Kadcyla

“Nonclinical single- and repeat-dose toxicology studies submitted to this BLA were conducted in rats and Cynomolgus monkeys.”

“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.”

“Likewise, studies in rats with ado-trastuzumab emtansine or DM1 alone resulted in similar toxicities, suggesting toxicities were mediated primarily by DM1.”

“Nonclinical single- and repeat-dose toxicology studies submitted to this BLA were conducted in rats and Cynomolgus monkeys.”

“Based on these findings and consistent with ICH S9, embryo-fetal developmental toxicity studies were not required for the indicated patient population.”

“Carcinogenicity studies have not been conducted with ado-trastuzumab emtansine.”

“Likewise, studies in rats with ado-trastuzumab emtansine or DM1 alone resulted in similar toxicities, suggesting toxicities were mediated primarily by DM1.”

“Therefore, long-term (e.g., 3- and 6-month) repeat-dose toxicology studies with ado-trastuzumab emtansine were conducted in monkeys.”

“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.”

“T-DM1 is intended for IV administration, and therefore this route of administration was used in the non-clinical studies.”

“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.”

“8 Carcinogenicity Not required and not submitted.”

“Based on these findings and consistent with ICH S9, embryo-fetal developmental toxicity studies were not required for the indicated patient population.”

“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.”

“DM1 was negative in an in vitro bacterial reverse mutation (Ames) assay.”

“The genotoxicity of DM1 was evaluated in a reverse mutation assay with Salmonella strains as well as an in vivo chromosome aberration test performed in rats.”

“DM1 was aneugenic or clastogenic in an in vivo single-dose rat bone marrow micronucleus assay at exposures that were comparable to mean maximum concentrations of DM1 measured in humans administered trastuzumab emtansine.”

“Not required and not submitted.”

“Not required and not submitted.”

“As 29.5 μM DM1 caused only 2.5% inhibition, both IC20 and IC50 were estimated to be greater than the tested highest dose.”

“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.”

“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.”

“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.”

“Neither T-DM1 nor free DM1 were associated with tissue persistence or accumulation.”

“Increased transaminases and centrilobular vacuolization in monkeys were correlated with hepatic toxicity observed in patients.”

“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.”

“Among patients who received KADCYLA as a single agent for a median duration of 10 months in seven clinical trials, 5% (64/1243) of patients tested positive for antibodies against ado-trastuzumab emtansine at one or more post-dose timepoints. Neutralizing antibodies against ado-trastuzumab emtansine were detected in 45% (18/40) of evaluable patients who were ADA positive.”

“In view of these results, 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.”

“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.”

“The animals received doses of TDM1 of 0 1, 3, or 10 mg/kg once every three weeks for 8 doses. Half the monkeys were allowed to recover for six weeks after the last dose.”

“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.”

“Based on these findings and consistent with ICH S9, embryo-fetal developmental toxicity studies were not required for the indicated patient population.”

“Based on these findings and consistent with ICH S9, embryo-fetal developmental toxicity studies were not required for the indicated patient population.”

“After consultation with the FDA, the Applicant did not conduct new reproductive toxicity studies with trastuzumab emtansine. The small molecule component, DM1, is a microtubule inhibitor which is genotoxic.”

“Carcinogenicity studies have not been conducted with ado-trastuzumab emtansine.”

“Not required and not submitted.”

“Not required and not submitted.”

“Administration of trastuzumab emtansine was well tolerated in rats and monkeys at doses up to 20 and 10 mg/kg, respectively, corresponding to 2040 µg DM1/m2 in both species, which is approximately equivalent to the clinical dose of trastuzumab emtansine in patients.”

“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.”

“Trastuzumab-MCC-DM1 caused tumor growth inhibition in all three models in the dose range of 3 to 31 mg/kg, depending on the model.”

“Anti-tumor activity of trastuzumab emtansine was evaluated in three independent animal models of HER2-positive human cancers (not formally reviewed). Two of these are xenograft models using human tumor cell lines.”

“Based on the nonclinical safety data trastuzumab emtansine has been adequately characterised in terms of its pharmacodynamic activity, pharmacokinetic properties and safety profile.”