Kadcyla
ado-trastuzumab emtansine
Species
MonkeyRat
Longest study
26 wk
Genotox
Partial / alternative Partial / alternative
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Conducted Stated
Speciesopen answer page →
Species
Rat and cynomolgus monkey (monkey pharmacologically relevant; long-term studies in monkey)
“Nonclinical single- and repeat-dose toxicology studies submitted to this BLA were conducted in rats and Cynomolgus monkeys.”
Why that species
Trastuzumab binds cynomolgus HER2 with similar affinity to human; does not bind rat HER2 (rat for off-target payload toxicity)
“it was previously demonstrated that trastuzumab binds to the Cynomolgus monkey receptor with similar affinity as to human HER2, but does not bind with high avidity to the rat receptor indicating Cynomolgus monkey is the more relevant pharmacologic species.”
Surrogate molecule
No surrogate; clinical ADC tested, plus free DM1 and MCC-DM1 studies in rat
“Likewise, studies in rats with ado-trastuzumab emtansine or DM1 alone resulted in similar toxicities, suggesting toxicities were mediated primarily by DM1.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“Therefore, long-term (e.g., 3- and 6-month) repeat-dose toxicology studies with ado-trastuzumab emtansine were conducted in monkeys.”
Pivotal GLP studies
GLP cynomolgus IV q3w x4 (12-week) with recovery and chronic q3w x8 with 6-week recovery; single-dose rat and monkey
“The Applicant did a second multidose toxicology study in Cynomolgus monkeys (study 07-0653). The animals received doses of TDM1 of 0 1, 3, or 10 mg/kg once every three weeks for 8 doses.”
Route in tox
IV
“T-DM1 is intended for IV administration, and therefore this route of administration was used in the non-clinical studies.”
Skipped studiesopen answer page →
Genotoxicity
Conducted on DM1: Ames negative; rat micronucleus positive (aneugenic/clastogenic); monkey micronucleus inconclusive
“DM1 was positive in an in vivo rat bone marrow micronucleus assay at exposures similar to the mean maximum concentrations of DM1 in patients in clinical trials, which is consistent with its mechanism of action.”
Carcinogenicity
Not conducted (not required, advanced cancer)
“8 Carcinogenicity Not required and not submitted.”
Reproductive & developmental
Not conducted (ICH S9; relied on trastuzumab data and DM1 mechanism); fertility effects from general tox
“Based on these findings and consistent with ICH S9, embryo-fetal developmental toxicity studies were not required for the indicated patient population.”
Safety pharmacology
Dedicated single-dose CV/respiratory telemetry study in female cynomolgus plus in vitro hERG with DM1
“Free DM1 does not inhibit the cardiac slow rectifier current at physiologically relevant concentrations. Trastuzumab emtansine does not cause changes in the monkey ECG but it does cause some elevation in blood pressures.”
First doseopen answer page →
First-in-human starting dose
HNSTD-based: monkey HNSTD 10 mg/kg (q3w x4), below 1/10 rat severely toxic dose, used to set Phase I start
“the highest non-severely toxic dose (HNSTD) in cynomolgus monkeys was 10 mg/kg for four injections every 3 weeks which was below the no observable adverse effect level in that species and below one-tenth of the severely toxic dose in rats, this information was used to determine a Phase I starting dose in humans.”
NOAEL / key findings
Monkey HNSTD 10 mg/kg q3w; liver enzymes, thrombocytopenia, lymphoid atrophy, axonal degeneration (sciatic nerve, spinal cord) at >=10 mg/kg
“Based on overall tolerability and reversibility of findings, the Applicant considered 10 mg/kg of trastuzumab emtansine given as four injections to Cynomolgus monkeys every 3 weeks to be the highest non-severely toxic dose.”
Risksopen answer page →
Immune & cytokine safety
No ADA detected after single dose in monkey safety pharmacology study; ADA assessed across monkey studies
“Blood samples for anti-drug antibody analysis were taken pre-dose and on Day 22. No anti-drug antibodies were detected in the post dose samples.”
Biodistribution & persistence
Confined largely to plasma; distribution parallels blood flow (lung, kidney, liver); no tissue persistence; predominantly fecal excretion
“Neither T-DM1 nor free DM1 were associated with tissue persistence or accumulation.”
Modality-specific risk
DM1 payload toxicity: hepatotoxicity, thrombocytopenia, peripheral neuropathy (axonal degeneration), pneumonitis
“Increased transaminases and centrilobular vacuolization in monkeys were correlated with hepatic toxicity observed in patients.”