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Ondansetron

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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.

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

Concurrent 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

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: 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

Adjuvant Period

Vice President Regulatory Affairs and Operations

President, CEO

Matthias Holdhoff, MD, PhD

Stuart Grossman, MD, PhD

David Kamson, MD, PhD

Jaishri Blakeley, MD, PhD

Lawrence Kleinberg, MD, PhD

John Laterra, MD, PhD

Kristin Redmond, MD, PhD

Karisa Schreck, MD, PhD

Carlos Romo, MD, PhD

Peter Sordillo, MD, PhD

The objective of this study is to assess the tolerability, safety, and efficacy of Liposomal Curcumin (LC) in combination with radiotherapy (RT) and Temozolomide (TMZ) in patients with newly diagnosed High-Grade Gliomas (HGG).

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.

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. There will be a maximum of 4 dose levels assessed in this study. The Safety Review Committee (SRC) will oversee dose level decisions throughout the dose escalation phase of the study.

Study of Liposomal Curcumin in Combination With RT and TMZ in Patients With Newly Diagnosed High-Grade Gliomas

Phase I/II Study of the Tolerability, Safety, and Efficacy of Liposomal Curcumin in Combination With Radiation and Temozolomide in Patients With Newly Diagnosed High-Grade Gliomas

The MTD/RP2D of LC in combination with RT and TMZ and adjuvant TMZ in newly diagnosed HGG will be determined by recording the number of observed dose limiting toxicities (DLTs). DLTs, as defined in this study occur if in the first three patients entered at a dose-level, more than one of these 3 experiences a serious adverse event, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5. If one of the first three patients entered at the level experiences an SAE (as defined by NCI CTCAE Version 5), then three additional patients are entered at that same dose level. If one of the additional three patients experiences an SAE (as defined by NCI CTCAE Version 5), the dose is not advanced beyond that level.

The safety and tolerability of LC infused IV over 3 hours will be assessed by recording the number of observed DLTs. DLTs, as defined in this study occur if in the first three patients entered at a dose-level, more than one of these 3 experiences a serious adverse event, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5. If one of the first three patients entered at the level experiences an SAE (as defined by NCI CTCAE Version 5), then three additional patients are entered at that same dose level. If one of the additional three patients experiences an SAE (as defined by NCI CTCAE Version 5), the dose is not advanced beyond that level.

The safety and tolerability of LC in combination with standard RT/TMZ and adjuvant TMZ will be assessed by recording the incidence of Adverse Events (AEs) using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.

Subjects will undergo medical history evaluations, physical and neurological examinations, brain MRI, functional assessment using the Karnofsky Performance Scale (KPS) Index, vital sign measurements, weight, adverse event assessments, concomitant medication assessments, and laboratory testing including but not limited to blood sample collection for hematology and chemistry, urinalysis, coagulation, lipid panel, electrocardiogram, and pregnancy test for females of childbearing potential.

The feasibility of weekly LC infusion will be assessed by recording the proportion of patients at each dose level who are able to complete at least 80% of the planned infusions of LC, 80% of RT, and 60% of TMZ during the first 10 weeks of treatment.

The efficacy of weekly LC infusion will be assessed by recording overall survival (OS) at each dose level, defined as the duration of time from the start of treatment with LC to time of death.

The efficacy of weekly LC infusion will be assessed by recording progression free survival (PFS) based on Response Assessment in Neuro-Oncology (RANO) criteria at each dose level, defined as defined as the duration of time from the start of treatment with LC to time of progression or death.

Avance Clinical Pty Ltd.

SignPath Pharma, Inc.

Spots Global Cancer Trial Database for adjuvant period