Clinical trial NCT05768919: Study of Liposomal Curcumin in Combination With RT and TMZ in Patients With Newly Diagnosed High-Grade Gliomas
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Glioblastoma
Keywords: High Grade Gliomas
Lead sponsor: SignPath Pharma, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Avance Clinical Pty Ltd.
First posted: 2023-03-15
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention model description: This study seeks the MTD/RP2D of LC when added to TMZ during concurrent XRT and adjuvant TMZ after XRT. 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.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: The number of observed Dose Limiting Toxicity (DLTs)
timeFrame: 10 weeks
measure: The number of observed Dose Limiting Toxicity (DLTs)
timeFrame: The duration of treatment for each patient, minimum of 34 weeks
Secondary outcomes:
measure: The incidence of Adverse Events
timeFrame: The duration of treatment for each patient, minimum of 34 weeks
measure: 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
timeFrame: 10 weeks
measure: Overall Survival (OS)
timeFrame: The duration of treatment for each patient, minimum of 34 weeks; OS is time from beginning of therapy to time of death.
measure: Progression free survival (PFS)
timeFrame: 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
Other outcomes:
Locations:
city: Washington
country: United States
facility: Sibley Memorial Hospital
state: District of Columbia
city: Baltimore
country: United States
facility: Johns Hopkins University/Johns Hopkins Hospital
state: Maryland
Study officials:
affiliation: Johns Hopkins University
name: Matthias Holdhoff, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: SignPath Pharma
name: Peter Sordillo, MD, PhD
role: STUDY_DIRECTOR
References:
citation: Sordillo PP, Sordillo LA, Helson L. The Kynurenine Pathway: A Primary Resistance Mechanism in Patients with Glioblastoma. Anticancer Res. 2017 May;37(5):2159-2171. doi: 10.21873/anticanres.11551.
citation: Glioblastoma cell-induced immunosuppression causing chemoresistance. Chapter in: Glioblastoma Resistance to Chemotherapy: Molecular Mechanisms and Innovative Reversal Strategies. Elsevier/Academic Press. 2021