Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase II, Phase I Biomarker/Laboratory analysis, Treatment Active 18 and over NCI NABTT-0503 NABTT-0503, NCT00404248

Objectives

Primary

1. Determine the maximum tolerated dose (MTD) of tetra-O-methyl nordihydroguaiaretic acid (EM-1421) in patients with recurrent high-grade glioma. (Phase I)
2. Determine the response rate in patients treated with EM-1421 administered at the MTD. (Phase II)

Secondary

1. Describe the pharmacokinetics of EM-1421 in these patients. (Phase I)
2. Determine the effects of hepatic enzyme-inducing anticonvulsants on the pharmacokinetic profile of EM-1421 in these patients. (Phase I)
3. Determine the toxicity of this drug in these patients. (Phase I)
4. Assess the tolerability of this drug in these patients. (Phase I)
5. Assess the antitumor activity of this drug, in terms of overall survival. (Phase I)
6. Assess the overall survival of these patients. (Phase II)
7. Assess the safety and tolerability of EM-1421 given at the MTD in these patients. (Phase II)

Entry 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

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

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
• PT/PTT/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)

Expected Enrollment

A total of 50 patients will be accrued for this study.

Outcomes

Maximum tolerated dose (Phase I)
Response rate (Phase II)

Pharmacokinetics (Phase I)
Toxicity (Phase I)
Effects of hepatic enzyme-inducing anticonvulsants on the pharmacokinetic profile (Phase I)
Safety (Phase II)
Tolerability (Phase I and II)
Overall survival (Phase I and II)
Treatment response (complete and partial remission and stable disease) (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.

Trial Contact Information

Trial Lead Organizations

New Approaches to Brain Tumor Therapy

Stuart Grossman, MD, Protocol chair		Ph: 410-955-8837 Email: Grossman@jhmi.edu

U.S.A.
Alabama
	Birmingham
	Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham
		Louis Nabors, MD	Ph:  205-934-1432
			Email: bnabors@uab.edu
Florida
	Tampa
	H. Lee Moffitt Cancer Center and Research Institute at University of South Florida
		Clinical Trials Office - H. Lee Moffitt Cancer Center and Reseach Institute	Ph:  800-456-7121
			Email: canceranswers@moffitt.org
Georgia
	Atlanta
	Winship Cancer Institute of Emory University
		Jeffrey Olson, MD	Ph:  404-778-5770 888-946-7447
Maryland
	Baltimore
	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
		Stuart Grossman, MD	Ph:  410-955-8837
			Email: Grossman@jhmi.edu
Massachusetts
	Boston
	Massachusetts General Hospital
		Tracy Batchelor, MD, MPH	Ph:  617-724-8770
Michigan
	Detroit
	Josephine Ford Cancer Center at Henry Ford Hospital
		Tom Mikkelsen, MD	Ph:  313-916-8641 888-734-5322
			Email: nstom@neuro.hfh.edu
North Carolina
	Winston-Salem
	Wake Forest University Comprehensive Cancer Center
		Clinical Trials Office - Wake Forest University Comprehensive Cancer Center	Ph:  336-713-6771
Ohio
	Cleveland
	Cleveland Clinic Taussig Cancer Center
		Gene Barnett, MD	Ph:  216-444-5381
			Email: barnett@neus.ccf.org
Pennsylvania
	Philadelphia
	Abramson Cancer Center of the University of Pennsylvania
		Clinical Trials Office - Abramson Cancer Center of the University of Pennsylvania	Ph:  800-474-9892

Registry Information
Official Title		Phase I/II Study of Intravenous Infusion of Tetra-o-Methyl Nordihydroguaiaretic Acid (EM-1421) in Subjects with Recurrent High Grade Glioma
Trial Start Date		2007-01-08
Trial Completion Date		2009-01-27 (estimated)
Registered in ClinicalTrials.gov		NCT00404248
Date Submitted to PDQ		2006-10-18
Information Last Verified		2008-04-20
NCI Grant/Contract Number		CA062475