Testing the Addition of an Anti-Cancer Drug, Triapine, to the Usual Radiation Therapy for Recurrent Glioblastoma or Astrocytoma

Inclusion Criteria:

• Patients must have histologically, molecularly, or cytologically confirmed recurrentastrocytic tumors including:

• GBM or variants, IDH-wildtype, grade 2-4 (standard curative measures availableor not)

• Astrocytoma, IDH-mutant, grade 2-4 (standard curative measures available ornot)

• Diffuse midline gliomas, including pediatric-type H3 G34 or E3 K27 mutanttumors.

• Tumors ≤ 6 cm in maximal diameter.

• Patients who had recent resection for recurrent tumor must have measurabledisease.

• Patients must have at least a 6-month break from last dose of radiation therapy.

Re-irradiation within 6 months may increase risk for radiation necrosis/edema, which will affect toxicity assessment and patient safety. Additionally, GBM and other high-grade astrocytic tumors can exhibit pseudo-progression within 6 months from completing definitive, 1st line radiation therapy, and re-irradiation during this period will increase risk for misattribution of effect.

• Prior history of standard dose radiation for gliomas of 59.4-60 gray (Gy) in 1.8-2Gy per fraction (or equivalent or lower) is allowed.

• Patients who received non-standard radiation dose regimen (e.g., 40 Gy, 34-35 Gy, 25Gy) or stereotactic radiosurgery are eligible as long as there is at least one ofthe following:

• A new tumor outside the original radiotherapy field as determined by theinvestigator.

• There is histologic confirmation of tumor on biopsy or resection.

• Imaging findings are consistent with true progressive disease (on standard MRIsequences, MRI spectroscopy/perfusion, or nuclear medicine imaging).

• Age ≥ 18 years. Because no dosing or adverse event data are currently available onthe use of triapine in patients < 18 years of age, children are excluded from thisstudy.

• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%).

• Absolute neutrophil count ≥ 1,500/mcL.

• Hemoglobin ≥ 8 g/dL.

• Platelets ≥ 100,000/mcL.

• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 3 x institutional ULN.

• Creatinine ≤ 1.5 x ULN OR glomerular filtration rate (GFR) ≥ 50 mL/min/1.73 m^2.

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months are eligible for this trial.

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated.

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load.

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial.

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, patients should be class II or better.

• Patients must be able to swallow whole capsules.

• Patients must be able to undergo MRIs with contrast. Patients with non-compatibledevices with MRI can be eligible if CT scans of sufficient quality are obtained.However, patients without non-compatible devices may not use CT scans to meet thisrequirement.

• The effects of triapine on the developing human fetus are unknown. For this reasonand because ribonucleotide reductase (RNR) inhibitor agent and radiation are knownto be teratogenic, women of child-bearing potential and men must agree to useadequate contraception (hormonal or barrier method of birth control; abstinence)prior to study entry, for the duration of study participation, and for 12 monthsafter finishing study treatment. People of child-bearing potential must have anegative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalentunits of human chorionic gonadotropin [HCG]) within 2 weeks of registration. Shoulda woman become pregnant or suspect she is pregnant while she or her partner isparticipating in this study, she should inform her treating physician immediately.Men treated or enrolled on this protocol must also agree to use adequatecontraception prior to the study, for the duration of study participation, and 12months after completion of triapine administration.

• Ability to understand and the willingness to sign a written informed consentdocument. Legally authorized representatives may sign and give informed consent onbehalf of study participants.

Exclusion Criteria:

• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia.

• Patients who are receiving any other investigational agents.

• Patients who are actively taking medications that are known to inducemethemoglobinemia (e.g. sulfonamides, nitrofurans, anti-malarials [primaquine,chloroquine], cyclophosphamide, and ifosfamide).

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to triapine.

• Patients with known G6PD deficiency. Testing for G6PD deficiency is not required.

• Patients with uncontrolled intercurrent illness, active infections, or any othersignificant condition(s) that would make participation in this protocol unreasonablyhazardous.

• Pregnant women are excluded from this study because triapine is a RNR inhibitoragent with the potential for teratogenic or abortifacient effects. Because there isan unknown but potential risk for adverse events in nursing infants secondary totreatment of the mother with triapine, breastfeeding should be discontinued if themother is treated with triapine. These potential risks may also apply to theradiation used in this study.