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

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Other)
• Overall Status: Completed
• CT.gov ID: NCT00404248
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 35
• Locations: 9
• Arms: 2
• Duration (Months): 61
• Patients Per Site: 3.9
• Patients Per Site Per Month: 0.1

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Brain and Central Nervous System Tumors	Drug: terameprocol; Other: pharmacological study	Phase 1/Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 35 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: Jan 1, 2007
• Actual Primary Completion Date: Jun 1, 2009
• Actual Study Completion Date: Feb 1, 2012

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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

2. 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 Outcome Measures

1. 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.

2. 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.

3. 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

4. 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.

5. Survival [time to death - up to 12 months]

   Survival measured from first day of treatment to date of death

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UAB Comprehensive Cancer Center	Birmingham	Alabama	United States	35294-3410
2	H. Lee Moffitt Cancer Center and Research Institute at University of South Florida	Tampa	Florida	United States	33612-9497
3	Winship Cancer Institute of Emory University	Atlanta	Georgia	United States	30322
4	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland	United States	21231
5	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
6	Josephine Ford Cancer Center at Henry Ford Hospital	Detroit	Michigan	United States	48202
7	Wake Forest University Comprehensive Cancer Center	Winston-Salem	North Carolina	United States	27157-1096
8	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio	United States	44195
9	Abramson Cancer Center of the University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104-4283

Sponsors and Collaborators

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

Investigators

• Study Chair: Stuart A. Grossman, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

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

Publications

None provided.

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• ClinicalTrials.gov Identifier: NCT00404248
• Other Study ID Numbers: NABTT-0503 CDR0000515952; U01CA062475; NABTT-0503
• First Posted: Nov 28, 2006
• Last Update Posted: Mar 6, 2019
• Last Verified: Mar 1, 2019

• Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: adult anaplastic astrocytoma; adult anaplastic oligodendroglioma; adult giant cell glioblastoma; recurrent adult brain tumor; adult glioblastoma; adult gliosarcoma
• Additional relevant MeSH terms: Nervous System Neoplasms; Central Nervous System Neoplasms

Study Results

Participant Flow

Recruitment Details	subjects were accrued 2007-2008 in outpatient clinic

Arm/Group Title	Arm 1 Enzyme Inducing Antiseizure Drug (+ EIASD) Level 1	Arm 2 +EIASD Level 2	Arm 3 +EIASD Level 3	Arm 4 +EIASD Level 4	Arm 5 Non-Enzyme Inducing Antiseizure Drug (-EIASD) Level 1	Arm 6 -EIASD Level 2	Arm 7 -EIASD Level 3	Arm 8 -EIASD Level 4	Arm 9 - Non Stratified (Both +EIASD and -EIASD)
Arm/Group Description	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	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.	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	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.	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	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	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	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	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.
Period Title: Overall Study
STARTED	3	4	5	2	3	3	6	6	3
COMPLETED	3	3	5	2	3	3	6	6	3
NOT COMPLETED	0	1	0	0	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Arm 1 +EIASD	Arm 2 -EIASD	Arm 3 no Stratification (+EIASD or -EIASD)	Total
Arm/Group 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	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 of all reporting groups
Overall Participants	14	18	3	35
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	47	45	57	46
Sex: Female, Male (Count of Participants)
Female	7 50%	11 61.1%	1 33.3%	19 54.3%
Male	7 50%	7 38.9%	2 66.7%	16 45.7%
Karnofsky Performance Status (participants) [Number]
100	2 14.3%	1 5.6%	1 33.3%	4 11.4%
90	6 42.9%	7 38.9%	0 0%	13 37.1%
80	0 0%	5 27.8%	0 0%	5 14.3%
70	4 28.6%	4 22.2%	1 33.3%	9 25.7%
60	2 14.3%	1 5.6%	1 33.3%	4 11.4%
Histologic diagnosis (participants) [Number]
Glioblastoma	5 35.7%	7 38.9%	3 100%	15 42.9%
anaplastic oligodendroglioma	5 35.7%	5 27.8%	0 0%	10 28.6%
anaplastic astrocytoma	4 28.6%	6 33.3%	0 0%	10 28.6%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1 +EIASD (Enzyme-inducing Antizeizure Drug)	ARM 2 -EIASD (Enzyme-inducing Antizeizure Drug)	ARM 3 (No Stratification)
Arm/Group Description	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	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	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.
Measure Participants	14	18	3
Number [mg/day x 5 days]	1700	1700	1700

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

+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/Group Title	+ EIASD Level 1 (750 mg/dayx5D)	+EIASD Level 2 (1100 mg/dayx5D)	+EIASD Level 3 (1700 mg/dayx5D)	+EIASD Level 4 (2200 mg/dayx5D)	-EIASD Level 1 (750 mg/dayx5D)	-EIASD Level 2 (1100 mg/dayx5D)	-EIASD Level 3 (1700 mg/dayx5D)	-EIASD Level 4 (2200 mg/dayx5D)	Non Stratified (Both +EIASD and -EIASD)
Arm/Group Description	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. PK data will be collected on day one of cycle one infusion +PEG Formulation	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. PK data will be collected on day one of cycle one infusion +PEG Formulation	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. PK data will be collected on day one of cycle one infusion +PEG Formulation; Includes patientss at the new formulation TC6 (-PEG)	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	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	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	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	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	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 )
Measure Participants	3	4	5	2	3	3	6	6	3
Number [Dose Limiting Toxicities (DLT)]	0	0	0	0	0	0	0	2	2

3. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

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/Group Title	Arm 1 +EIASD	Arm 2 -EIASD
Arm/Group Description	subjects on the +EIASD treatment arm were taking one of these antiseizure durgs: 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
Measure Participants	9	16
Mean (Standard Deviation) [Liters/hour]	53.7 (14.6)	54.4 (20.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 1 +EIASD (Enzyme-inducing Antizeizure Drug), ARM 2 -EIASD (Enzyme-inducing Antizeizure Drug)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.3
	Confidence Interval	(1-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

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/Group Title	Arm 1 +EIASD	Arm 2 -EIASD
Arm/Group Description	subjects on the +EIASD treatment arm were taking one of these antiseizure durgs: 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
Measure Participants	9	16
Mean (Standard Deviation) [Liters]	706 (425)	612 (478)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 1 +EIASD (Enzyme-inducing Antizeizure Drug), ARM 2 -EIASD (Enzyme-inducing Antizeizure Drug)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	15.4
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

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/Group Title	Arm 1 +EIASD	Arm 2 -EIASD
Arm/Group Description	subjects on the +EIASD treatment arm were taking one of these antiseizure durgs: 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
Measure Participants	9	16
Mean (Standard Deviation) [Hour]	18.2 (8.8)	17.1 (9.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 1 +EIASD (Enzyme-inducing Antizeizure Drug), ARM 2 -EIASD (Enzyme-inducing Antizeizure Drug)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6.4
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Phase 1 Terameprocol
Arm/Group Description	subjects were either on the +EIASD antiseizure durgs: (phenytoin, carbamazepine, phenobarbital, primidone and oxcarbazepine). or not on antiseizure drugs - or those effecting hepatic enzymes ( -EIASD) such as gabapentin, lamotrigine, valproic acid, levetiracetam, tiagavine, topiramate, zonisamide and felbamate. PK (pharmacological study) data will be collected on day one of cycle one infusion
Measure Participants	32
Complete Response	0 0%
Partial Response	0 0%
Progressive Disease	23 164.3%
Stable Disease	9 64.3%

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

3 pts still alive at time of analysis

Arm/Group Title	Phase 1 Terameprocol
Arm/Group Description	subjects were either on the +EIASD antiseizure durgs: (phenytoin, carbamazepine, phenobarbital, primidone and oxcarbazepine). or not on antiseizure drugs - or those effecting hepatic enzymes ( -EIASD) such as gabapentin, lamotrigine, valproic acid, levetiracetam, tiagavine, topiramate, zonisamide and felbamate. PK (pharmacological study) data will be collected on day one of cycle one infusion
Measure Participants	32
Median (Standard Deviation) [months]	5.5 (8.4)

Adverse Events

Time Frame	While patients were actively on treatment and for 30 days post treatment
Arm/Group Title	+ EIASD Level 1 (750 mg/dayx5D)		+EIASD Level 2 (1100 mg/dayx5D)		+EIASD Level 3 (1700 mg/dayx5D)		+EIASD Level 4 (2200 mg/dayx5D)		-EIASD Level 1 (750 mg/dayx5D)		-EIASD Level 2 (1100 mg/dayx5D)		-EIASD Level 3 (1700 mg/dayx5D)		-EIASD Level 4 (2200 mg/dayx5D)		Non Stratified (Both +EIASD and -EIASD)
Arm/Group Description	subjects on the +EIASD (Level 1) treatment arm were taking one of these antiseizure durgs: 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. PK data will be collected on day one of cycle one infusion +PEG Formulation		subjects on the +EIASD (Level 2) treatment arm were taking one of these antiseizure durgs: 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. PK data will be collected on day one of cycle one infusion +PEG Formulation		subjects on the +EIASD (Level 3) treatment arm were taking one of these antiseizure durgs: 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. PK data will be collected on day one of cycle one infusion +PEG Formulation; Includes pts at the new formulation TC6 (-PEG)		subjects on the +EIASD (Level 4) treatment arm were taking one of these antiseizure durgs: 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		Subjects in the -EIASD group were either not being treated with antiseizure drugs or were taking ones that did not significantly induce hypatic enzynmes such as gabapentin, lamotrigine, valproic acid, levetiracetam, tiagavine, 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		Subjects in the -EIASD group were either not being treated with antiseizure drugs or were taking ones that did not significantly induce hypatic enzynmes such as gabapentin, lamotrigine, valproic acid, levetiracetam, tiagavine, 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		Subjects in the -EIASD group were either not being treated with antiseizure drugs or were taking ones that did not significantly induce hypatic enzynmes such as gabapentin, lamotrigine, valproic acid, levetiracetam, tiagavine, 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		Subjects in the -EIASD group were either not being treated with antiseizure drugs or were taking ones that did not significantly induce hypatic enzynmes such as gabapentin, lamotrigine, valproic acid, levetiracetam, tiagavine, 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		Subjects in this group were not stratified based on anti-seizure 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.
All Cause Mortality
	+ EIASD Level 1 (750 mg/dayx5D)		+EIASD Level 2 (1100 mg/dayx5D)		+EIASD Level 3 (1700 mg/dayx5D)		+EIASD Level 4 (2200 mg/dayx5D)		-EIASD Level 1 (750 mg/dayx5D)		-EIASD Level 2 (1100 mg/dayx5D)		-EIASD Level 3 (1700 mg/dayx5D)		-EIASD Level 4 (2200 mg/dayx5D)		Non Stratified (Both +EIASD and -EIASD)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	+ EIASD Level 1 (750 mg/dayx5D)		+EIASD Level 2 (1100 mg/dayx5D)		+EIASD Level 3 (1700 mg/dayx5D)		+EIASD Level 4 (2200 mg/dayx5D)		-EIASD Level 1 (750 mg/dayx5D)		-EIASD Level 2 (1100 mg/dayx5D)		-EIASD Level 3 (1700 mg/dayx5D)		-EIASD Level 4 (2200 mg/dayx5D)		Non Stratified (Both +EIASD and -EIASD)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/4 (0%)		0/5 (0%)		0/2 (0%)		0/3 (0%)		0/3 (0%)		0/6 (0%)		2/6 (33.3%)		2/3 (66.7%)
Gastrointestinal disorders
illeus	0/3 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0
General disorders
Constitutional Symptoms -other	0/3 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1
Renal and urinary disorders
interstitial nephritis	0/3 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1
Respiratory, thoracic and mediastinal disorders
dyspnea	0/3 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0
hypoxia	0/3 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1
Other (Not Including Serious) Adverse Events
	+ EIASD Level 1 (750 mg/dayx5D)		+EIASD Level 2 (1100 mg/dayx5D)		+EIASD Level 3 (1700 mg/dayx5D)		+EIASD Level 4 (2200 mg/dayx5D)		-EIASD Level 1 (750 mg/dayx5D)		-EIASD Level 2 (1100 mg/dayx5D)		-EIASD Level 3 (1700 mg/dayx5D)		-EIASD Level 4 (2200 mg/dayx5D)		Non Stratified (Both +EIASD and -EIASD)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		4/4 (100%)		5/5 (100%)		1/2 (50%)		2/3 (66.7%)		3/3 (100%)		6/6 (100%)		3/6 (50%)		3/3 (100%)
Blood and lymphatic system disorders
anemia	0/3 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0
Cardiac disorders
hypertension	0/3 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0
Gastrointestinal disorders
nausea	0/3 (0%)	0	0/4 (0%)	0	1/5 (20%)	1	0/2 (0%)	0	2/2 (100%)	2	1/3 (33.3%)	2	0/6 (0%)	0	1/6 (16.7%)	1	1/3 (33.3%)	1
Constipation	1/3 (33.3%)	1	0/4 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	1/3 (33.3%)	1
diarrhea	0/3 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/3 (0%)	0
abdominal distension	0/3 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0
dyspepsia	0/3 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	2	1/6 (16.7%)	1	0/3 (0%)	0
ileus	0/3 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0
fecal incontinence	0/3 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/3 (0%)	0
dehydration	0/3 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1
anorexia	0/3 (0%)	0	1/4 (25%)	1	1/5 (20%)	1	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0
General disorders
fatigue	1/3 (33.3%)	1	1/4 (25%)	5	1/5 (20%)	1	0/2 (0%)	0	0/3 (0%)	0	3/3 (100%)	4	0/6 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1
injection site reaction NOS	0/3 (0%)	0	0/4 (0%)	0	1/5 (20%)	1	1/2 (50%)	2	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	1/6 (16.7%)	1	0/3 (0%)	0
fever	0/3 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1
General disorders and administration site condistions -other	0/3 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1
gait disturbance	0/3 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	2	0/6 (0%)	0	0/3 (0%)	0
Investigations
lipase	0/3 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0
Aspartate aminotransferase increased	0/3 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/3 (0%)	0
Alanine aminotransferase increased	0/3 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/3 (0%)	0
platelet count decreased	0/3 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/3 (0%)	0
Metabolism and nutrition disorders
hypophosphatemia	0/3 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0
hypoalbuminemia	0/3 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/3 (0%)	0
Musculoskeletal and connective tissue disorders
back pain	0/3 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0
generalized muscle weakness	0/3 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	1/6 (16.7%)	1	1/3 (33.3%)	1
Nervous system disorders
Seizure	0/3 (0%)	0	1/4 (25%)	1	1/5 (20%)	1	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0
dizziness	1/3 (33.3%)	2	0/4 (0%)	0	1/5 (20%)	2	0/2 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	3	0/6 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0
headache	1/3 (33.3%)	1	0/4 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0
ataxia	1/3 (33.3%)	1	0/4 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0
tremor	0/3 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/6 (33.3%)	2	0/6 (0%)	0	0/3 (0%)	0
somnolence	0/3 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1
Psychiatric disorders
mood alteration - euphoria	0/3 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0
Renal and urinary disorders
proteinuria	0/3 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0
urinary incontinence	0/3 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/3 (0%)	0
acute kidney injury	0/3 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1
Respiratory, thoracic and mediastinal disorders
hypoxia	0/3 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	2/3 (66.7%)	2
laryngeal inflammation	0/3 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1
dyspnea	0/3 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0
Skin and subcutaneous tissue disorders
erythrodema	0/3 (0%)	0	0/4 (0%)	0	1/5 (20%)	1	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0
rash acneiform	0/3 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	3	0/6 (0%)	0	2/3 (66.7%)	3

Limitations/Caveats

We were not able to complete the phase 2 portion of this study as the company had internal issues and no longer had funds to support the project. We did complete the phase I and determined the (Maxium Tolerated Dose) MTD, 1700mg/day x 5 days

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.