Vanflyta
quizartinib
Species
MonkeyRatDog
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, dog and cynomolgus monkey
“Repeat-dose toxicology studies were conducted in Sprague-Dawley rats, beagle dogs, and cynomolgus monkeys given quizartinib dihydrochloride for up to 13 weeks.”
Why that species
Cynomolgus monkey selected as alternate non-rodent based on PK and toxicology data
“Based on pharmacokinetic (PK) and toxicology data, the cynomolgus monkey was selected as a potential alternate nonrodent model for evaluating the toxicity profile of quizartinib to predict human safety risk.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Repeat-dose toxicology studies were conducted in Sprague-Dawley rats, beagle dogs, and cynomolgus monkeys given quizartinib dihydrochloride for up to 13 weeks.”
Species: general tox
Rat, beagle dog and cynomolgus monkey (up to 13 weeks)
“Repeat-dose toxicology studies were conducted in Sprague-Dawley rats, beagle dogs, and cynomolgus monkeys given quizartinib dihydrochloride for up to 13 weeks.”
Species: DART
Rat (EFD only)
“In an embryo-fetal development (EFD) study in rats, quizartinib at doses resulting in exposures approximately 3 times the exposure at the maximum recommended human dose (MRHD) was associated with adverse developmental outcomes including structural abnormalities (anasarca and edema) and alterations to growth (lower fetal weights and effects on skeletal ossification).”
Species: carcinogenicity
Not conducted (not required for the AML indication)
“No carcinogenicity studies were conducted or are required to support the marketing of quizartinib for the current indication.”
Surrogate used in
No surrogate used
“Repeat-dose toxicology studies were conducted in Sprague-Dawley rats, beagle dogs, and cynomolgus monkeys given quizartinib dihydrochloride for up to 13 weeks.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat, dog and monkey)
“NOAELs in the 13-week repeated dose toxicity studies were 3 mg/kg/day in rats, 5 mg/kg/day in dogs, and 3 mg/kg/day in monkeys.”
Pivotal GLP studies
13-week rat, dog and cynomolgus monkey repeat-dose studies
“NOAELs in the 13-week repeated dose toxicity studies were 3 mg/kg/day in rats, 5 mg/kg/day in dogs, and 3 mg/kg/day in monkeys.”
Route in tox
Oral (gavage)
“A 13-Week Oral Gavage Toxicity Study of AC220 in the Cynomolgus Monkey With a 4 Week Recovery Period”
Skipped studiesopen answer page →
Genotoxicity
Positive in Ames; negative in mouse lymphoma, human lymphocyte chromosome aberration and rat micronucleus assays
“In genotoxicity studies, quizartinib was mutagenic in a bacterial reverse mutation assay. Quizartinib was not genotoxic in the following assays: mouse lymphoma thymidine kinase mutation assay, chromosome aberration assay in human peripheral blood lymphocytes, and rat bone marrow micronucleus assay (tested to the maximum tolerated dose, MTD).”
Carcinogenicity
Not conducted; not required for the AML indication
“No carcinogenicity studies were conducted or are required to support the marketing of quizartinib for the current indication.”
Reproductive & developmental
Rat EFD: anasarca/edema, lower fetal weight and ossification effects at ~3x MRHD exposure
“In an embryo-fetal development (EFD) study in rats, quizartinib at doses resulting in exposures approximately 3 times the exposure at the maximum recommended human dose (MRHD) was associated with adverse developmental outcomes including structural abnormalities (anasarca and edema) and alterations to growth (lower fetal weights and effects on skeletal ossification).”
Safety pharmacology
No hERG inhibition at clinical concentrations; dose-dependent sustained QTc prolongation in monkeys
“However, quizartinib and the major metabolite AC886 did not inhibit hERG, INa, INa-L, or ICa-L currents at clinically relevant concentrations. In vivo, a single dose of quizartinib administered to monkeys induced a dose-dependent increase in corrected QT interval (QTc) with sustained prolongation over 24 hours.”
Genotox: Ames
Positive (mutagenic)
“In genotoxicity studies, quizartinib was mutagenic in a bacterial reverse mutation assay.”
Genotox: in vitro mammalian
Mouse lymphoma TK assay and human lymphocyte chromosome aberration: negative
“Quizartinib was not genotoxic in the following assays: mouse lymphoma thymidine kinase mutation assay, chromosome aberration assay in human peripheral blood lymphocytes, and rat bone marrow micronucleus assay (tested to the maximum tolerated dose, MTD).”
Genotox: in vivo
Rat bone marrow micronucleus negative (equivocal in 28-day rat study); Big Blue transgenic rat negative
“Of note, an equivocal result (positive genotoxicity but within the range of historical control data) at a dose approximating the MTD was obtained in the micronucleus assessment in a 28-day rat toxicology study. An additional genotoxicity study was conducted in transgenic F344 homozygous Big Blue rats, and the results were negative.”
Carcinogenicity model
Not conducted (ICH S9, anticancer)
“The lack of dedicated carcinogenicity studies is acceptable.”
Carcinogenicity timing
Not conducted and not required for the current indication
“No carcinogenicity studies were conducted or are required to support the marketing of quizartinib for the current indication.”
hERG / QT
No hERG inhibition at clinical concentrations, but IKs inhibition and dose-dependent sustained QTc prolongation in monkeys
“In summary, quizartinib showed IKs current inhibition at clinically relevant physiologic concentrations based on free drug concentration. However, quizartinib and the major metabolite AC886 did not inhibit hERG, INa, INa-L, or ICa-L currents at clinically relevant concentrations. In vivo, a single dose of quizartinib administered to monkeys induced a dose-dependent increase in corrected QT interval (QTc) with sustained prolongation over 24 hours.”
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 Vanflyta 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: 13-week NOAELs: rat 3, dog 5, monkey 3 mg/kg/day (FDA multi-discipline review, p. 58)
NOAEL / key findings
13-week NOAELs: rat 3, dog 5, monkey 3 mg/kg/day
“NOAELs in the 13-week repeated dose toxicity studies were 3 mg/kg/day in rats, 5 mg/kg/day in dogs, and 3 mg/kg/day in monkeys.”
Risksopen answer page →
Immune & cytokine safety
Hematologic and lymphoid toxicities from exaggerated pharmacology
“Hematologic and lymphoid toxicities were common and attributable to exaggerated pharmacology.”
Biodistribution & persistence
Melanin binding: pigmented skin accumulated ~9-fold more radioactivity than non-pigmented skin
“Binding to melanin was evident as pigmented skin accumulated about 9-fold more radioactivity than non-pigmented skin.”
Modality-specific risk
QT prolongation via potassium channel inhibition; transient blood pressure increases
“Overall, these studies demonstrated quizartinib exposure was associated with inhibition of potassium channel currents, prolongation of QT intervals, and transient increases in blood pressure.”
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: QT PROLONGATION, TORSADES DE POINTES, and CARDIAC ARREST
- QT Prolongation, Torsades de Pointes, and Cardiac Arrest
- Vanflyta rems
- Embryo-Fetal Toxicity
CardiovascularEmbryo-fetal toxicity
US prescribing information, Boxed Warning and Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
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 Vanflyta 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: 13-week NOAELs: rat 3, dog 5, monkey 3 mg/kg/day (FDA multi-discipline review, p. 58)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week rat, dog and cynomolgus monkey studies, each with 4-week recovery
“Repeat-dose toxicity studies were conducted in Sprague-Dawley rats, beagle dogs and cynomolgus monkeys given quizartinib dihydrochloride for up to 13 weeks, including a 4-week recovery period for all pivotal studies.”
Pivotal GLP studies
13-week rat, dog and cynomolgus monkey repeat-dose studies
“NOAELs in the 13-week repeated dose toxicity studies were 3 mg/kg/day in rats, 5 mg/kg/day in dogs, and 3 mg/kg/day in monkeys.”
DART package
Species: DART
Rat (EFD only)
“In an embryo-fetal development (EFD) study in rats, quizartinib at doses resulting in exposures approximately 3 times the exposure at the maximum recommended human dose (MRHD) was associated with adverse developmental outcomes including structural abnormalities (anasarca and edema) and alterations to growth (lower fetal weights and effects on skeletal ossification).”
Reproductive & developmental
Rat EFD: anasarca/edema, lower fetal weight and ossification effects at ~3x MRHD exposure
“In an embryo-fetal development (EFD) study in rats, quizartinib at doses resulting in exposures approximately 3 times the exposure at the maximum recommended human dose (MRHD) was associated with adverse developmental outcomes including structural abnormalities (anasarca and edema) and alterations to growth (lower fetal weights and effects on skeletal ossification).”
PPND / ePPND: when
No PPND study performed; accepted given the patient population
“No pre- and postnatal studies were performed. Considering the patient population, this is agreed.”
Carcinogenicity
Species: carcinogenicity
Not conducted (not required for the AML indication)
“No carcinogenicity studies were conducted or are required to support the marketing of quizartinib for the current indication.”
Carcinogenicity model
Not conducted (ICH S9, anticancer)
“The lack of dedicated carcinogenicity studies is acceptable.”
Carcinogenicity timing
Not conducted and not required for the current indication
“No carcinogenicity studies were conducted or are required to support the marketing of quizartinib for the current indication.”
Safety marginopen answer page →
Safety margin at NOAEL
13-week NOAELs for haematopoietic inhibition: monkey MOE 0.07-0.10, dog 0.41-0.54, rat 1.42-1.51
“NOAELs for severe haematopoietic inhibition are 3 mg/kg/day for rats (MOE: 1.42-1.51) and monkeys (MOE: 0.07- 0.10) and 5 mg/kg/day for dogs (MOE: 0.41-0.54).”
NOAEL / key findings
13-week NOAELs: rat 3, dog 5, monkey 3 mg/kg/day
“NOAELs in the 13-week repeated dose toxicity studies were 3 mg/kg/day in rats, 5 mg/kg/day in dogs, and 3 mg/kg/day in monkeys.”
Efficacy evidenceopen answer page →
Efficacy evidence
MV4-11 (FLT3-ITD) mouse xenograft: tumor growth inhibition and increased lifespan
“Using the MV4-11 cell line, quizartinib also displayed in vivo anti-tumor activity in a mouse tumor xenograft model and increased the lifespan of animals.”
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: dose-dependent tumour growth inhibition at 1-10 mg/kg over 28 days, no regrowth for 32 days after stopping
“Dose-dependent inhibition of quizartinib of tumour growth was demonstrated from 1 to 10 mg/kg, on a 28-day treatment and no regrowth until 32 days after discontinuation of quizartinib dihydrochloride was observed.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
No exposure margin at NOAELs for severe haematopoietic inhibition in monkeys (MOE 0.07-0.10) and dogs (MOE 0.41-0.54)
“NOAELs for severe haematopoietic inhibition are 3 mg/kg/day for rats (MOE: 1.42-1.51) and monkeys (MOE: 0.07- 0.10) and 5 mg/kg/day for dogs (MOE: 0.41-0.54).”
GenotoxicityAcceptedBeyond the letter
Positive in vitro Ames test; negative in vivo transgenic rodent mutation assay
Why: Negative in vivo transgenic rodent mutation assay overrules the in vitro Ames finding · Weight of evidence
“The assay was negative, indicating no mutagenic potential of quizartinib in this model, which overrules the positive in vitro findings in the Ames test.”
“Overall, it can be concluded that quizartinib has low genotoxic potential.”
DARTAcceptedBeyond the letter
No pre- and postnatal development study
Why: Patient population · Other reason
“No pre- and postnatal studies were performed. Considering the patient population, this is agreed.”
Safety pharmacologyVerdict not stated
No stand-alone CNS or respiratory safety pharmacology studies; endpoints from up to 13-week general toxicology studies
Why: No CNS or pulmonary effects in rat, dog or monkey general toxicology studies
“Stand-alone CNS and respiratory system safety pharmacology studies were not conducted. However, there was no indication of CNS or pulmonary effects in the rat, dog, or monkey general toxicology studies of up to 13 week duration.”
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