Trial Outcomes & Findings for Tetra-O-Methyl Nordihydroguaiaretic Acid in Treating Patients With Recurrent High-Grade Glioma (NCT NCT00404248)

Last Updated: 2019-03-06

Results Overview

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

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

35 participants

Primary outcome timeframe

first 30 days of treatment

Results posted on

2019-03-06

Participant Flow

subjects were accrued 2007-2008 in outpatient clinic

Participant milestones

Participant milestones
Measure	Arm 1 Enzyme Inducing Antiseizure Drug (+ EIASD) Level 1 subjects on the +EIASD (Level 1) 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. Dose level 1= 750mg/day. NO intrasubject dose escalation. Pharmacokinetics (PK) data will be collected on day one of cycle one infusion	Arm 2 +EIASD Level 2 subjects on the +EIASD (Level 2) 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. Dose level 2= 1100mg/day. NO intrasubject dose escalation.	Arm 3 +EIASD Level 3 subjects on the +EIASD (Level 3) 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. Dose level 3= 1700mg/day. NO intrasubject dose escalation. Includes pts at the new formulation TC6 at 1700mg	Arm 4 +EIASD Level 4 subjects on the +EIASD (Level 4) 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. Dose level 4= 2220mg/day. NO intrasubject dose escalation.	Arm 5 Non-Enzyme Inducing Antiseizure Drug (-EIASD) Level 1 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. Level 1 = 750mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion	Arm 6 -EIASD Level 2 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. Level 2 = 1100mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion	Arm 7 -EIASD Level 3 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. Level 3 = 1700mg/day. NO intrasubject dose escalation. this Arm including pts treated at the new formulation TC6 at 1700mg PK data will be collected on day one of cycle one infusion	Arm 8 -EIASD Level 4 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. Level 4 = 2200mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion	Arm 9 - Non Stratified (Both +EIASD and -EIASD) Subjects in this group were not stratified based on anti-sezuire medication.. Subjects will take terameprocol for 5 consecutive days each month by IV. This was for dose 2200mg/day. New formulation TC6.
Overall Study STARTED	3	4	5	2	3	3	6	6	3
Overall Study COMPLETED	3	3	5	2	3	3	6	6	3
Overall Study NOT COMPLETED	0	1	0	0	0	0	0	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Arm 1 Enzyme Inducing Antiseizure Drug (+ EIASD) Level 1 subjects on the +EIASD (Level 1) 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. Dose level 1= 750mg/day. NO intrasubject dose escalation. Pharmacokinetics (PK) data will be collected on day one of cycle one infusion	Arm 2 +EIASD Level 2 subjects on the +EIASD (Level 2) 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. Dose level 2= 1100mg/day. NO intrasubject dose escalation.	Arm 3 +EIASD Level 3 subjects on the +EIASD (Level 3) 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. Dose level 3= 1700mg/day. NO intrasubject dose escalation. Includes pts at the new formulation TC6 at 1700mg	Arm 4 +EIASD Level 4 subjects on the +EIASD (Level 4) 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. Dose level 4= 2220mg/day. NO intrasubject dose escalation.	Arm 5 Non-Enzyme Inducing Antiseizure Drug (-EIASD) Level 1 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. Level 1 = 750mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion	Arm 6 -EIASD Level 2 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. Level 2 = 1100mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion	Arm 7 -EIASD Level 3 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. Level 3 = 1700mg/day. NO intrasubject dose escalation. this Arm including pts treated at the new formulation TC6 at 1700mg PK data will be collected on day one of cycle one infusion	Arm 8 -EIASD Level 4 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. Level 4 = 2200mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion	Arm 9 - Non Stratified (Both +EIASD and -EIASD) Subjects in this group were not stratified based on anti-sezuire medication.. Subjects will take terameprocol for 5 consecutive days each month by IV. This was for dose 2200mg/day. New formulation TC6.
Overall Study pts declining status	0	1	0	0	0	0	0	0	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm 1 +EIASD n=14 Participants 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 2 -EIASD n=18 Participants 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	Arm 3 no Stratification (+EIASD or -EIASD) n=3 Participants 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	Total n=35 Participants Total of all reporting groups
Age, Continuous	47 years n=99 Participants	45 years n=107 Participants	57 years n=206 Participants	46 years n=7 Participants
Sex: Female, Male Female	7 Participants n=99 Participants	11 Participants n=107 Participants	1 Participants n=206 Participants	19 Participants n=7 Participants
Sex: Female, Male Male	7 Participants n=99 Participants	7 Participants n=107 Participants	2 Participants n=206 Participants	16 Participants n=7 Participants
Karnofsky Performance Status 100	2 participants n=99 Participants	1 participants n=107 Participants	1 participants n=206 Participants	4 participants n=7 Participants
Karnofsky Performance Status 90	6 participants n=99 Participants	7 participants n=107 Participants	0 participants n=206 Participants	13 participants n=7 Participants
Karnofsky Performance Status 80	0 participants n=99 Participants	5 participants n=107 Participants	0 participants n=206 Participants	5 participants n=7 Participants
Karnofsky Performance Status 70	4 participants n=99 Participants	4 participants n=107 Participants	1 participants n=206 Participants	9 participants n=7 Participants
Karnofsky Performance Status 60	2 participants n=99 Participants	1 participants n=107 Participants	1 participants n=206 Participants	4 participants n=7 Participants
Histologic diagnosis Glioblastoma	5 participants n=99 Participants	7 participants n=107 Participants	3 participants n=206 Participants	15 participants n=7 Participants
Histologic diagnosis anaplastic oligodendroglioma	5 participants n=99 Participants	5 participants n=107 Participants	0 participants n=206 Participants	10 participants n=7 Participants
Histologic diagnosis anaplastic astrocytoma	4 participants n=99 Participants	6 participants n=107 Participants	0 participants n=206 Participants	10 participants n=7 Participants

PRIMARY outcome

Timeframe: first 30 days of treatment

Outcome measures

Outcome measures
Measure	Arm 1 +EIASD (Enzyme-inducing Antizeizure Drug) n=14 Participants subjects on the +EIASD (Level 1) 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. Various Dose levels 1= 750mg/dayx5; 2=1100mg/dayx5; 3=1700mg/dayx5; 4=2200mg/dayx5 NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion	ARM 2 -EIASD (Enzyme-inducing Antizeizure Drug) n=18 Participants 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. Various Dose levels 1= 750mg/dayx5; 2=1100mg/dayx5; 3=1700mg/dayx5; 4=2200mg/dayx5 NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion	ARM 3 (No Stratification) n=3 Participants Subjects in this group were not stratified based on anti-sezuire medication.. Subjects will take terameprocol for 5 consecutive days each month by IV. This was for dose 2200mg/day. New formulation TC6.	+EIASD Level 4 (2200 mg/dayx5D) subjects on the +EIASD (Level 4) 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. Dose level 4= 2220mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion +PEG Formulation	-EIASD Level 1 (750 mg/dayx5D) 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. Level 1 = 750mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion +PEG Formulation	-EIASD Level 2 (1100 mg/dayx5D) 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. Level 2 = 1100mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion +PEG Formulation	-EIASD Level 3 (1700 mg/dayx5D) 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. Level 3 = 1700mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion +PEG Formulation and new TC6 -PEG Formulation - Pts treated from both formulations	-EIASD Level 4 (2200 mg/dayx5D) 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. Level 4 = 2200mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion +PEG Formulation	Non Stratified (Both +EIASD and -EIASD) Subjects in this group were not stratified based on anti-sezuire medication.. Subjects will take terameprocol for 5 consecutive days each month by IV. This was for dose 2200mg/day. New formulation TC6 - NONPEG or -PEG. (polyethylene glycol )
Maximum Tolerated Dose (Phase I)	1700 mg/day x 5 days	1700 mg/day x 5 days	1700 mg/day x 5 days	—	—	—	—	—	—

PRIMARY outcome

Timeframe: 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

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

Outcome measures

Outcome measures
Measure	Arm 1 +EIASD (Enzyme-inducing Antizeizure Drug) n=3 Participants subjects on the +EIASD (Level 1) 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. Various Dose levels 1= 750mg/dayx5; 2=1100mg/dayx5; 3=1700mg/dayx5; 4=2200mg/dayx5 NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion	ARM 2 -EIASD (Enzyme-inducing Antizeizure Drug) n=4 Participants 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. Various Dose levels 1= 750mg/dayx5; 2=1100mg/dayx5; 3=1700mg/dayx5; 4=2200mg/dayx5 NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion	ARM 3 (No Stratification) n=5 Participants Subjects in this group were not stratified based on anti-sezuire medication.. Subjects will take terameprocol for 5 consecutive days each month by IV. This was for dose 2200mg/day. New formulation TC6.	+EIASD Level 4 (2200 mg/dayx5D) n=2 Participants subjects on the +EIASD (Level 4) 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. Dose level 4= 2220mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion +PEG Formulation	-EIASD Level 1 (750 mg/dayx5D) n=3 Participants 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. Level 1 = 750mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion +PEG Formulation	-EIASD Level 2 (1100 mg/dayx5D) n=3 Participants 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. Level 2 = 1100mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion +PEG Formulation	-EIASD Level 3 (1700 mg/dayx5D) n=6 Participants 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. Level 3 = 1700mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion +PEG Formulation and new TC6 -PEG Formulation - Pts treated from both formulations	-EIASD Level 4 (2200 mg/dayx5D) n=6 Participants 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. Level 4 = 2200mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion +PEG Formulation	Non Stratified (Both +EIASD and -EIASD) n=3 Participants Subjects in this group were not stratified based on anti-sezuire medication.. Subjects will take terameprocol for 5 consecutive days each month by IV. This was for dose 2200mg/day. New formulation TC6 - NONPEG or -PEG. (polyethylene glycol )
Maximum Tolerated Dose (Phase I) - Dose Limiting Toxicity (DLT)	0 Dose Limiting Toxicities (DLT)	0 Dose Limiting Toxicities (DLT)	0 Dose Limiting Toxicities (DLT)	0 Dose Limiting Toxicities (DLT)	0 Dose Limiting Toxicities (DLT)	0 Dose Limiting Toxicities (DLT)	0 Dose Limiting Toxicities (DLT)	2 Dose Limiting Toxicities (DLT)	2 Dose Limiting Toxicities (DLT)

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Arm 1 +EIASD (Enzyme-inducing Antizeizure Drug) n=9 Participants subjects on the +EIASD (Level 1) 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. Various Dose levels 1= 750mg/dayx5; 2=1100mg/dayx5; 3=1700mg/dayx5; 4=2200mg/dayx5 NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion	ARM 2 -EIASD (Enzyme-inducing Antizeizure Drug) n=16 Participants 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. Various Dose levels 1= 750mg/dayx5; 2=1100mg/dayx5; 3=1700mg/dayx5; 4=2200mg/dayx5 NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion	ARM 3 (No Stratification) Subjects in this group were not stratified based on anti-sezuire medication.. Subjects will take terameprocol for 5 consecutive days each month by IV. This was for dose 2200mg/day. New formulation TC6.	+EIASD Level 4 (2200 mg/dayx5D) subjects on the +EIASD (Level 4) 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. Dose level 4= 2220mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion +PEG Formulation	-EIASD Level 1 (750 mg/dayx5D) 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. Level 1 = 750mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion +PEG Formulation	-EIASD Level 2 (1100 mg/dayx5D) 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. Level 2 = 1100mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion +PEG Formulation	-EIASD Level 3 (1700 mg/dayx5D) 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. Level 3 = 1700mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion +PEG Formulation and new TC6 -PEG Formulation - Pts treated from both formulations	-EIASD Level 4 (2200 mg/dayx5D) 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. Level 4 = 2200mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion +PEG Formulation	Non Stratified (Both +EIASD and -EIASD) Subjects in this group were not stratified based on anti-sezuire medication.. Subjects will take terameprocol for 5 consecutive days each month by IV. This was for dose 2200mg/day. New formulation TC6 - NONPEG or -PEG. (polyethylene glycol )
Pharmacokinetics - Total Body Clearance	53.7 Liters/hour Standard Deviation 14.6	54.4 Liters/hour Standard Deviation 20.8	—	—	—	—	—	—	—

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Arm 1 +EIASD (Enzyme-inducing Antizeizure Drug) n=9 Participants subjects on the +EIASD (Level 1) 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. Various Dose levels 1= 750mg/dayx5; 2=1100mg/dayx5; 3=1700mg/dayx5; 4=2200mg/dayx5 NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion	ARM 2 -EIASD (Enzyme-inducing Antizeizure Drug) n=16 Participants 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. Various Dose levels 1= 750mg/dayx5; 2=1100mg/dayx5; 3=1700mg/dayx5; 4=2200mg/dayx5 NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion	ARM 3 (No Stratification) Subjects in this group were not stratified based on anti-sezuire medication.. Subjects will take terameprocol for 5 consecutive days each month by IV. This was for dose 2200mg/day. New formulation TC6.	+EIASD Level 4 (2200 mg/dayx5D) subjects on the +EIASD (Level 4) 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. Dose level 4= 2220mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion +PEG Formulation	-EIASD Level 1 (750 mg/dayx5D) 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. Level 1 = 750mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion +PEG Formulation	-EIASD Level 2 (1100 mg/dayx5D) 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. Level 2 = 1100mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion +PEG Formulation	-EIASD Level 3 (1700 mg/dayx5D) 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. Level 3 = 1700mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion +PEG Formulation and new TC6 -PEG Formulation - Pts treated from both formulations	-EIASD Level 4 (2200 mg/dayx5D) 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. Level 4 = 2200mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion +PEG Formulation	Non Stratified (Both +EIASD and -EIASD) Subjects in this group were not stratified based on anti-sezuire medication.. Subjects will take terameprocol for 5 consecutive days each month by IV. This was for dose 2200mg/day. New formulation TC6 - NONPEG or -PEG. (polyethylene glycol )
Pharmacokinetics - Steady-State Apparent Volume Distribution	706 Liters Standard Deviation 425	612 Liters Standard Deviation 478	—	—	—	—	—	—	—

SECONDARY outcome

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

effect of hepatic enzyme-inducing drugs on PKs

Outcome measures

Outcome measures
Measure	Arm 1 +EIASD (Enzyme-inducing Antizeizure Drug) n=9 Participants subjects on the +EIASD (Level 1) 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. Various Dose levels 1= 750mg/dayx5; 2=1100mg/dayx5; 3=1700mg/dayx5; 4=2200mg/dayx5 NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion	ARM 2 -EIASD (Enzyme-inducing Antizeizure Drug) n=16 Participants 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. Various Dose levels 1= 750mg/dayx5; 2=1100mg/dayx5; 3=1700mg/dayx5; 4=2200mg/dayx5 NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion	ARM 3 (No Stratification) Subjects in this group were not stratified based on anti-sezuire medication.. Subjects will take terameprocol for 5 consecutive days each month by IV. This was for dose 2200mg/day. New formulation TC6.	+EIASD Level 4 (2200 mg/dayx5D) subjects on the +EIASD (Level 4) 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. Dose level 4= 2220mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion +PEG Formulation	-EIASD Level 1 (750 mg/dayx5D) 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. Level 1 = 750mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion +PEG Formulation	-EIASD Level 2 (1100 mg/dayx5D) 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. Level 2 = 1100mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion +PEG Formulation	-EIASD Level 3 (1700 mg/dayx5D) 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. Level 3 = 1700mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion +PEG Formulation and new TC6 -PEG Formulation - Pts treated from both formulations	-EIASD Level 4 (2200 mg/dayx5D) 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. Level 4 = 2200mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion +PEG Formulation	Non Stratified (Both +EIASD and -EIASD) Subjects in this group were not stratified based on anti-sezuire medication.. Subjects will take terameprocol for 5 consecutive days each month by IV. This was for dose 2200mg/day. New formulation TC6 - NONPEG or -PEG. (polyethylene glycol )
Pharmacokinetics - Terminal Phase Half-life	18.2 Hour Standard Deviation 8.8	17.1 Hour Standard Deviation 9.4	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: About 2 years

Population: 3 pt did not have proper scans to be evaluable for analysis

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.

Outcome measures

Outcome measures
Measure	Arm 1 +EIASD (Enzyme-inducing Antizeizure Drug) n=32 Participants subjects on the +EIASD (Level 1) 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. Various Dose levels 1= 750mg/dayx5; 2=1100mg/dayx5; 3=1700mg/dayx5; 4=2200mg/dayx5 NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion	ARM 2 -EIASD (Enzyme-inducing Antizeizure Drug) 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. Various Dose levels 1= 750mg/dayx5; 2=1100mg/dayx5; 3=1700mg/dayx5; 4=2200mg/dayx5 NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion	ARM 3 (No Stratification) Subjects in this group were not stratified based on anti-sezuire medication.. Subjects will take terameprocol for 5 consecutive days each month by IV. This was for dose 2200mg/day. New formulation TC6.	+EIASD Level 4 (2200 mg/dayx5D) subjects on the +EIASD (Level 4) 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. Dose level 4= 2220mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion +PEG Formulation	-EIASD Level 1 (750 mg/dayx5D) 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. Level 1 = 750mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion +PEG Formulation	-EIASD Level 2 (1100 mg/dayx5D) 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. Level 2 = 1100mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion +PEG Formulation	-EIASD Level 3 (1700 mg/dayx5D) 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. Level 3 = 1700mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion +PEG Formulation and new TC6 -PEG Formulation - Pts treated from both formulations	-EIASD Level 4 (2200 mg/dayx5D) 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. Level 4 = 2200mg/day. NO intrasubject dose escalation. PK data will be collected on day one of cycle one infusion +PEG Formulation	Non Stratified (Both +EIASD and -EIASD) Subjects in this group were not stratified based on anti-sezuire medication.. Subjects will take terameprocol for 5 consecutive days each month by IV. This was for dose 2200mg/day. New formulation TC6 - NONPEG or -PEG. (polyethylene glycol )
Efficacy - Best Overall Response Stable Disease	9 participants	—	—	—	—	—	—	—	—
Efficacy - Best Overall Response Complete Response	0 participants	—	—	—	—	—	—	—	—
Efficacy - Best Overall Response Partial Response	0 participants	—	—	—	—	—	—	—	—
Efficacy - Best Overall Response Progressive Disease	23 participants	—	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: time to death - up to 12 months

Population: 3 pts still alive at time of analysis

Survival measured from first day of treatment to date of death