Brain and Central Nervous System Tumors
Conditions
Keywords
adult anaplastic astrocytoma, adult anaplastic oligodendroglioma, adult giant cell glioblastoma, recurrent adult brain tumor, adult glioblastoma, adult gliosarcoma
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.
Interventions
DRUGterameprocol
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.
OTHERpharmacological 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.
Sponsors
National Cancer Institute (NCI)
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (Phase I) | first 30 days of treatment | 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) | First 30 days | 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
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics - Terminal Phase Half-life | 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. | effect of hepatic enzyme-inducing drugs on PKs |
| Pharmacokinetics - Total Body Clearance | 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. | 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. |
| Survival | time to death - up to 12 months | Survival measured from first day of treatment to date of death |
| Efficacy - Best Overall Response | About 2 years | 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. |
| Pharmacokinetics - Steady-State Apparent Volume Distribution | 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. | 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. |
Countries
United States
Participant flow
Recruitment details
subjects were accrued 2007-2008 in outpatient clinic
Participants by arm
| Arm | Count |
|---|---|
| Arm 1 +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 | 14 |
| Arm 2 -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 | 18 |
| Arm 3 no Stratification (+EIASD or -EIASD) Subjects were not stratified by antiseizure drugs
Subjects will take terameprocol for 5 consecutive days each month by IV. Starting dose is 750mg/day. Only dose tested: 2200.
NO intrasubject dose escalation.
PK (pharmacological study) data will be collected on day one of cycle one infusion | 3 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | pts declining status | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Arm 3 no Stratification (+EIASD or -EIASD) | Arm 1 +EIASD | Arm 2 -EIASD | Total |
|---|---|---|---|---|
| Age, Continuous | 57 years | 47 years | 45 years | 46 years |
| Histologic diagnosis anaplastic astrocytoma | 0 participants | 4 participants | 6 participants | 10 participants |
| Histologic diagnosis anaplastic oligodendroglioma | 0 participants | 5 participants | 5 participants | 10 participants |
| Histologic diagnosis Glioblastoma | 3 participants | 5 participants | 7 participants | 15 participants |
| Karnofsky Performance Status 100 | 1 participants | 2 participants | 1 participants | 4 participants |
| Karnofsky Performance Status 60 | 1 participants | 2 participants | 1 participants | 4 participants |
| Karnofsky Performance Status 70 | 1 participants | 4 participants | 4 participants | 9 participants |
| Karnofsky Performance Status 80 | 0 participants | 0 participants | 5 participants | 5 participants |
| Karnofsky Performance Status 90 | 0 participants | 6 participants | 7 participants | 13 participants |
| Sex: Female, Male Female | 1 Participants | 7 Participants | 11 Participants | 19 Participants |
| Sex: Female, Male Male | 2 Participants | 7 Participants | 7 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 4 / 4 | 5 / 5 | 1 / 2 | 2 / 3 | 3 / 3 | 6 / 6 | 3 / 6 | 3 / 3 |
| serious Total, serious adverse events | 0 / 3 | 0 / 4 | 0 / 5 | 0 / 2 | 0 / 3 | 0 / 3 | 0 / 6 | 2 / 6 | 2 / 3 |
Outcome results
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
Time frame: first 30 days of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 +EIASD (Enzyme-inducing Antizeizure Drug) | Maximum Tolerated Dose (Phase I) | 1700 mg/day x 5 days |
| ARM 2 -EIASD (Enzyme-inducing Antizeizure Drug) | Maximum Tolerated Dose (Phase I) | 1700 mg/day x 5 days |
| ARM 3 (No Stratification) | Maximum Tolerated Dose (Phase I) | 1700 mg/day x 5 days |
Primary
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
Time frame: First 30 days
Population: +EIASD on hepatic enzyme-inducing drugs; -EIASE not on hepatic enzyme-induzing drug or drugs that significantly induce the hepatic enzyme.~IV Formulations: +PEG; 10mg/mL solution of PEG 300, hydroxypropyl-B-cyclodextrin \& water ; -PEG; 6mg/mL, hydroxypropyl-B-cyclodextrin \& water - NEW TC6 formulation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 +EIASD (Enzyme-inducing Antizeizure Drug) | Maximum Tolerated Dose (Phase I) - Dose Limiting Toxicity (DLT) | 0 Dose Limiting Toxicities (DLT) |
| ARM 2 -EIASD (Enzyme-inducing Antizeizure Drug) | Maximum Tolerated Dose (Phase I) - Dose Limiting Toxicity (DLT) | 0 Dose Limiting Toxicities (DLT) |
| ARM 3 (No Stratification) | Maximum Tolerated Dose (Phase I) - Dose Limiting Toxicity (DLT) | 0 Dose Limiting Toxicities (DLT) |
| +EIASD Level 4 (2200 mg/dayx5D) | Maximum Tolerated Dose (Phase I) - Dose Limiting Toxicity (DLT) | 0 Dose Limiting Toxicities (DLT) |
| -EIASD Level 1 (750 mg/dayx5D) | Maximum Tolerated Dose (Phase I) - Dose Limiting Toxicity (DLT) | 0 Dose Limiting Toxicities (DLT) |
| -EIASD Level 2 (1100 mg/dayx5D) | Maximum Tolerated Dose (Phase I) - Dose Limiting Toxicity (DLT) | 0 Dose Limiting Toxicities (DLT) |
| -EIASD Level 3 (1700 mg/dayx5D) | Maximum Tolerated Dose (Phase I) - Dose Limiting Toxicity (DLT) | 0 Dose Limiting Toxicities (DLT) |
| -EIASD Level 4 (2200 mg/dayx5D) | Maximum Tolerated Dose (Phase I) - Dose Limiting Toxicity (DLT) | 2 Dose Limiting Toxicities (DLT) |
| Non Stratified (Both +EIASD and -EIASD) | Maximum Tolerated Dose (Phase I) - Dose Limiting Toxicity (DLT) | 2 Dose Limiting Toxicities (DLT) |
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.
Time frame: About 2 years
Population: 3 pt did not have proper scans to be evaluable for analysis
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1 +EIASD (Enzyme-inducing Antizeizure Drug) | Efficacy - Best Overall Response | Partial Response | 0 participants |
| Arm 1 +EIASD (Enzyme-inducing Antizeizure Drug) | Efficacy - Best Overall Response | Progressive Disease | 23 participants |
| Arm 1 +EIASD (Enzyme-inducing Antizeizure Drug) | Efficacy - Best Overall Response | Stable Disease | 9 participants |
| Arm 1 +EIASD (Enzyme-inducing Antizeizure Drug) | Efficacy - Best Overall Response | Complete Response | 0 participants |
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.
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.
Population: no PKs were collected for Arm 3. Due to incomplete collection of PKs on Cycle 1 Day 5 only the PKs from Cycle 1 Day 1 were used in the analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 +EIASD (Enzyme-inducing Antizeizure Drug) | Pharmacokinetics - Steady-State Apparent Volume Distribution | 706 Liters | Standard Deviation 425 |
| ARM 2 -EIASD (Enzyme-inducing Antizeizure Drug) | Pharmacokinetics - Steady-State Apparent Volume Distribution | 612 Liters | Standard Deviation 478 |
p-value: 0.6t-test, 2 sided
Secondary
Pharmacokinetics - Terminal Phase Half-life
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.
Population: no PKs for Arm 3 (All EIASD) were collected. Due to incomplete collection of PKs on Cycle 1 Day 5 only the PKs from Cycle 1 Day 1 were used in the analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 +EIASD (Enzyme-inducing Antizeizure Drug) | Pharmacokinetics - Terminal Phase Half-life | 18.2 Hour | Standard Deviation 8.8 |
| ARM 2 -EIASD (Enzyme-inducing Antizeizure Drug) | Pharmacokinetics - Terminal Phase Half-life | 17.1 Hour | Standard Deviation 9.4 |
p-value: 0.8t-test, 2 sided
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.
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.
Population: No PKs were collected for the three patients who were treated on Arm 3 (all EIASD). Due to incomplete collection of PKs on Cycle 1 Day 5 only the PKs from Cycle 1 Day 1 were used in the analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 +EIASD (Enzyme-inducing Antizeizure Drug) | Pharmacokinetics - Total Body Clearance | 53.7 Liters/hour | Standard Deviation 14.6 |
| ARM 2 -EIASD (Enzyme-inducing Antizeizure Drug) | Pharmacokinetics - Total Body Clearance | 54.4 Liters/hour | Standard Deviation 20.8 |
p-value: 0.9t-test, 2 sided
Secondary
Survival
Survival measured from first day of treatment to date of death
Time frame: time to death - up to 12 months
Population: 3 pts still alive at time of analysis
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Arm 1 +EIASD (Enzyme-inducing Antizeizure Drug) | Survival | 5.5 months | Standard Deviation 8.4 |