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

Официальное название

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

Обзор

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).

Подробное описание

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.

Вмешательства

• Препарат Treatment Period 1
  Agent: LipoCurc Premedication/Precautions: Dexamethasone 4mg IV, Diphenhydramine 25 mg IV - Dose: per treatment assignment Route: IV over approximately 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 Premedica
• Препарат Treatment Period 2
  Agent: LipoCurc Premedication/Precautions: Dexamethasone 4 mg IV Diphenhydramine 25 mg IV Dose: Per treatment assignment Route: IV over approximately 3 hours Schedule: Weekly: Weeks 7,8,9,10 Cycle length: 4 weeks
• Препарат Treatment Period 3
  Agent: LipoCurc Premedication/Precautions: Dexamethasone 4 mg IV Diphenhydramine 25 mg IV Dose: Per treatment assignment Route: IV over approximately 3 hours Schedule: Weekly: Adjuvant Cycles 11-34 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 week
• Препарат Treatment Period 4a
  Agent: LipoCurc Premedication/Precautions: Dexamethasone 4 mg IV Diphenhydramine 25 mg IV Dose: Per treatment assignment Route: IV over approximately 3 hours Schedule: Weekly: 35+ Weeks 1, 2, 3, 4 of each cycle Cycle Length: 4 weeks

Первичные конечные точки

• The number of observed Dose Limiting Toxicity (DLTs) [Срок оценки: 10 weeks]
• The number of observed Dose Limiting Toxicity (DLTs) [Срок оценки: The duration of treatment for each patient, minimum of 34 weeks]

Вторичные конечные точки (4)

• The incidence of Adverse Events [Срок оценки: The duration of treatment for each patient, minimum of 34 weeks]
• 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 [Срок оценки: 10 weeks]
• Overall Survival (OS) [Срок оценки: The duration of treatment for each patient, minimum of 34 weeks; OS is time from beginning of therapy to time of death.]
• Progression free survival (PFS) [Срок оценки: 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]

Критерии участия

Критерии включения

• ≥18 years of age
• 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
• Planning standard therapy with TMZ and XRT for 6 weeks and adjuvant TMZ for six 28-day cycles.
• 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
• 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
• 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
• 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

Критерии исключения

• 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
• Patient has not recovered from AEs due to prior anticancer therapy (i.e., residual toxicities > Grade 1), with the exception of alopecia
• Receiving any other investigational agent
• Active infection requiring systemic antibiotics
• History of allergic reaction to compounds that are chemically or biologically similar to LC
• Patient is taking a medication that may potentiate hemolysis
• Unstable angina or myocardial infarction within the past 6 months
• Prolonged QTc interval, Fridericia formula (QTcF) (> 450 msec for males or > 460 msec for females)
• Psychiatric illness or social situation that could limit compliance with study requirements
• Pregnant or breastfeeding

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 2 центра

• Sibley Memorial Hospital — Washington D.C.
• Johns Hopkins University/Johns Hopkins Hospital — Baltimore

Публикации

• 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. PMID 28476779
• Glioblastoma cell-induced immunosuppression causing chemoresistance. Chapter in: Glioblastoma Resistance to Chemotherapy: Molecular Mechanisms and Innovative Reversal Strategies. Elsevier/Academic Press. 2021

Идентификаторы

NCT: NCT05768919 · 1004

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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