Enhertu
fam-trastuzumab deruxtecan · HER2Japan and US: multicenter first-in-human study (Study DS8201-A-J101)
Adcetris: what was done before first-in-human, and what came after?
brentuximab vedotin · CD30
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 Adcetris 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: Monkey NOAEL 1 mg/kg, HNSTD 3 mg/kg, 6 mg/kg lethal; rat HNSTD 5 mg/kg; bone marrow/neutropenia, lymphoid, rat liver and testis (EMA assessment report, p. 37)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
Cynomolgus monkey 24-week IV infusion study (every 3 weeks × 9 doses) with 6-week recovery
“8216375 Cynomolgus monkey 5 (control) or 10 (treated) /sex/gp SGN-35: 1, 3 30 min IV infusion 24 weeks (q3wk × 9) recovery 6 weeks”
Pivotal GLP studies
Rat 4-week IV (weekly x4) with recovery; cynomolgus 9-week (q3w x4) and 24/26-week (q3w x9) IV infusion studies
“With repeat-dose administration of brentuximab vedotin, unconjugated brentuximab, and MMAE in rats and monkeys the principal test article-related effects of brentuximab vedotin and MMAE in both species included changes in the bone marrow and lymphoid tissues;”
DART package
Species: DART
Rat (embryo-fetal development, IV, organogenesis)
“In an embryo-fetal developmental study, pregnant rats received 2 intravenous doses of 0.3, 1, 3, or 10 mg/kg brentuximab vedotin during the period of organogenesis (once each on Pregnancy Days 6 and 13).”
Reproductive & developmental
Rat EFD: embryo-fetal lethality at >=3 mg/kg, placental transfer; no fertility studies; testicular toxicity in rat repeat-dose
“In rats, brentuximab vedotin was clearly embryo-foetal toxic, causing loss of almost all embryos at 3 mg/kg and above.”
PPND / ePPND: when
Not conducted: no prenatal or postnatal studies submitted, acceptable for relapsed or refractory HL and sALCL
“No carcinogenicity studies, fertility and early embryonic development studies and prenatal or postnatal studies (including maternal function) or studies in which the offspring (juvenile animals) are further dosed and evaluated were submitted, which is acceptable as brentuximab vedotin is intended for the treatment of patients with relapsed or refractory HL and sALCL.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Carcinogenicity studies with brentuximab vedotin or the small molecule (MMAE) have not been conducted.”
Carcinogenicity model
Not conducted (relapsed or refractory HL and sALCL indication)
“No carcinogenicity studies, fertility and early embryonic development studies and prenatal or postnatal studies (including maternal function) or studies in which the offspring (juvenile animals) are further dosed and evaluated were submitted, which is acceptable as brentuximab vedotin is intended for the treatment of patients with relapsed or refractory HL and sALCL.”
Carcinogenicity timing
Not required: no carcinogenicity studies submitted, acceptable for relapsed or refractory HL and sALCL
“No carcinogenicity studies, fertility and early embryonic development studies and prenatal or postnatal studies (including maternal function) or studies in which the offspring (juvenile animals) are further dosed and evaluated were submitted, which is acceptable as brentuximab vedotin is intended for the treatment of patients with relapsed or refractory HL and sALCL.”
Same question, other ADCs
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
Trodelvy
sacituzumab govitecan · Trop-2Not stated in public reviews
Zynlonta
loncastuximab tesirine · CD19Not stated in public reviews