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Phase I/II Study of Intravenous Infusion of Tetra-o-Methyl Nordihydroguaiaretic Acid (EM-1421) in Subjects With Recurrent High Grade Glioma


Phase 1/Phase 2
18 Years
N/A
Not Enrolling
Both
Brain and Central Nervous System Tumors

Thank you

Trial Information

Phase I/II Study of Intravenous Infusion of Tetra-o-Methyl Nordihydroguaiaretic Acid (EM-1421) in Subjects 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.

Inclusion 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

- 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)

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

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose (Phase I)

Safety Issue:

Yes

Principal Investigator

Stuart A. Grossman, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Sidney Kimmel Comprehensive Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

NABTT-0503 CDR0000515952

NCT ID:

NCT00404248

Start Date:

January 2007

Completion Date:

February 2012

Related Keywords:

  • Brain and Central Nervous System Tumors
  • adult anaplastic astrocytoma
  • adult anaplastic oligodendroglioma
  • adult giant cell glioblastoma
  • recurrent adult brain tumor
  • adult glioblastoma
  • adult gliosarcoma
  • Nervous System Neoplasms
  • Central Nervous System Neoplasms

Name

Location

Abramson Cancer Center of the University of PennsylvaniaPhiladelphia, Pennsylvania  19104-4283
Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimore, Maryland  21231-2410
Cleveland Clinic Taussig Cancer CenterCleveland, Ohio  44195
Josephine Ford Cancer Center at Henry Ford HospitalDetroit, Michigan  48202
Winship Cancer Institute of Emory UniversityAtlanta, Georgia  30322
Wake Forest University Comprehensive Cancer CenterWinston-Salem, North Carolina  27157-1096
Massachusetts General HospitalBoston, Massachusetts  02114-2617
H. Lee Moffitt Cancer Center and Research Institute at University of South FloridaTampa, Florida  33612
UAB Comprehensive Cancer CenterBirmingham, Alabama  35294