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Brain and Central Nervous System TumorsPhase 1/2NCT00404248

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

A Phase 1/2 study testing terameprocol and pharmacological study in people with Brain and Central Nervous System Tumors, run by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins at 9 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Brain and Central Nervous System Tumors
What is being tested?
terameprocol and pharmacological study
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
35 participants
Where
9 sitesUnited States
Study dates
Jan 2007to Feb 2012
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

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

Trial locations and contacts

9 sites in 1 country.

9 sites in 1 country

United States9 sites

  • Winship Cancer Institute of Emory University

    Atlanta, Georgia, 30322

  • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

    Baltimore, Maryland, 21231

  • UAB Comprehensive Cancer Center

    Birmingham, Alabama, 35294-3410

  • Massachusetts General Hospital

    Boston, Massachusetts, 02114

  • Cleveland Clinic Taussig Cancer Center

    Cleveland, Ohio, 44195

  • Josephine Ford Cancer Center at Henry Ford Hospital

    Detroit, Michigan, 48202

  • Abramson Cancer Center of the University of Pennsylvania

    Philadelphia, Pennsylvania, 19104-4283

  • H. Lee Moffitt Cancer Center and Research Institute at University of South Florida

    Tampa, Florida, 33612-9497

  • Wake Forest University Comprehensive Cancer Center

    Winston-Salem, North Carolina, 27157-1096

Other trials in United States

About this study

Official title: 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.

Read the 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.

Being tested
terameprocol, pharmacological study
Keywords
adult anaplastic astrocytoma, adult anaplastic oligodendroglioma, adult giant cell glioblastoma, recurrent adult brain tumor, adult glioblastoma, adult gliosarcoma
Medical subject headings
Central Nervous System Neoplasms, Astrocytoma, Oligodendroglioma, Glioblastoma, Brain Neoplasms, Gliosarcoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • terameprocolDrug

    Also called EM-1421

    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.

  • pharmacological studyOther

    Also called PK

    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.

Study groups in NCT00404248
Study groupRoleWhat they receive
With Enzyme-inducing antiseizure drugs (+EIASD)Active comparatorsubjects 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
Receives: Drug: terameprocol; Other: pharmacological study
With Non enzyme-inducing antiseizure drugs (-EIASD)Active comparatorSubjects 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
Receives: Drug: terameprocol; Other: pharmacological study

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    Measured: first 30 days of treatment

  2. 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

    Measured: First 30 days

Secondary outcomes (5)

  1. 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.

    Measured: 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.

  2. 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.

    Measured: 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.

  3. Pharmacokinetics - Terminal Phase Half-life

    effect of hepatic enzyme-inducing drugs on PKs

    Measured: 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.

  4. 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.

    Measured: About 2 years

  5. Survival

    Survival measured from first day of treatment to date of death

    Measured: time to death - up to 12 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted28 Nov 2006 (estimated)
  2. Study startJan 2007
  3. Primary completionJun 2009
  4. Study completionFeb 2012

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
35 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00404248
Sponsor's protocol ID
NABTT-0503 CDR0000515952
Other IDs
U01CA062475, NABTT-0503
Status last verified
Mar 2019
First submitted
27 Nov 2006
Last updated
6 Mar 2019
Data monitoring committee
Yes

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.

    PubMed 22323663

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing terameprocol and pharmacological study in people with Brain and Central Nervous System Tumors, run by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins at 9 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 6 Mar 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 9 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 11 Aug 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum Tolerated Dose (Phase I) (time frame: first 30 days of treatment). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00404248, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Mar 2019.

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