Nordihydroguaiaretic Acid (NDGA) 2000mg given orally daily in 3 divided doses (750mg in the morning and in the evening, and 500mg at midday) over a 28-day cycle.

NDGA

Sex: Female, Male

Region of Enrollment

Participants who experienced a PSA decline of at least 50%, confirmed by a second PSA value 4 or more weeks later. The reference PSA for decline was a PSA measured within 2 weeks of beginning study treatment. If at most 1 PSA response was observed among the first 12 patients, then accrual would stop and the trial would close for futility.

Prostate Specific Antigen (PSA) Response According to Consensus Criteria

Number of participants experiencing PSA decline during the first 3 treatment cycles

PSA Decline

PSADT was calculated using the formula natural log 2 divided by the slope of the natural log of the PSA versus time. Pretreatment PSADT was calculated using a minimum of 3 values; end of study PSADT incorporated all measured PSA values on study starting Cycle 2-Day 1 until the patient was removed from the study.

Change in Prostate Specific Antigen Doubling Time (PSADT)

End-of-study imaging was assessed for disease progression per Response Evaluation Criteria In Solid Tumors (RECIST) criteria: * Progressive Disease (PD)=At least a 20% increase in the sum of the largest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

Disease Progression at End of Study

Overall Study

Dr. Terence Friedlander

Prostate Cancer

Nordihydroguaiaretic Acid (NDGA)

UCSF Helen Diller Family Comprehensive Cancer Center

Pharmacokinetic and Efficacy Study of Nordihydroguaiaretic Acid (NDGA) in Non Metastatic Recurrent Prostate Cancer

A Phase II Pharmacokinetic and Efficacy Study of Nordihydroguaiaretic Acid (NDGA) in Non-Metastatic Recurrent Prostate Cancer

University of California, San Francisco

Insmed Incorporated

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

Arm 1 +EIASD

Arm 2 -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

Arm 3 no Stratification (+EIASD or -EIASD)

Total

this is a performance assessment, or functional impairment. 100% is a perfect score no impariment (highest score) and 60% Requires occasional assistance, but is able to care for most of his personal needs. You had to have at least a 60% to be eligible fof the study.

Karnofsky Performance Status

Histologic diagnosis

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

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 1 +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 2 -EIASD (Enzyme-inducing Antizeizure Drug)

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.

ARM 3 (No Stratification)

Maximum Tolerated Dose (Phase I)

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

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

+ EIASD Level 1 (750 mg/dayx5D)

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

+EIASD Level 2 (1100 mg/dayx5D)

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)

+EIASD Level 3 (1700 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 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 1 = 750mg/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 2 = 1100mg/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 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 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 4 = 2200mg/day. NO intrasubject dose escalation.
PK data will be collected on day one of cycle one infusion
+PEG Formulation

-EIASD Level 4 (2200 mg/dayx5D)

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 )

Non Stratified (Both +EIASD and -EIASD)

Maximum Tolerated Dose (Phase I) - Dose Limiting Toxicity (DLT)

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.

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

Pharmacokinetics - Total Body Clearance

Pharmacokinetics - Steady-State Apparent Volume Distribution

effect of hepatic enzyme-inducing drugs on PKs

Pharmacokinetics - Terminal Phase Half-life

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.

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

Phase 1 Terameprocol

Efficacy - Best Overall Response

Survival measured from first day of treatment to date of death

Survival

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 1 Enzyme Inducing Antiseizure Drug (+ EIASD) Level 1

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 2 +EIASD Level 2

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 3 +EIASD Level 3

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 4 +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 1 = 750mg/day. NO intrasubject dose escalation.
PK data will be collected on day one of cycle one infusion

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 2 = 1100mg/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 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 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 4 = 2200mg/day. NO intrasubject dose escalation.
PK data will be collected on day one of cycle one infusion

Arm 8 -EIASD Level 4

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.

Arm 9 - Non Stratified (Both +EIASD and -EIASD)

Director of Adult Brain Tumor Consortum

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.

Brain and Central Nervous System Tumors

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.

terameprocol

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.

pharmacological study

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

nordihydroguaiaretic acid/vēzis

Pharmacokinetic and Efficacy Study of Nordihydroguaiaretic Acid (NDGA) in Non Metastatic Recurrent Prostate Cancer

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

Nordihydroguaiaretic Acid in Treating Patients With Nonmetastatic Relapsed Prostate Cancer

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