The definition of dose limiting toxicity (DLT) is in accord with the NCI Common Terminology Criteria for Adverse Events v4.0 (CTCAE). Dose limiting toxicity will be defined as:

• Grade 3 or 4 neutropenia complicated by fever, or greater than 38.5°C documented infection, or Grade 4 neutropenia of greater than 7 days duration


• Grade 4 thrombocytopenia or grade 3 thrombocytopenia complicated by hemorrhage


• Any grade greater than 3 non-hematologic toxicity unless there is clear alternative evidence that the adverse event (AE) was not caused by Kevetrin


• Grade 3 diarrhea, nausea, or vomiting may be excluded from dose-limiting toxicities provided that the maximum time limit for supportive measures is 48 hours."

These are the pharmacodynamic toxicity effects seen in animal studies:"GLP Toxicology and Safety Pharmacology Studies of Kevetrin
Repeat dose toxicology studies: IV weekly x 5 weeks
• Rats (60, 90, 120 mg/kg) NOAEL = 90 mg/kg
o minor changes in hematology, clinical chemistries
Cardiovascular effects: 60 mg/kg (dogs)
• No effect on ECG
• Transient increase in heart rate, arterial pressure, diastolic
pressure resolved  within 7 hours after dosing
Dogs (5, 25, 60 mg/kg) NOAEL = 5 mg/kg Cellceutix is a publicly traded company, stock ticker: o vomiting, loose stool, diarrhea (during dosing only)
biologically significant decrease in MCHC and
increases in RBC, hematocrit, and sodium (high
dose)

Neurological effects: 120 mg/kg IV (rats)
• No apparent neuropharmacological, temperature effects
Pulmonary effects: 120 mg/kg IV (rats)
• No biologically relevant effects on respiratory rate, tidal
volume or minute volume

And this: Toxicology and Safety Pharmacology of Kevetrin
Repeat dose toxicology studies: IV weekly x 5 weeks
• Rats (60, 90, 120 mg/kg) NOAEL = 90 mg/kg
minor changes in hematology, clinical chemistries
• Dogs (5, 25, 60 mg/kg) NOAEL = 5 mg/kg
iti l t l di h d i d i l )
Cardiovascular effects: 60 mg/kg (dogs)
• No effect on ECG
• Transient increase in heart rate, arterial pressure, diastolic
pressure – resolved within 7 hours after dosing
Neurological effects: 120 mg/kg IV (rats) p y p y
o vomiting, loose stool, diarrhea (during dosing only)
o biologically significant decrease in MCHC and
increases in RBC, hematocrit, and sodium (high dose)
• No apparent neuropharmacological, temperature effects
Pulmonary effects: 120 mg/kg IV (rats)
• No biologically relevant effects on respiratory rate, tidal
volume or minute volume

Humans starting at much lower dose. Animals treated to DLT. My guess is humans may experience some of the milder effects known to chemo drugs - nausea, vomiting, diarrhea, alteration in cbc reflecting some dehydration - but nothing severe - because even at maximum dose the animals tolerated fairly well. Would love to hear other opinions on this.