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

Phase 1

Recruiting

• Conditions: Glioblastoma
• Interventions: Drug: Treatment Period 1; Drug: Treatment Period 2; Drug: Treatment Period 3; Drug: Treatment Period 4a

• Registration Number: NCT05768919
• Lead Sponsor: SignPath Pharma, Inc.

Brief Summary

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).

Detailed Description

This study is a Phase Ib-IIa, 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 (XRT), and TMZ and adjuvant TMZ in newly diagnosed High-Grade Gliomas.

The secondary objectives are to estimate the safety and tolerability of LC in combination with standard XRT and TMZ and adjuvant TMZ, to determine the feasibility of treatment during first 10 week.

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: up to 24 in Study Part 1 and up to 6 in Study Part 2.

All patients will be treated with open-label intravenous (IV) LC on a weekly basis for a minimum of 34 infusions which begins following healing of glioma resection and at the approximate time of the initiation of SOC XRT and TMZ therapy. Patients will have LC therapy discontinued when there is either evidence of a) disease progression, b) safety concerns leading to discontinuation, or c) the patient requests to terminate LC therapy. LC weekly treatment will be continued following 34 weeks of treatment depending on patient's desires. Regular phone (or clinic) follow-up follows cessation of LC treatment (if stopped) to capture patient data on OS and PFS.

Study Timeline

• Study First Submitted: 2023-02-08
• Study First Submitted QC: 2023-03-02
• Study Start: 2023-03-03
• Study First Posted: 2023-03-15
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-26
• Last Update Posted: 2024-11-28
• Primary Completion: 2026-02
• Study Completion: 2027-05

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 30

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 XRT/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 XRT for 6 weeks and adjuvant TMZ for six 28-day cycles.

4. Karnofsky Performance Scale (KPS) ≥ 70%

   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 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 (XRT, 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 (i.e., 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
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, Fridericia formula (QTcF) (> 450 msec for males or > 460 msec for females)
9. Psychiatric illness or social situation that could limit compliance with study requirements
10. Pregnant or breastfeeding

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Tolerability, Safety, and Efficacy of LC in Combination with RT and TMZ	Treatment Period 1	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.
Tolerability, Safety, and Efficacy of LC in Combination with RT and TMZ	Treatment Period 2	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.
Tolerability, Safety, and Efficacy of LC in Combination with RT and TMZ	Treatment Period 3	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.
Tolerability, Safety, and Efficacy of LC in Combination with RT and TMZ	Treatment Period 4a	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.

Primary Outcome Measures

Name	Time	Method
The number of observed Dose Limiting Toxicity (DLTs)	The duration of treatment for each patient, minimum of 34 weeks	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.

Secondary Outcome Measures

Name	Time	Method
The incidence of Adverse Events	The duration of treatment for each patient, minimum of 34 weeks	The safety and tolerability of LC in combination with standard XRT/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 proportion of patients at each dose level who receive at least 80% of the planned infusions of LC, 80% of XRT, and 60% of TMZ during the first 10 weeks of treatment	10 weeks	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 XRT, and 60% of TMZ during the first 10 weeks of treatment.
Overall Survival (OS)	The duration of treatment for each patient, minimum of 34 weeks; OS is time from beginning of therapy to time of death.	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.
Progression free survival (PFS)	The duration of treatment for each patient, minimum of 34 weeks; PFS is time from the start of therapy until the date when tumor progression is documented	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.

Trial Locations

Locations (2)

Sibley Memorial Hospital; 🇺🇸 Washington, District of Columbia, United States

Johns Hopkins University/Johns Hopkins Hospital; 🇺🇸 Baltimore, Maryland, United States