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

Johns Hopkins Medicine

Status and phase: Completed; Phase 2; Phase 1

Conditions: Brain and Central Nervous System Tumors

Treatments: Drug: terameprocol; Other: pharmacological study

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT00404248

NABTT-0503 CDR0000515952

U01CA062475 (U.S. NIH Grant/Contract)

NABTT-0503

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 35 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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35 participants in 2 patient groups

With Enzyme-inducing antiseizure drugs (+EIASD)

Active Comparator group

Description:

subjects on the +EIASD treatment arm were taking one of these antiseizure drugs: phenytoin, carbamazepine, phenobarbital, primidone and oxcarbazepine. Subjects will take terameprocol for 5 consecutive days each month by IV. Starting dose is 750mg/day. Dose escalation is 750, 1100, 1700, 2200, 3000, 4000, 5300, 7000, and 9300. NO intrasubject dose escalation. PK (pharmacological study) data will be collected on day one of cycle one infusion

Treatment:

Other: pharmacological study

Drug: terameprocol

With Non enzyme-inducing antiseizure drugs (-EIASD)

Active Comparator group

Description:

Subjects in the -EIASD group were either not being treated with antiseizure drugs or were taking ones that did not significantly induce hepatic enzymes such as gabapentin, lamotrigine, valproic acid, levetiracetam, tiagabine, topiramate, zonisamide and felbamate. Subjects will take terameprocol for 5 consecutive days each month by IV. Starting dose is 750mg/day. Dose escalation is 750, 1100, 1700, 2200, 3000, 4000, 5300, 7000, and 9300. NO intrasubject dose escalation. PK (pharmacological study) data will be collected on day one of cycle one infusion

Treatment:

Other: pharmacological study

Drug: terameprocol