Clinical Trial Finder

Inclusion Criteria:

1. ≥18 years of age. 2. Histologically confirmed HGG (WHO grade III or IV, including GBM, astrocytoma, gliosarcoma, H3K27M mutant diffuse midline glioma). Patients with methylated or unmethylated O(6)-methylguanine-DNA methyltransferase (MGMT) promoter are eligible, as are IDH WT and mutant patients as long as the treatment plan is for combined RT/TMZ. The neuropathologic diagnosis of HGG will be made at the respective institution. If any question arises regarding the accuracy of the neuropathologic diagnosis, slides (and pathological blocks, if necessary) will be centrally reviewed. 3. Planning standard therapy with TMZ and RT for 6 weeks. 4. Karnofsky Performance Scale (KPS) ≥ 60% Adequate organ and marrow function defined as:

• - Hgb > 9 g/dL.

• - ANC ≥ 1500/µL.

• - Platelet count ≥ 100,000/µL.

• - Total bilirubin ≤ 1.5 * institutional ULN.

• - AST and ALT ≤ 3 * institutional ULN.

• - Creatinine ≤ 1.5 * institutional ULN OR.

• - Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 unless data exist supporting safe use at lower values of renal function, but eGFR must be ≥ 30 mL/min/1.73 m2.

5. Patients with human immunodeficiency virus (HIV) who are on effective antiretroviral therapy are eligible if the viral load was assessed as undetectable within 6 months prior to baseline. 6. Women: WOCBP must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for the duration of study participation. 7. Men: must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 4 months after completion of LC administration.

Exclusion Criteria:

1. Any concurrent cancer diagnosis that is untreated, actively treated, or has undergone any therapy (RT, cytotoxic, targeted, immunotherapeutic, etc) within 2 years of study enrollment, with the exception of squamous or basal cell skin cancer. 2. Patient has not recovered from AEs due to prior anticancer therapy (ie, residual toxicities > Grade 1), with the exception of alopecia. 3. Receiving any other investigational agent. 4. Active infection requiring systemic antibiotics. 5. History of allergic reaction to compounds that are chemically or biologically similar to LC (see Protocol Section 5.5.1.2 and Section 5.5.1.3 of protocol) 6. Patient is taking a medication that may potentiate hemolysis. 7. Unstable angina or myocardial infarction within the past 6 months. 8. Prolonged QTc interval, Bazett formula (QTcB) (> 450 msec for males or > 460 msec for females) 9. Psychiatric illness or social situation that could limit compliance with study r requirements. 10. Pregnant or breastfeeding

This study is a Phase 1/2, single-center, single-institution, open-label, dose-escalation study in patients with newly diagnosed high-grade malignant gliomas. Dose finding will be performed using a time-to-event Bayesian optimal interval (TITE-BOIN) rule-based schema. The primary objectives of the study are to determine the maximum tolerated dose /recommended phase 2 dose of Liposomal Curcumin (LC) in combination with radiotherapy (RT), and TMZ and adjuvant TMZ in newly diagnosed High-Grade Gliomas, and to determine the safety and tolerability of LC IV infused over 3-hours. The secondary objectives are to estimate the safety and tolerability of LC in combination with standard RT and TMZ and adjuvant TMZ, to determine the feasibility of weekly LC infusion, defined as the number of patients being able to complete 80% of the planned doses of LC, 80% of RT, and 60% of TMZ within the first 10 weeks of treatment, and to assess efficacy as defined by overall survival (OS) and progression free survival (PFS) observed for each dose level. This study is an unblinded, sequential treatment intervention employing 3 dose levels. Approximately 50 patients will be screened to achieve up to 30 patients assigned to study intervention. The duration of treatment for each patient will be up to 34 weeks. Treatment starts with the beginning of infusion and ends, if tolerated, at the end of Cycle 6 of adjuvant TMZ.

Arms

Experimental: Tolerability, Safety, and Efficacy of LC in Combination with RT and TMZ

Define the MTD/recommended Phase 2 dose (RP2D) of LC, administered IV weekly in combination with standard CRT (60 Gy in 30-33 fractions M-F, and daily oral TMZ 75 mg/m2), in patients with high grade malignant gliomas. This study seeks the MTD/RP2D of LC when added to TMZ during concurrent RT and adjuvant TMZ after RT. The study will evaluate escalating doses of LC delivered by IV infusion weekly as a gravity infusion (without infusion pump). Within each cohort, the dose will remain the same. In the first cohort, dosing will begin at Level 1 (300 mg/m2). The infusion of LC will begin at the start of CRT. Patients will be evaluable for the cohort if they have completed 80% of the planned doses of LC, 80% of RT and 60% of TMZ within the first 10 weeks of treatment. Patients who experience a dose-limiting toxicity (DLT) will be evaluable for the cohort if they have received at least 1 dose of LC.

Interventions

Drug: - Concurrent CRT Period

Agent: LipoCurc Premedication/Precautions: Dexamethasone 4mg IV, Diphenhydramine 25 mg IV - Dose: per treatment assignment Route: IV over 3 hours Schedule: Weekly: Weeks 1,2, 3,4,5,6 Cycle length: 6 weeks Agent: TMZ Premedications/Precautions No food 2 hr before and after dosing Antiemetic (eg, ondansetron, prochlorperazine) 30 minutes before dosing Stool softener PRN. Dose: 75 mg/m2 Route: Oral Schedule: Daily during term of RT Cycle Length: 6 weeks Agent: Radiotherapy Premedications/Precautions: n/a Dose: 2 Gy Route: External beam therapy Schedule: Monday-Friday Cycle Length 6 weeks

Drug: - Post-CRT Period

Agent: LipoCurc Premedication/Precautions: Dexamethasone 4 mg IV Diphenhydramine 25 mg IV Dose: Per treatment assignment Route: IV over 3 hours Schedule: Weekly: Weeks 7,8,9,10 Cycle length: 4 weeks

Drug: - Adjuvant Period

Agent: LipoCurc Premedication/Precautions: Dexamethasone 4 mg IV Diphenhydramine 25 mg IV Dose: Per treatment assignment Route: IV over 3 hours Schedule: Weekly: Adjuvant Cycles 1-6: Weeks 1, 2, 3, 4 of each cycle Cycle Length: 4 weeks Agent: TMZ Premedication/Precautions: No food 2 hr before and after dosing. Antiemetic (eg, ondansetron, prochlorperazine) 30 minutes before dosing Stool softener prn Dose: 150-200 mg/m2 (Cycles 1-6) Route: Oral Schedule: Daily Cycle Length: 4 weeks