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

Brain and Central Nervous System Tumors Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00404248
• Other study ID #: NABTT-0503 CDR0000515952
• Secondary ID: U01CA062475NABTT
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: January 2007
• Est. completion date: February 2012

Study information

• Verified date: March 2019
• Source: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 35
• Est. completion date: February 2012
• Est. primary completion date: June 2009
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 ß-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

Related Conditions & MeSH terms

• Brain and Central Nervous System Tumors
• Central Nervous System Neoplasms
• Nervous System Neoplasms

Intervention

Drug:
• terameprocol
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.

Other:
• pharmacological study
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.

Locations

Country	Name	City	State
United States	Winship Cancer Institute of Emory University	Atlanta	Georgia
United States	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland
United States	UAB Comprehensive Cancer Center	Birmingham	Alabama
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio
United States	Josephine Ford Cancer Center at Henry Ford Hospital	Detroit	Michigan
United States	Abramson Cancer Center of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	H. Lee Moffitt Cancer Center and Research Institute at University of South Florida	Tampa	Florida
United States	Wake Forest University Comprehensive Cancer Center	Winston-Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (1)

Grossman SA, Ye X, Peereboom D, Rosenfeld MR, Mikkelsen T, Supko JG, Desideri S; Adult Brain Tumor Consortium. Phase I study of terameprocol in patients with recurrent high-grade glioma. Neuro Oncol. 2012 Apr;14(4):511-7. doi: 10.1093/neuonc/nor230. Epub — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	first 30 days of treatment
Primary	Maximum Tolerated Dose (Phase I) - Dose Limiting Toxicity (DLT)	Dose limiting Toxicity defined as: Treatment related events; absolute neutrophil count	First 30 days
Secondary	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.	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.
Secondary	Pharmacokinetics - Steady-State Apparent Volume Distribution	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.	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.
Secondary	Pharmacokinetics - Terminal Phase Half-life	effect of hepatic enzyme-inducing drugs on PKs	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.
Secondary	Efficacy - Best Overall Response	Response Criteria: Complete Response (CR): complete disappearance of all tumor, off all steroids, stable or improving neuro exam for min of 4wks; Partial Response (PR): Greater than 50% reduction in tumor size, bi-dimensional MRI/CT, stable steroids, stable or improving neuro for min of 4 wks; Progressive Disease (PD): Progressive neurologic abnormalities not explanined by causes unrelated to tumor progression, or 25% increase in size of tumor by MRI/CT scan, or if new lesion appears; Stable Disease (SD): patient whose clinical status and MRI/CT measurements do not meet the criteria for CR, PR or PD.	About 2 years
Secondary	Survival	Survival measured from first day of treatment to date of death	time to death - up to 12 months

External Links

•   Clinical trial summary from the National Cancer Institute's PDQ® database