ iv. Injectable

⁃ Progestogen-only hormonal contraception

• v. Oral

∙ vi. Injectable

⁃ Highly Effective Methods That Have Low User Dependency (Failure rate of \<1% per year when used consistently and correctly)

• Progestogen- only contraceptive implant

∙ Intrauterine hormone-releasing system (IUS) Intrauterine device (IUD)

∙ Bilateral tubal occlusion

∙ Vasectomized partner (A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used).

∙ Sexual abstinence (Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatment. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant).

∙ NOTES: Use should be consistent with local regulations regarding the use of contraceptive methods for participants of clinical studies.

‣ a. Typical use failure rates are lower than perfect-use failure rates (i.e. when used consistently and correctly).

⁃ b. If hormonal contraception efficacy is potentially decreased due to interaction with study treatment, condoms must be used in addition to the hormonal contraception during the treatment period and for at least during study treatment and for 120 days after study treatment discontinuation after the last dose of study treatment or the initiation of other cancer therapy (whichever is shorter).

⁃ c. If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive implants are limited to those which inhibit ovulation.

• Male participants must agree to use at least one of the following methods of contraception starting with the first dose of study therapy through 120 days after the last dose of therapy or the initiation of other cancer therapy (whichever is shorter):

‣ Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent

⁃ Use a male condom plus partner use of a contraceptive method with a failure rate of \<1% per year when having penile-vaginal intercourse with a woman of childbearing potential who is not currently pregnant.

• a. Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile penetration.