Tukysa
tucatinib
Species
MonkeyRat
Longest study
13 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey
“Twice daily oral administration of tucatinib was assessed in repeat-dose toxicity studies for up to 3 months in rats and monkeys, consistent with the clinical route of administration and intended dosing schedule.”
Why that species
Sequence homology, historical use (rat) and higher oral tolerability (monkey)
“The pharmacological relevance of the toxicological species was discussed by the applicant and taking sequence homology information as well as a justification based on historical use (rat) and higher oral tolerability (monkey) into account, the chosen species were considered acceptable.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In a 90-day cynomolgus monkey study, males and females (6/sex/group) were administered tucatinib at 0, 2.5, 10, or 20 mg/kg/dose twice daily (5, 20, or 40 mg/kg/day) via oral gavage.”
Species: general tox
Rat and monkey (twice-daily oral, up to 3 months)
“Twice daily oral administration of tucatinib was assessed in repeat-dose toxicity studies for up to 3 months in rats and monkeys, consistent with the clinical route of administration and intended dosing schedule.”
Species: DART
Rat and rabbit (pilot embryo-fetal development studies)
“The Applicant conducted pilot embryo-fetal development studies in rats and rabbits.”
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.”
Surrogate used in
No surrogate used; tucatinib tested directly in rat and monkey
“Twice daily oral administration of tucatinib was assessed in repeat-dose toxicity studies for up to 3 months in rats and monkeys, consistent with the clinical route of administration and intended dosing schedule.”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“Twice daily oral administration of tucatinib was assessed in repeat-dose toxicity studies for up to 3 months in rats and monkeys, consistent with the clinical route of administration and intended dosing schedule.”
Pivotal GLP studies
Twice-daily oral GLP repeat-dose studies up to 3 months in rats and monkeys
“Twice daily oral administration of tucatinib was assessed in repeat-dose toxicity studies for up to 3 months in rats and monkeys, consistent with the clinical route of administration and intended dosing schedule. The pivotal repeat-dose toxicology studies were conducted in compliance with Good Laboratory Practice regulations (21 CFR part 58).”
Route in tox
Oral gavage (rats, monkeys); naso-gastric administration in a monkey study
“Repeat dose studies were conducted in rats via oral gavage (Study 1140-028; GLP Study 8369684) and in monkeys via naso-gastric (Study JAY00093; GLP study) and oral gavage (Study 8369685; GLP study).”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration and mouse bone marrow micronucleus assays
“Tucatinib did not induce mutations in the bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro chromosome aberration test or the in vivo mouse bone marrow micronucleus assay at doses up to the high dose of 2000 mg/kg.”
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.”
Reproductive & developmental
Rat and rabbit EFD: teratogenic in rabbits, embryo-fetal toxicity in rats
“Tucatinib administered to pregnant dams caused teratogenicity in rabbits and embryo-fetal toxicity in rats.”
Safety pharmacology
No adverse ECG, respiratory or neurobehavioral effects in safety pharmacology studies
“Tucatinib had no adverse effect on ECG, respiration, or neurological behavior in safety pharmacology studies.”
Genotox: Ames
Negative
“Tucatinib did not induce mutations in the bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro chromosome aberration test or the in vivo mouse bone marrow micronucleus assay at doses up to the high dose of 2000 mg/kg.”
Genotox: in vitro mammalian
In vitro chromosome aberration: negative
“Tucatinib did not induce mutations in the bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro chromosome aberration test or the in vivo mouse bone marrow micronucleus assay at doses up to the high dose of 2000 mg/kg.”
Genotox: in vivo
Mouse bone marrow micronucleus up to 2000 mg/kg: negative
“Tucatinib did not induce mutations in the bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro chromosome aberration test or the in vivo mouse bone marrow micronucleus assay at doses up to the high dose of 2000 mg/kg.”
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 conducted: not warranted for an advanced cancer indication
“No carcinogenicity studies were conducted or warranted to support this NDA, as the proposed indication was for advanced cancer.”
hERG / QT
Low potential for hERG interaction; no clinically relevant effects in monkey CV safety study
“In terms of safety pharmacology, tucatinib appeared selective for the intended HER2 tyrosine kinase target, showed low potential for interaction with cardiovascular targets (hERG, Human Embryonic Kidney (HEK293) Cells) and showed no clinically relevant adverse effects in the in vivo CV safety study in monkey.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Tukysa 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 oncology small molecules (ICH S9)
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.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Targets: GI tract and liver (rat, monkey); hemolymphoid, skeletal muscle and reproductive system (rat) (FDA multi-discipline review, p. 34)
NOAEL / key findings
Targets: GI tract and liver (rat, monkey); hemolymphoid, skeletal muscle and reproductive system (rat)
“Administration of tucatinib to rats and monkeys resulted in body weight loss, reduced food consumption, and adverse effects in the gastrointestinal (GI) system (rat and monkey), liver (rat and monkey), hemolymphoid system (rat), skeletal muscle (rat), and reproductive system (rat).”
Risksopen answer page →
Immune & cytokine safety
Lymphoid depletion (hemolymphoid system) in rats
“Additional target organs in rats included the hemolymphoid system (lymphoid depletion), male and female reproductive organs, and skeletal muscle (myofiber degeneration/regeneration and hemorrhage) in male rats in the 28-day study.”
Biodistribution & persistence
Rat: highest in uveal tract, eyes, pigmented skin, liver, testes; not detected in CNS
“the highest distribution of tucatinib in rats was in the uveal tract, eyes, pigmented skin, liver, testes, epididymis (male), and thymus (female); tucatinib was not detected in CNS tissues.”
Modality-specific risk
GI and liver toxicity (major toxicities in rats and monkeys)
“Toxicities in the GI system and liver were observed in both rats and monkeys and are considered the major toxicities associated with tucatinib treatment.”
Anti-drug antibodies: animals
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.
Anti-drug antibodies: patients
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.
Label warnings
Boxed warning: Hepatotoxicity
- Hepatotoxicity
- Diarrhea
- Embryo-Fetal Toxicity
- Increased Serum Creatinine Without Affecting Renal Function
HepatotoxicityGastrointestinalEmbryo-fetal toxicityNephrotoxicity
US prescribing information, Boxed Warning and Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
US and Canada: first-in-human dose escalation in patients with advanced solid tumors (4 sites)
“Subjects with advanced solid tumors 4 sites: 2 US 2 Canada”
Repeat-dose tox before first-in-human
28-day rat and monkey studies submitted with the original IND
“The 28-day rat and monkey toxicology studies were reviewed by FDA under IND 78304, the original IND submitted with tucatinib.”
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Tukysa 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 oncology small molecules (ICH S9)
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.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Targets: GI tract and liver (rat, monkey); hemolymphoid, skeletal muscle and reproductive system (rat) (FDA multi-discipline review, p. 34)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week GLP rat and cynomolgus monkey oral studies, each with 28-day recovery
“13-Week GLP Twice Daily Oral Gavage Toxicity Study of Tucatinib in Cynomolgus Monkeys Followed by a 28-Day Recovery Period”
Pivotal GLP studies
Twice-daily oral GLP repeat-dose studies up to 3 months in rats and monkeys
“Twice daily oral administration of tucatinib was assessed in repeat-dose toxicity studies for up to 3 months in rats and monkeys, consistent with the clinical route of administration and intended dosing schedule. The pivotal repeat-dose toxicology studies were conducted in compliance with Good Laboratory Practice regulations (21 CFR part 58).”
DART package
Species: DART
Rat and rabbit (pilot embryo-fetal development studies)
“The Applicant conducted pilot embryo-fetal development studies in rats and rabbits.”
Reproductive & developmental
Rat and rabbit EFD: teratogenic in rabbits, embryo-fetal toxicity in rats
“Tucatinib administered to pregnant dams caused teratogenicity in rabbits and embryo-fetal toxicity in rats.”
PPND / ePPND: when
PPND not conducted: acceptable under ICH S9
“Studies investigating prenatal and postnatal development were not submitted. This is acceptable according to ICH S9.”
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 conducted: not warranted for an advanced cancer indication
“No carcinogenicity studies were conducted or warranted to support this NDA, as the proposed indication was for advanced cancer.”
Safety marginopen answer page →
Safety margin at NOAEL
Rat and monkey liver and GI toxicity at safety margins below 1 (clinically relevant doses)
“Repeat-dose toxicology studies in rats and cynomolgus monkeys showed primarily effects on liver presumably as an adaptive response to enzyme induction and GI at safety margins below 1 i.e. at clinically relevant doses leading to weight loss, dehydration and emesis.”
NOAEL / key findings
Targets: GI tract and liver (rat, monkey); hemolymphoid, skeletal muscle and reproductive system (rat)
“Administration of tucatinib to rats and monkeys resulted in body weight loss, reduced food consumption, and adverse effects in the gastrointestinal (GI) system (rat and monkey), liver (rat and monkey), hemolymphoid system (rat), skeletal muscle (rat), and reproductive system (rat).”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse xenograft models of HER2-expressing tumors (anti-tumor activity, HER2 phosphorylation inhibition)
“In vivo, single agent tucatinib showed anti-tumor activity and inhibition of HER2 phosphorylation in mouse xenograft models of HER2 expressing tumor cells.”
Why that model
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.
Reviewer's view of the efficacy data
EMA: in vitro and in vivo proof of concept considered well established
“In vitro and in vivo proof of concept is considered well established.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
No exposure margin: liver and GI toxicity in rats and monkeys at safety margins below 1 (clinically relevant doses)
“Repeat-dose toxicology studies in rats and cynomolgus monkeys showed primarily effects on liver presumably as an adaptive response to enzyme induction and GI at safety margins below 1 i.e. at clinically relevant doses leading to weight loss, dehydration and emesis.”
Impurity or metaboliteAccepted
Two human faecal metabolites (M18, M28) not observed in nonclinical species and not characterised
Why: Minor metabolites; advanced cancer indication · Within the guideline · Serious disease
“It appears that two human in vivo metabolites (M18 and M28, accounting for 6.07% and 3.86% of the dose in feces) are not observed in nonclinical species.”
“Taking the indication for advance cancer into consideration, the lack of any characterisation of these two minor metabolites are accepted.”
Similar precedents
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