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Precedia/Antibody-drug conjugates/First dose

How was the first-in-human dose set for approved ADCs?

From the FDA and EMA reviews of all 14 approved ADCs. Each answer links to the regulator's own sentence.

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Short answer
2 of 14 public reviews say how the first human dose was set; 2 more say it partly.
Stated2/14
Partly stated2/14
Not stated publicly10/14
Why most are blank, and what to do instead

Approval reviews rarely explain the first human dose: that rationale is in the IND, which is confidential. These are the methods regulators expect for ADCs, each step quoted from the guidance:

ADCs and immune-activating products in oncology (ICH S9 and S9 Q&A)

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.

Read the sourced method →
HNSTD/STD10: oncology start dose under ICH S9 (1/6 HNSTD, 1/10 STD10)

HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.

Read the sourced method →

Precedent by precedent

14 approved ADCs, with the reviewers' own words.

Enhertu

fam-trastuzumab deruxtecan · HER2
First-in-human starting dose
1/12 HED of monkey HNSTD (0.8 mg/kg), also matching minimum effective trough concentration
“The FIH dose of 0.8 mg/kg was selected based on one-twelfth of the human equivalent dose of the highest non-severely toxic dose (HNSTD) in cynomolgus monkeys in toxicology studies and was also estimated to provide trough concentration in humans comparable to the minimum effective concentrations in nonclinical studies.”
✓ VerifiedFDA multi-discipline review, p. 80Source ↗
NOAEL / key findings
HNSTD 30 mg/kg monkey, 197 mg/kg rat; bone marrow, intestine, skin, lung, testis, kidney; lung toxicity at 78.8 mg/kg
“The highest non-severely toxic dose of trastuzumab deruxtecan was established at 197 mg/kg in rats (non-binding species), and 30 mg/kg in cynomolgus monkey”
✓ VerifiedEMA assessment report, p. 49Source ↗

Kadcyla

ado-trastuzumab emtansine · HER2
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.”
✓ VerifiedEMA assessment report, p. 36Source ↗
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.”
✓ VerifiedFDA pharmacology/toxicology review, p. 153Source ↗

Elahere

mirvetuximab soravtansine · FRα
First-in-human starting dose
Rationale not stated; FIH Study 0401 escalated from 0.15 mg/kg (TBW) to 7.0 mg/kg
“MIRV: Dose escalation: 0.15 mg/kg TBW to 7.0 mg/kg TBW (n = 44 Q3W; n = 25 QW)”
✓ VerifiedEMA assessment report, p. 64Source ↗
NOAEL / key findings
10-week monkey NOAEL 4 mg/kg q3w (Cmax margin ~1); single-dose HNSTD 10 mg/kg, NOAEL 3 mg/kg; cornea, skin, bone marrow
“In a 10-week toxicity study in monkeys a mid-dose of 4 mg/kg/dose Q3W of MIRV was selected to characterize potential toxicity at an exposure metric which was predicted to be similar to that of the IV dose (6 mg/kg, AIBW) utilized for the registrational studies. This dose was considered as NOAEL.”
✓ VerifiedEMA assessment report, p. 56Source ↗

Zynlonta

loncastuximab tesirine · CD19
First-in-human starting dose
1/6 HNSTD in cynomolgus monkey cited as rationale for species choice; actual FIH calculation not detailed
“The cynomolgus monkey was selected as nonclinical species for safety evaluation of loncastuximab tesirine, given the greater predictive value of PK data generated in this species for humans, potential for reduced impact of antidrug antibody (ADA) formation on drug exposure, and the proven utility of 1/6th highest non‐severely toxic dose (HNSTD) for setting clinical starting doses with ADCs.”
✓ VerifiedFDA multi-discipline review, p. 49Source ↗
NOAEL / key findings
No NOAEL stated; 13-week monkey kidney and testis findings at all doses (≥0.075 mg/kg); skin hyperpigmentation dose-limiting; bone marrow, lung
“Also, adverse findings in male reproductive organs were present at 0.6 mg/kg only in the 4‐week study and at all doses (≥ 0.075 mg/kg) in the 13‐week study.”
✓ VerifiedFDA multi-discipline review, p. 51Source ↗

Adcetris

brentuximab vedotin · CD30
First-in-human starting dose
Not stated in public reviews
Not public: the starting-dose rationale sits in the confidential IND. How it's usually set for ADCs →
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
“At 3 mg/kg (HNSTD), a similar, but less severe cyclic decrease in neutrophil counts was observed, while at 1 mg/kg (NOAEL) no biologically relevant effects on neutrophil counts was observed.”
✓ VerifiedEMA assessment report, p. 37Source ↗

Besponsa

inotuzumab ozogamicin · CD22
First-in-human starting dose
Not stated in public reviews
Not public: the starting-dose rationale sits in the confidential IND. How it's usually set for ADCs →
NOAEL / key findings
No NOAEL in rat or monkey chronic studies; liver (sinusoidal injury), hematolymphoid, reproductive organs; monkey glomerulonephritis death at 5 ug/kg
“Taken together, the primary inotuzumab ozogamicin target organs identified by the chronic toxicity studies were the liver, hematolymphopoietic tissues, and the male and female reproductive organs.”
✓ VerifiedFDA multi-discipline review, p. 34Source ↗

Datroway

datopotamab deruxtecan · Trop-2
First-in-human starting dose
Not stated in public reviews
Not public: the starting-dose rationale sits in the confidential IND. How it's usually set for ADCs →
NOAEL / key findings
Monkey NOAEL 10 mg/kg for lung, cornea, skin, liver, thymus (intestinal toxicity at ≥10); rat NOAEL 20-60 mg/kg; ADA limits margins
“The NOAELs for pulmonary, corneal, dermal, hepatic, and lymphoid (thymic) toxicity was concluded to be 10 mg/kg.”
✓ VerifiedFDA multi-discipline review, p. 66Source ↗

Decnupaz

pivekimab sunirine · CD123
First-in-human starting dose
Not stated in public reviews
Not public: the starting-dose rationale sits in the confidential IND. How it's usually set for ADCs →
NOAEL / key findings
FDA: no NOAEL in 13-week (thymic atrophy ≥0.01 mg/kg); single-dose max nonlethal 0.4 mg/kg; marrow, GI, skin, thymus
“Adverse toxicity was observed at all doses since even the lowest tested dose of 0.01 Ab mg/kg produced thymic atrophy in males.”
✓ VerifiedFDA multi-discipline review, p. 61Source ↗

Emrelis

telisotuzumab vedotin · c-Met
First-in-human starting dose
Not stated in public reviews
Not public: the starting-dose rationale sits in the confidential IND. How it's usually set for ADCs →
NOAEL / key findings
13-week cyno: no adverse findings to 3 mg/kg; 4-week: neutropenia/marrow at ≥6 mg/kg, ovary/uterus ≥3 mg/kg, eye, thymus
“Myelosuppression occurred at the middle and high doses, which correlated histologically with decreased bone marrow cellularity.”
✓ VerifiedFDA multi-discipline review, p. 34Source ↗

Mylotarg

gemtuzumab ozogamicin · CD33
First-in-human starting dose
Not stated in public reviews
Not public: the starting-dose rationale sits in the confidential IND. How it's usually set for ADCs →
NOAEL / key findings
6-week NOAEL 2.4 mg/m2/wk monkey, 0.6 rat; 12-week monkey no NOAEL; liver, kidney, marrow, lymphoid, reproductive organs
“The NOAEL was defined at 2.4 mg/m2 /week based on target organ toxicity in the kidney, liver, and lympho-hematopoietic organs at ≥7.2 mg/m2 /week.”
✓ VerifiedFDA pharmacology/toxicology review, p. 18Source ↗

Padcev

enfortumab vedotin · Nectin-4
First-in-human starting dose
Not stated in public reviews
Not public: the starting-dose rationale sits in the confidential IND. How it's usually set for ADCs →
NOAEL / key findings
Monkey HNSTD/MTD 3 mg/kg, rat MTD 5 mg/kg; skin, injection site, bone marrow, liver, eye, male reproductive organs
“In the 4-week monkey study (# 20005664), AGS-22M6E systemic exposure at 3 mg/kg (MTD/HNSTD) was 2450 µg.hr/mL (Day 1) and 903 µg.hr/mL (Day 22).”
✓ VerifiedFDA multi-discipline review, p. 56Source ↗

Polivy

polatuzumab vedotin · CD79b
First-in-human starting dose
Not stated in public reviews
Not public: the starting-dose rationale sits in the confidential IND. How it's usually set for ADCs →
NOAEL / key findings
Rat STD10 10 mg/kg; monkey surrogate HNSTD 3 mg/kg; bone marrow, lymphoid, liver, male reproductive organs (testes irreversible)
“The main target organs are bone marrow, lymphoid organs, reproductive organs and liver with less severe effects on eye, skin and pancreas.”
✓ VerifiedEMA assessment report, p. 55Source ↗

Tivdak

tisotumab vedotin · Tissue factor
First-in-human starting dose
Not stated in public reviews
Not public: the starting-dose rationale sits in the confidential IND. How it's usually set for ADCs →
NOAEL / key findings
Monkey NOAEL 1 mg/kg (females; <1 mg/kg males), HNSTD 3 mg/kg; skin, bone marrow, eye, testes; skin deaths at 5 mg/kg
“The NOAEL for males was <1 mg/kg. The applicant also provided exposure (Cmax and AUC) ratios between monkey and human at the highest non-severely toxic dose of 3 mg/kg, which was approximately 1.35- to 2.56-fold that in humans.”
✓ VerifiedEMA assessment report, p. 50Source ↗

Trodelvy

sacituzumab govitecan · Trop-2
First-in-human starting dose
Not stated in public reviews
Not public: the starting-dose rationale sits in the confidential IND. How it's usually set for ADCs →
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
“In the absence of a NOAEL, the HNSTD in this study was 60 mg/kg/dose.”
✓ VerifiedEMA assessment report, p. 30Source ↗