Erbitux
cetuximab
Species
MonkeyRat
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey (pivotal); supporting 4-week rat study
“The pivotal repeat-dose toxicity study is a 39 week study in Cynomolgus monkeys (study 070-087). A 4-week study in Sprague-Dawley rats was also conducted (study 54167).”
Why that species
Cynomolgus monkey considered appropriate; adverse reactions similar to those in humans
“The Cynomolgus monkey was considered an appropriate species for safety testing of cetuximab. The similarity of adverse reactions seen in monkeys and humans supports this notion.”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkey
“A comprehensive 39-week repeat-dose toxicology study in the Cynomolgus monkey was conducted.”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“The pivotal repeat-dose toxicity study is a 39 week study in Cynomolgus monkeys (study 070-087).”
Pivotal GLP studies
39-week IV cynomolgus study: 12/38/120 mg/kg initial dose, then weekly 7.5/24/75 mg/kg
“The initial doses and subsequent weekly doses were 12 and 7.5 mg/kg for the low dose group, 38 and 24 mg/kg for the intermediate dose group, and 120 and 75 5 mg/kg for the high dose group.”
Route in tox
Intravenous infusion
“Toxicokinetics after repeated infusions of cetuximab to Cynomolgus monkeys, (0, 12, 38 and 120 mg/kg at week 1, subsequent weekly doses 0, 7.5, 24 and 75 mg/kg).”
Skipped studiesopen answer page →
Genotoxicity
Conducted (partial): Ames test and rat micronucleus test negative
“the applicant decided to perform a partial genotoxicity study using in vitro and in vivo assays in terms of an AMES test and a rat micronucleus test. No genotoxic potential of Cetuximab was observed.”
Carcinogenicity
Not conducted; not required given life-expectancy in the intended advanced cancer indication
“Based on the life-expectancy in the intended therapeutic indication, no long-term carcinogenisity studies are required80.”
Reproductive & developmental
Monkey embryo-fetal study: embryolethality and abortions, no fetal malformations
“While no fetal malformations occurred in offspring, there was an increased incidence of embryolethality and abortions at doses approximately 1 to 4 times the recommended dose of ERBITUX based on BSA.”
Safety pharmacology
Single-dose monkey CV/respiratory study plus endpoints in 39-week study: no cardiovascular or respiratory effects
“In conclusion, there were no indications of an effect of cetuximab on the cardiovascular and respiratory system.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Erbitux don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oncology monoclonal antibodies (ICH S9)
In cancer patients the start dose should be pharmacologically active yet reasonably safe. A common small-molecule approach is one-tenth of the dose severely toxic to 10% of rodents, or one-sixth of the highest non-severely toxic dose in non-rodents.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Skin primary target organ with dose-dependent effects at all doses; severe skin reactions and 5 deaths at high dose (EMA assessment report, p. 11)
NOAEL / key findings
Skin primary target organ with dose-dependent effects at all doses; severe skin reactions and 5 deaths at high dose
“Clinical and necropsy findings indicated that the skin was the primary target organ, with dose-dependent effects observed at all dose levels. Severe skin reactions and 5 intercurrent deaths were observed in the high dose group.”
Risksopen answer page →
Immune & cytokine safety
Anti-drug antibodies in 3/22 monkeys (13.6%), affecting serum concentration in one
“Antibody responses were observed in 3/22 (13.6%) Cynomolgus monkeys. An effect on cetuximab serum concentrations was observed for one of these animals only.”
Biodistribution & persistence
Saturable clearance at higher doses; distribution mainly within plasma volume
“Clearance decreased and terminal half-life increased with increasing dose, indicating a saturated clearance at higher doses. Distribution volume indicated that cetuximab is mainly located in the plasma volume.”
Modality-specific risk
EGFR-mediated maturation defect of the epidermis (skin toxicity)
“Pathogenetically the skin lesions were considered to be related to a Cetuximab induced maturation defect of the epidermis.”