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

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

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.

Study Overview

• Status: Completed
• Conditions: Brain and Central Nervous System Tumors
• Intervention / Treatment: Drug: terameprocol; Other: pharmacological study

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.

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294-3410
      • Uab Comprehensive Cancer Center
  • Florida
    • Tampa, Florida, United States, 33612-9497
      • H. Lee Moffitt Cancer Center and Research Institute at University of South Florida
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute of Emory University
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Josephine Ford Cancer Center at Henry Ford Hospital
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157-1096
      • Wake Forest University Comprehensive Cancer Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Taussig Cancer Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104-4283
      • Abramson Cancer Center of the University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: With Enzyme-inducing antiseizure drugs (+EIASD); 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	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 Names: EM-1421; 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.; Other Names: PK
ACTIVE_COMPARATOR: With Non enzyme-inducing antiseizure drugs (-EIASD); 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	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 Names: EM-1421; 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.; Other Names: PK

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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	First 30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.
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.
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.
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
Survival	Survival measured from first day of treatment to date of death	time to death - up to 12 months

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: National Cancer Institute (NCI)

Publications and helpful links

General Publications

• 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.

Helpful Links

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

Study record dates

Study Major Dates

• Study Start: January 1, 2007
• Primary Completion (ACTUAL): June 1, 2009
• Study Completion (ACTUAL): February 1, 2012

Study Registration Dates

• First Submitted: November 27, 2006
• First Submitted That Met QC Criteria: November 27, 2006
• First Posted (ESTIMATE): November 28, 2006

Study Record Updates

• Last Update Posted (ACTUAL): March 6, 2019
• Last Update Submitted That Met QC Criteria: March 1, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: adult glioblastoma; adult giant cell glioblastoma; adult gliosarcoma; recurrent adult brain tumor; adult anaplastic astrocytoma; adult anaplastic oligodendroglioma
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms; Neoplasms by Site; Nervous System Neoplasms; Central Nervous System Neoplasms
• Other Study ID Numbers: NABTT-0503 CDR0000515952; U01CA062475 (U.S. NIH Grant/Contract); NABTT-0503