Rozlytrek
entrectinib
Species
RatDog
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 dog
“considering that the majority of toxicology studies, including the pivotal 13-week rat and dog studies, tested the Form II (A) also used in clinical trials, results from toxicology studies are considered reliable for extrapolation to humans.”
Why that species
100% or near-100% sequence homology of the entrectinib binding site in the toxicology species
“Sequence comparisons showed 100% or near 100% sequence homologies in the entrectinib binding site, building confidence on the theoretical validity of the selected species used for the safety validation.”
Surrogate molecule
No surrogate; the clinical compound was tested
“considering that the majority of toxicology studies, including the pivotal 13-week rat and dog studies, tested the Form II (A) also used in clinical trials, results from toxicology studies are considered reliable for extrapolation to humans.”
Species: general tox
Rat and dog (pivotal 13-week studies)
“considering that the majority of toxicology studies, including the pivotal 13-week rat and dog studies, tested the Form II (A) also used in clinical trials, results from toxicology studies are considered reliable for extrapolation to humans.”
Species: DART
Rat (EFD) only; no dedicated fertility studies
“Dedicated fertility studies in animals have not been performed to evaluate the effect of entrectinib. No adverse effects of entrectinib on male and female reproductive organs were observed in the repeatdose toxicology studies in rats and dogs at approximately 2.4-fold and 0.6-fold, respectively, the human exposure by AUC at the recommended human dose. In an embryo-foetal developmental study in rats, maternal toxicity”
Species: carcinogenicity
Not conducted
“No carcinogenicity studies have been performed to establish the carcinogenic potential of entrectinib.”
Surrogate used in
No surrogate used; entrectinib tested directly
“considering that the majority of toxicology studies, including the pivotal 13-week rat and dog studies, tested the Form II (A) also used in clinical trials, results from toxicology studies are considered reliable for extrapolation to humans.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat and dog)
“considering that the majority of toxicology studies, including the pivotal 13-week rat and dog studies, tested the Form II (A) also used in clinical trials, results from toxicology studies are considered reliable for extrapolation to humans.”
Pivotal GLP studies
13-week rat and dog repeat-dose studies
“considering that the majority of toxicology studies, including the pivotal 13-week rat and dog studies, tested the Form II (A) also used in clinical trials, results from toxicology studies are considered reliable for extrapolation to humans.”
Route in tox
Oral
“The studies were carried out primarily with oral administration, which is the proposed clinical route of administration. Pharmacokinetic analysis following repeated doses was performed in pharmacology studies in mice and in all repeated-dose toxicology studies.”
Skipped studiesopen answer page →
Genotoxicity
Ames negative; aneugenic in vitro (human lymphocytes); negative in rat micronucleus and comet assays
“Entrectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay, but demonstrated a potential for abnormal chromosome segregation (aneugenicity) in cultured human peripheral blood lymphocytes. Entrectinib was not clastogenic or aneugenic in the in vivo micronucleus assay in rats and did not induce DNA damage in a comet assay in rats.”
Carcinogenicity
Not conducted
“Carcinogenicity studies were not conducted with entrectinib.”
Reproductive & developmental
Rat EFD: maternal toxicity and fetal malformations (body closure, vertebrae, ribs) at 200 mg/kg/day
“In an embryo-foetal developmental study in rats, maternal toxicity (decreased body weight gain and food consumption) and foetal malformations (including body closure defects and malformations of the vertebrae and ribs), were observed at 200 mg/kg/day of entrectinib”
Safety pharmacology
hERG IC50 0.6 µM (free drug), indicating potential cardiovascular risk
“In vitro, entrectinib inhibited hERG with an IC50 of 0.6 µM as a free drug, indicating a potential for cardiovascular risk.”
Genotox: Ames
Negative (Ames)
“Entrectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay, but demonstrated a potential for abnormal chromosome segregation (aneugenicity) in cultured human peripheral blood lymphocytes.”
Genotox: in vitro mammalian
In vitro micronucleus in human lymphocytes: positive (aneugenic)
“Entrectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay, but demonstrated a potential for abnormal chromosome segregation (aneugenicity) in cultured human peripheral blood lymphocytes.”
Genotox: in vivo
In vivo rat micronucleus and comet assays: negative
“Entrectinib was not clastogenic or aneugenic in the in vivo micronucleus assay in rats and did not induce DNA damage in a comet assay in rats.”
Carcinogenicity model
Not conducted
“No carcinogenicity studies have been performed to establish the carcinogenic potential of entrectinib.”
Carcinogenicity timing
No carcinogenicity studies submitted with the application; no reason stated
“No carcinogenicity studies have been submitted as part of the application.”
hERG / QT
hERG IC50 0.6 µM (free drug), indicating potential cardiovascular risk
“In vitro, entrectinib inhibited hERG with an IC50 of 0.6 µM as a free drug, indicating a potential for cardiovascular risk.”
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 Rozlytrek 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: CNS (convulsions, abnormal gait, tremors), skin (scabs/sores), decreased RBC parameters, at sub-clinical exposures (EMA assessment report, p. 66)
NOAEL / key findings
Targets: CNS (convulsions, abnormal gait, tremors), skin (scabs/sores), decreased RBC parameters, at sub-clinical exposures
“Entrectinib-related toxicities in repeat-dose studies in adult rats and dogs, and juvenile rats were observed in the CNS (convulsions, abnormal gait, tremors) at ≥0.2 times the human exposures by Cmax at the recommended dose, skin (scabs/sores) and decreased RBC parameters at ≥0.1 times the human exposure by AUC at the recommended dose.”
Risksopen answer page →
Immune & cytokine safety
Lymphoid depletion in rat spleen (≥25 mg/kg/day), lymph nodes and thymus (≥200 mg/kg/day)
“Lymphoid depletion was observed at ≥25 mg/kg/day in the 4-week study in spleen, and also in lymph nodes and thymus at ≥200 mg/kg/day in the 4-week 2x2 intermittent dosing and 14-day studies.”
Biodistribution & persistence
Brain-penetrant: steady-state brain-to-plasma ratios ~0.4 (mouse), 0.6–1.5 (rat), 1.4–2.2 (dog)
“In addition, after repeated oral doses brain-to-plasma concentration ratios of entrectinib were higher at 24 hours post last dose in mice (~0.4), rats (0.6–1.5), and dogs (1.4-2.2), indicating brain penetration occurred under steady-state conditions.”
Modality-specific risk
QT/QTcF prolongation in dogs at 120 mg/kg/day
“In the 4-week (2x2 intermittent dosing) study, moderate prolongation of the QT/QTcF intervals was noted at 120 mg/kg/day (recorded on Day 11), where a Cmax of >7 µM was observed.”
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
- Congestive Heart Failure
- Ventricular Arrhythmias
- Central Nervous System Effects
- Skeletal Fractures
- Hepatotoxicity
- Hyperuricemia
- Vision Disorders
- Embryo-Fetal Toxicity
CardiovascularNeurotoxicityMusculoskeletalHepatotoxicityMetabolic & endocrineOcular toxicityEmbryo-fetal toxicity
US prescribing information, 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 Rozlytrek 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: CNS (convulsions, abnormal gait, tremors), skin (scabs/sores), decreased RBC parameters, at sub-clinical exposures (EMA assessment report, p. 66)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week rat and dog (oral); rat study with 8-week recovery
“No corneal findings were seen in the 13-week plus 8-week study in rats, nor in all toxicity studies in dogs.”
Pivotal GLP studies
13-week rat and dog repeat-dose studies
“considering that the majority of toxicology studies, including the pivotal 13-week rat and dog studies, tested the Form II (A) also used in clinical trials, results from toxicology studies are considered reliable for extrapolation to humans.”
DART package
Species: DART
Rat (EFD) only; no dedicated fertility studies
“Dedicated fertility studies in animals have not been performed to evaluate the effect of entrectinib. No adverse effects of entrectinib on male and female reproductive organs were observed in the repeatdose toxicology studies in rats and dogs at approximately 2.4-fold and 0.6-fold, respectively, the human exposure by AUC at the recommended human dose. In an embryo-foetal developmental study in rats, maternal toxicity”
Reproductive & developmental
Rat EFD: maternal toxicity and fetal malformations (body closure, vertebrae, ribs) at 200 mg/kg/day
“In an embryo-foetal developmental study in rats, maternal toxicity (decreased body weight gain and food consumption) and foetal malformations (including body closure defects and malformations of the vertebrae and ribs), were observed at 200 mg/kg/day of entrectinib”
PPND / ePPND: when
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.
Carcinogenicity
Species: carcinogenicity
Not conducted
“No carcinogenicity studies have been performed to establish the carcinogenic potential of entrectinib.”
Carcinogenicity model
Not conducted
“No carcinogenicity studies have been performed to establish the carcinogenic potential of entrectinib.”
Carcinogenicity timing
No carcinogenicity studies submitted with the application; no reason stated
“No carcinogenicity studies have been submitted as part of the application.”
Safety marginopen answer page →
Safety margin at NOAEL
No margin: CNS toxicity at ≥0.2x human Cmax and skin/RBC effects at ≥0.1x human AUC
“Entrectinib-related toxicities in repeat-dose studies in adult rats and dogs, and juvenile rats were observed in the CNS (convulsions, abnormal gait, tremors) at ≥0.2 times the human exposures by Cmax at the recommended dose, skin (scabs/sores) and decreased RBC parameters at ≥0.1 times the human exposure by AUC at the recommended dose.”
NOAEL / key findings
Targets: CNS (convulsions, abnormal gait, tremors), skin (scabs/sores), decreased RBC parameters, at sub-clinical exposures
“Entrectinib-related toxicities in repeat-dose studies in adult rats and dogs, and juvenile rats were observed in the CNS (convulsions, abnormal gait, tremors) at ≥0.2 times the human exposures by Cmax at the recommended dose, skin (scabs/sores) and decreased RBC parameters at ≥0.1 times the human exposure by AUC at the recommended dose.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse xenograft models (cell line- and patient-derived) with TRK, ROS1 and ALK fusions, including an orthotopic glioma model
“entrectinib demonstrated response towards 9 TRK1,3-driven and 3 ROS1-driven tumour models (both cell-based and patient-derived xenografts of which only 1 orthotopic model for glioma)”
Why that model
Non-clinical models cannot reflect the clinical range of tissue contexts and gene fusions of a histology-independent indication
“it is understood that it is not possible to reflect with non-clinical models the wide clinical pattern in terms of tissue environment and pathophysiological context including gene fusion events.”
Reviewer's view of the efficacy data
EMA: pharmacology package insufficient to extrapolate activity to all TRK fusions and tumour histologies, including paediatric tumours
“In light of the claimed site and histology independent indication, the non-clinical pharmacological data-package is considered insufficient to extrapolate activity in all clinical TRK fusions and tumour histologies including paediatric tumours.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
No exposure margins: CNS toxicity at 0.2 times human Cmax and skin, red-cell effects at 0.1 times human AUC
“Entrectinib-related toxicities in repeat-dose studies in adult rats and dogs, and juvenile rats were observed in the CNS (convulsions, abnormal gait, tremors) at ≥0.2 times the human exposures by Cmax at the recommended dose, skin (scabs/sores) and decreased RBC parameters at ≥0.1 times the human exposure by AUC at the recommended dose.”
GLPCriticised but acceptedBeyond the letter
In vitro hERG assay conducted non-GLP, contrary to ICH S7B
Why: QT prolongation already observed in clinical studies · Human data
“It is noted, the in vitro hERG assay, in the safety pharmacology package and reported in study 1087275, was carried out under non-GLP conditions. It should have been conducted according to GLP, as stated in ICH-S7B.”
“However, since QT prolongation have been observed in the clinical studies, the absence of GLP conditions in this in vitro hERG assay does not warrant any further action.”
Efficacy modelQuestioned
Pharmacology package insufficient to extrapolate activity to all TRK fusions and tumour histologies, including paediatric tumours
“In light of the claimed site and histology independent indication, the non-clinical pharmacological data-package is considered insufficient to extrapolate activity in all clinical TRK fusions and tumour histologies including paediatric tumours.”
Impurity or metaboliteAcceptedBeyond the letter
Human-specific N-glucuronide metabolite M11 not further studied
Why: M11 is a direct N-glucuronide conjugate considered inactive · Pharmacology or kinetics
“The main metabolite M11, a direct N-glucuronide conjugate only detected in man and considered inactive was not further studied. This is considered acceptable.”
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