Back to resultsTetra-O-Methyl Nordihydroguaiaretic Acid in Treating Patients With Recurrent High-Grade Glioma
Primary Purpose
Brain and Central Nervous System Tumors
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
terameprocol
pharmacological study
Sponsored by
About this trial
This is an interventional treatment trial for Brain and Central Nervous System Tumors focused on measuring adult anaplastic astrocytoma, adult anaplastic oligodendroglioma, adult giant cell glioblastoma, recurrent adult brain tumor, adult glioblastoma, adult gliosarcoma
Eligibility 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
Sites / Locations
- UAB Comprehensive Cancer Center
- H. Lee Moffitt Cancer Center and Research Institute at University of South Florida
- Winship Cancer Institute of Emory University
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
- Massachusetts General Hospital
- Josephine Ford Cancer Center at Henry Ford Hospital
- Wake Forest University Comprehensive Cancer Center
- Cleveland Clinic Taussig Cancer Center
- Abramson Cancer Center of the University of Pennsylvania
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Active Comparator
Arm Label
With Enzyme-inducing antiseizure drugs (+EIASD)
With Non enzyme-inducing antiseizure drugs (-EIASD)
Arm 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
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
Outcomes
Primary Outcome Measures
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
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
Secondary Outcome Measures
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.
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.
Pharmacokinetics - Terminal Phase Half-life
effect of hepatic enzyme-inducing drugs on PKs
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.
Survival
Survival measured from first day of treatment to date of death
Full Information
NCT ID
NCT00404248
First Posted
November 27, 2006
Last Updated
March 1, 2019
Sponsor
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators
National Cancer Institute (NCI)
1. Study Identification
Unique Protocol Identification Number
NCT00404248
Brief Title
Tetra-O-Methyl Nordihydroguaiaretic Acid in Treating Patients With Recurrent High-Grade Glioma
Official Title
Phase I/II Study of Intravenous Infusion of Tetra-o-Methyl Nordihydroguaiaretic Acid (EM-1421) in Subjects With Recurrent High Grade Glioma
Study Type
Interventional
2. Study Status
Record Verification Date
March 2019
Overall Recruitment Status
Completed
Study Start Date
January 2007 (undefined)
Primary Completion Date
June 2009 (Actual)
Study Completion Date
February 2012 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators
National Cancer Institute (NCI)
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief 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.
Detailed 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Brain and Central Nervous System Tumors
Keywords
adult anaplastic astrocytoma, adult anaplastic oligodendroglioma, adult giant cell glioblastoma, recurrent adult brain tumor, adult glioblastoma, adult gliosarcoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
35 (Actual)
8. Arms, Groups, and Interventions
Arm Title
With Enzyme-inducing antiseizure drugs (+EIASD)
Arm Type
Active Comparator
Arm 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
Arm Title
With Non enzyme-inducing antiseizure drugs (-EIASD)
Arm Type
Active Comparator
Arm 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
Intervention Type
Drug
Intervention Name(s)
terameprocol
Other Intervention Name(s)
EM-1421
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
pharmacological study
Other Intervention Name(s)
PK
Intervention Description
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.
Primary Outcome Measure Information:
Title
Maximum Tolerated Dose (Phase I)
Description
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
Title
Maximum Tolerated Dose (Phase I) - Dose Limiting Toxicity (DLT)
Description
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 Outcome Measure Information:
Title
Pharmacokinetics - Total Body Clearance
Description
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.
Title
Pharmacokinetics - Steady-State Apparent Volume Distribution
Description
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.
Title
Pharmacokinetics - Terminal Phase Half-life
Description
effect of hepatic enzyme-inducing drugs on PKs
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.
Title
Efficacy - Best Overall Response
Description
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.
Time Frame
About 2 years
Title
Survival
Description
Survival measured from first day of treatment to date of death
Time Frame
time to death - up to 12 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Stuart A. Grossman, MD
Organizational Affiliation
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Official's Role
Study Chair
Facility Information:
Facility Name
UAB Comprehensive Cancer Center
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35294-3410
Country
United States
Facility Name
H. Lee Moffitt Cancer Center and Research Institute at University of South Florida
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612-9497
Country
United States
Facility Name
Winship Cancer Institute of Emory University
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21231
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Josephine Ford Cancer Center at Henry Ford Hospital
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48202
Country
United States
Facility Name
Wake Forest University Comprehensive Cancer Center
City
Winston-Salem
State/Province
North Carolina
ZIP/Postal Code
27157-1096
Country
United States
Facility Name
Cleveland Clinic Taussig Cancer Center
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
Abramson Cancer Center of the University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104-4283
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
22323663
Citation
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 2012 Feb 8.
Results Reference
result
Links:
URL
https://clinicaltrials.gov/ct2/show/NCT00404248?term=NABTT+0503&rank=1
Description
Clinical trial summary from the National Cancer Institute's PDQ® database
Learn more about this trial
Tetra-O-Methyl Nordihydroguaiaretic Acid in Treating Patients With Recurrent High-Grade Glioma
We'll reach out to this number within 24 hrs