Adcetris
brentuximab vedotin · CD30Conducted on MMAE: Ames and mouse lymphoma negative; rat micronucleus positive (aneugenic)
Mylotarg: genotox, carcinogenicity and repro: done or skipped?
gemtuzumab ozogamicin · CD33
Genotoxicity
Conducted: ADC clastogenic in mouse micronucleus; free calicheamicin DMH mutagenic and clastogenic in vitro
“Gemtuzumab ozogamicin was found to be clastogenic. This is consistent with the known induction of DNA breaks by calicheamicin and other enediyne antitumour antibiotics.”
Carcinogenicity
Not conducted; rat liver preneoplastic oval cell hyperplasia noted in tox studies
“No carcinogenicity studies have been conducted with gemtuzumab ozogamicin (see discussion on non-clinical aspects).”
Reproductive & developmental
Rat male/female fertility and rat EFD (one species agreed); embryolethal, teratogenic, male fertility impaired; no PPND
“Based on the unequivocally positive results obtained from a pilot study, the Agency previously agreed with the Applicant that one species would be sufficient to support an NDA application for CMA-676 in a leukemia indication.”
Safety pharmacology
Standalone non-GLP studies (mouse, rat, dog CV) plus payload hERG; dog BP decrease and HR increase at >=13 mg/m2
“Gemtuzumab ozogamicin was evaluated for potential effects on nervous, cardiovascular, gastrointestinal, hepatic, and renal systems in vivo and/or in vitro.”
Same question, other ADCs
Besponsa
inotuzumab ozogamicin · CD22Conducted: calicheamicin positive in Ames and in vitro micronucleus; ADC clastogenic in mouse micronucleus
Datroway
datopotamab deruxtecan · Trop-2Not conducted with ADC; DXd Ames negative, clastogenic in vitro chromosome aberration and in vivo rat micronucleus
Decnupaz
pivekimab sunirine · CD123Not conducted with ADC (ICH S9); FGN849 positive in Ames TA102, in vitro and in vivo micronucleus
Elahere
mirvetuximab soravtansine · FRαNot conducted with ADC; DM4 and S-methyl-DM4 Ames negative, rat bone marrow micronucleus positive
Emrelis
telisotuzumab vedotin · c-MetNot conducted with ADC; MMAE aneugenic (positive rat micronucleus), Ames and mouse lymphoma negative
Enhertu
fam-trastuzumab deruxtecan · HER2Not conducted with ADC; DXd clastogenic (rat micronucleus, CHL chromosome aberration), Ames negative
Kadcyla
ado-trastuzumab emtansine · HER2Conducted on DM1: Ames negative; rat micronucleus positive (aneugenic/clastogenic); monkey micronucleus inconclusive
Padcev
enfortumab vedotin · Nectin-4Not conducted with ADC; MMAE Ames and mouse lymphoma negative, rat micronucleus positive (aneugenic)
Polivy
polatuzumab vedotin · CD79bNot conducted with ADC; MMAE Ames and mouse lymphoma negative, rat micronucleus positive (aneugenic)
Tivdak
tisotumab vedotin · Tissue factorNot conducted with ADC; MMAE: Ames and mouse lymphoma negative, rat micronucleus positive (aneugenic)
Trodelvy
sacituzumab govitecan · Trop-2Not conducted with ADC; SN-38 Ames negative, in vitro micronucleus positive (clastogenic)
Zynlonta
loncastuximab tesirine · CD19Not conducted with ADC; SG3199 clastogenic in vitro (micronucleus, chromosome aberration); Ames not assessable (cytotoxicity)