Tetra-O-Methyl Nordihydroguaiaretic Acid in Treating Patients With Recurrent High-Grade Glioma

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins35 enrolled

Overview

RATIONALE: Drugs used in chemotherapy, such as tetra-O-methyl nordihydroguaiaretic acid (EM-1421), work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. PURPOSE: This phase I/II trial is studying the side effects and best dose of EM-1421 and to see how well it works in treating patients with recurrent high-grade glioma.

OBJECTIVES: Primary * Determine the maximum tolerated dose (MTD) of tetra-O-methyl nordihydroguaiaretic acid (EM-1421) in patients with recurrent high-grade glioma. (Phase I) * Determine the response rate in patients treated with EM-1421 administered at the MTD. (Phase II) Secondary * Describe the pharmacokinetics of EM-1421 in these patients. (Phase I) * Determine the effects of hepatic enzyme-inducing anticonvulsants on the pharmacokinetic profile of EM-1421 in these patients. (Phase I) * Determine the toxicity of this drug in these patients. (Phase I) * Assess the tolerability of this drug in these patients. (Phase I) * Assess the antitumor activity of this drug, in terms of overall survival. (Phase I) * Assess the overall survival of these patients. (Phase II) * Assess the safety and tolerability of EM-1421 given at the MTD in these patients. (Phase II) OUTLINE: This is a multicenter, phase I, dose-escalation study followed by a phase II, open-label study. Patients are stratified according to the use of cytochrome P450-inducing anticonvulsants (use of anticonvulsant drugs that induce hepatic metabolic enzymes vs use of anticonvulsant drugs that cause modest or no induction of hepatic metabolic enzymes or no use of anticonvulsant drugs). * Phase I: Patients receive tetra-O-methyl nordihydroguaiaretic acid (EM-1421) IV on days 1-5. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of EM-1421 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 3 of 6 patients experience dose-limiting toxicity. * Phase II: Patients receive EM-1421 as in phase I at the MTD. Blood is collected on days 1 and 5 of courses 1 and 2 of treatment for pharmacokinetic studies. After completion of study therapy, patients are followed every 2 months. PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Brain and Central Nervous System Tumors

Interventions

terameprocolDRUG

terameprocol will be given IV 5 consecutive days every 28 days. Starting dose 750mg/day. Cohorts of 3pts. A Dose Limiting Toxicity (DLT) target rate of Less than or equal to 33%. Dose levels: 750, 1100, 1700, 2200, 3000, 4000, 5300, 7000, 9300 mg.

pharmacological studyOTHER

All pts on both arms will have pks, blood collections. 5ml of blood will be drawn on Cycle 1 day 1, Cycle 1 Day 5, Cycle 2 day 1 and Cycle 2 day 5. A total of 10 samples will be drawn at each of these time points. 1hr pre-infusion, 15 min, 1hr, 1.15, 1.5, 2, 3,4,6 and 24hr post infusion.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

DISEASE CHARACTERISTICS: * Histologically confirmed malignant glioma, including any of the following subtypes: * Anaplastic astrocytoma * Anaplastic oligodendroglioma * Glioblastoma multiforme * Progressive or recurrent disease after radiation therapy with or without chemotherapy * Patients with a previous low-grade glioma that has progressed to biopsy-confirmed high-grade glioma after radiation therapy with or without chemotherapy are eligible * Contrast-enhancing measurable disease by MRI or CT scan PATIENT CHARACTERISTICS: * Karnofsky performance status 60-100% * Absolute neutrophil count ≥ 1,500/mm³ * Hemoglobin ≥ 9 g/dL * Platelet count ≥ 100,000/mm³ * Creatinine ≤ 1.5 mg/dL * Bilirubin ≤ 1.5 mg/dL * Transaminases ≤ 4 times upper limit of normal * Prothrombin Time (PT)/partial thromboplastin time (PTT) /international normalized ratio (INR) normal * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective barrier contraception during and for 2 months after completion of study treatment * Mini Mental State Exam score ≥ 15 * No serious concurrent infection or medical illness that would impair the ability to safely receive study treatment * No other prior or concurrent malignancy within the past 5 years except for curatively treated carcinoma in situ or basal cell carcinoma of the skin * No known sensitivity to any of the study medication components (i.e., polyethylene glycol \[PEG 300\] and 2-hydroxypropyl β-cyclodextrin) PRIOR CONCURRENT THERAPY: * See Disease Characteristics * Recovered from prior therapy * At least 3 months since prior radiation therapy * At least 3 weeks since prior chemotherapy (6 weeks for nitrosoureas) * At least 2 weeks since prior Federal Drug Administration (FDA)-approved noncytotoxic therapy (e.g., celecoxib or thalidomide) * At least 3 weeks since prior investigational noncytotoxic agents * At least 10 days since prior anticonvulsant drugs that induce hepatic metabolic enzymes, including any of the following: * Phenytoin * Carbamazepine * Phenobarbital * Primidone * Oxcarbazepine * Ethosuximide * No other concurrent therapy for this tumor, including systemic chemotherapy or radiation therapy * Concurrent steroids allowed

Locations (9)

UAB Comprehensive Cancer Center

Birmingham, Alabama, United States

H. Lee Moffitt Cancer Center and Research Institute at University of South Florida

Tampa, Florida, United States

Winship Cancer Institute of Emory University

Atlanta, Georgia, United States

Outcomes

Primary Outcomes

Maximum Tolerated Dose (Phase I)

Using the PEG formulation pts both with and without enzyme inducing antiseizure drugs (EIASD) were treated at Doses 750, 1100, 1700, 2200 mg/day for five days = 28pts Using the PEG free formulation pts with and without EIASD) were treated at 1700 and 2200 mg/day X 5 days = 8pgs

Time frame: first 30 days of treatment

Maximum Tolerated Dose (Phase I) - Dose Limiting Toxicity (DLT)

Dose limiting Toxicity defined as: Treatment related events; absolute neutrophil count \</=500 /mm3; platelets count \</=25,000/mm3; febrile neutropenia; any grade 3 or 4 non-hematologic toxicity; any delay in starting subsequent course of treatment for \>14 days because of incomplete recovery from treatment

Time frame: First 30 days

Secondary Outcomes

Pharmacokinetics - Total Body Clearance

effect of hepatic enzyme-inducing drugs on PKs Cycle 1 Day 1 of treatment: Predose: 1hour(hr) prior, 15minutes(min) prior; postdose: 1 hr15 min; 1.5hr, 2, 3,4, 6, 24 hrs. Cycle Day 5 of treatment: Predose: 1hour(hr) prior, 15minutes(min) prior; postdose: 1 hr15 min; 1.5hr, 2, 3,4, 6, 24 hrs.

Time frame: Cycle 1 Day 1- Predose: 1hour(hr) prior, 15minutes(min) prior; postdose: 1 hr15 min; 1.5hr, 2, 3,4, 6, 24 hrs. and Cycle 1 Day 5 Predose: 1hour(hr) prior, 15minutes(min) prior; postdose: 1 hr15 min; 1.5hr, 2, 3,4, 6, 24 hrs.

Pharmacokinetics - Steady-State Apparent Volume Distribution

Data from ClinicalTrials.gov

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