Enhertu
fam-trastuzumab deruxtecan · HER2Japan and US: multicenter first-in-human study (Study DS8201-A-J101)
Trodelvy: what was done before first-in-human, and what came after?
sacituzumab govitecan · Trop-2
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Trodelvy 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 ADCs
ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.
“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”
This product's starting point
NOAEL / key findings: Acute study HNSTD 60 mg/kg (no NOAEL); 13-week NOAEL/HNSTD 50 mg/kg; bone marrow, lymphoid, GI, liver, skin, female reproductive organs (EMA assessment report, p. 30)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week cynomolgus monkey, IV once weekly for 2 weeks of each 3-week cycle, 4 cycles; recovery phase included
“In a 13-week toxicity study, monkeys were given sacituzumab govitecan at doses of 12.5, 25, and 50 mg/kg once weekly via a 1-hour infusion for 2 weeks of a 3-week cycle for 4 treatment cycles.”
Pivotal GLP studies
GLP monkey 2-dose acute study (60, 120 mg/kg) and 13-week monkey study (days 1, 8 q21d x4 cycles, 6-week recovery), IV
“In a 13-week toxicity study, monkeys were given sacituzumab govitecan at doses of 12.5, 25, and 50 mg/kg once weekly via a 1-hour infusion for 2 weeks of a 3-week cycle for 4 treatment cycles.”
DART package
Species: DART
Not conducted (not warranted per ICH S9)
“No embryo-fetal developmental toxicology studies were conducted or warranted to support this BLA submission, based on ICH S9.”
Reproductive & developmental
Not conducted (ICH S9); SN-38 genotoxic so embryo-fetal toxicity expected; female repro organ findings in monkey
“No embryo-fetal developmental toxicology studies were conducted or warranted to support this BLA submission, based on ICH S9.”
PPND / ePPND: when
No reproductive and developmental toxicity studies conducted or required (genotoxic SN-38 payload)
“There were no reproductive and developmental toxicology studies conducted with sacituzumab govitecan or required to support this BLA. Sacituzumab govitecan contains a genotoxic component, SN-38, and is toxic to rapidly dividing cells.”
Carcinogenicity
Species: carcinogenicity
Not conducted (advanced cancer indication)
“No carcinogenicity studies were conducted or warranted to support this NDA, as the proposed indication was for advanced cancer.”
Carcinogenicity model
Not conducted (advanced cancer indication)
“No carcinogenicity studies were conducted or warranted to support this NDA, as the proposed indication was for advanced cancer.”
Carcinogenicity timing
Not required for advanced cancer (ICH S9)
“No assessment of carcinogenicity has been conducted in accordance with ICH S9 according to which carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer.”
Same question, other ADCs
Adcetris
brentuximab vedotin · CD30Not stated in public reviews
Besponsa
inotuzumab ozogamicin · CD22Not stated in public reviews
Datroway
datopotamab deruxtecan · Trop-2Not stated in public reviews
Decnupaz
pivekimab sunirine · CD123Not stated in public reviews
Elahere
mirvetuximab soravtansine · FRαNot stated in public reviews
Emrelis
telisotuzumab vedotin · c-MetNot stated in public reviews
Kadcyla
ado-trastuzumab emtansine · HER2Not stated in public reviews
Mylotarg
gemtuzumab ozogamicin · CD33Not stated in public reviews
Padcev
enfortumab vedotin · Nectin-4Not stated in public reviews
Polivy
polatuzumab vedotin · CD79bNot stated in public reviews
Tivdak
tisotumab vedotin · Tissue factorNot stated in public reviews
Zynlonta
loncastuximab tesirine · CD19Not stated in public reviews