Tabrecta
capmatinib
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
“The Applicant evaluated the toxicity profile of capmatinib in GLP-compliant studies in Sprague-Dawley rats and Cynomolgus monkeys with durations of treatment of up to 13 weeks.”
Why that species
Historical use in safety testing and highly conserved MET receptor sequence
“The rat and monkey were selected as the rodent and non-rodent species, respectively, for repeat-dose toxicity testing because both have historically been used in safety evaluations, and both species have a highly conserved MET receptor target protein sequence.”
Surrogate molecule
No surrogate; the clinical compound was tested
“The Applicant evaluated the toxicity profile of capmatinib in GLP-compliant studies in Sprague-Dawley rats and Cynomolgus monkeys with durations of treatment of up to 13 weeks.”
Species: general tox
Rat and cynomolgus monkey (up to 13 weeks)
“The Applicant evaluated the toxicity profile of capmatinib in GLP-compliant studies in Sprague-Dawley rats and Cynomolgus monkeys with durations of treatment of up to 13 weeks.”
Species: DART
Rat and rabbit (EFD)
“To address the potential reproductive effects of capmatinib, Novartis conducted embryo-fetal development studies in rats and rabbits.”
Species: carcinogenicity
Not conducted (advanced cancer indication)
“Carcinogenicity studies were not conducted for capmatinib or necessary for a drug intended for the treatment of patients with advanced cancer.”
Surrogate used in
No surrogate used; capmatinib tested directly
“The Applicant evaluated the toxicity profile of capmatinib in GLP-compliant studies in Sprague-Dawley rats and Cynomolgus monkeys with durations of treatment of up to 13 weeks.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat and monkey)
“The Applicant evaluated the toxicity profile of capmatinib in GLP-compliant studies in Sprague-Dawley rats and Cynomolgus monkeys with durations of treatment of up to 13 weeks.”
Pivotal GLP studies
4- and 13-week rat and monkey studies
“Pivotal repeat dose toxicity studies were conducted in rats and monkeys for a 4- and 13-week dosing period.”
Route in tox
Oral
“The oral route was chosen because it is the intended route of administration in humans.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration (human lymphocytes) and rat bone marrow micronucleus assays
“Capmatinib was not mutagenic in an in vitro bacterial reverse mutation assay and did not cause chromosomal aberrations in an in vitro chromosome aberration assay in human peripheral blood lymphocytes. Capmatinib was not clastogenic in an in vivo bone marrow micronucleus test in rats.”
Carcinogenicity
Not conducted (advanced cancer indication)
“Carcinogenicity studies were not conducted for capmatinib or necessary for a drug intended for the treatment of patients with advanced cancer.”
Reproductive & developmental
Rat and rabbit EFD: malformations at maternal exposures below human AUC
“Oral administration of capmatinib to pregnant rats and rabbits during the period of organogenesis resulted in malformations at maternal exposures less than the human exposure based on AUC at the 400 mg twice daily clinical dose ( see Data ).”
Safety pharmacology
No significant cardiac, CNS or respiratory effects; hERG IC50 40x free human Cmax
“Safety pharmacology studies with capmatinib indicated no significant effects on cardiac, CNS or respiratory functions. hERG IC50 is at 40 times the expected free drug Cmax (0.464 µM) at maximal therapeutic dose of 400 mg bid in humans.”
Genotox: Ames
Negative
“Capmatinib was not mutagenic in an in vitro bacterial reverse mutation assay and did not cause chromosomal aberrations in an in vitro chromosome aberration assay in human peripheral blood lymphocytes.”
Genotox: in vitro mammalian
Chromosome aberration in human peripheral blood lymphocytes: negative
“Capmatinib was not mutagenic in an in vitro bacterial reverse mutation assay and did not cause chromosomal aberrations in an in vitro chromosome aberration assay in human peripheral blood lymphocytes.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“Capmatinib was not clastogenic in an in vivo bone marrow micronucleus test in rats.”
Carcinogenicity model
Not conducted; not needed for advanced cancer
“Carcinogenicity studies were not conducted for capmatinib or necessary for a drug intended for the treatment of patients with advanced cancer.”
Carcinogenicity timing
Not required for advanced cancer indication
“Carcinogenicity studies were not conducted for capmatinib or necessary for a drug intended for the treatment of patients with advanced cancer.”
hERG / QT
hERG IC50 40x expected free Cmax at 400 mg bid
“hERG IC50 is at 40 times the expected free drug Cmax (0.464 µM) at maximal therapeutic dose of 400 mg bid in humans.”
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 Tabrecta 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 40 (male) and 20 (female) mg/kg/day; monkey 30 mg/kg/day (EMA assessment report, p. 23)
NOAEL / key findings
13-week NOAELs: rat 40 (male) and 20 (female) mg/kg/day; monkey 30 mg/kg/day
“The applicant established the NOAEL values (40 mg/kg/day for males and 20 mg/kg/day for females in the case of rat, and 30 mg/Kg/day for monkey species), based on the findings observed”
Risksopen answer page →
Immune & cytokine safety
No specific immunotoxicity studies conducted
“No specific immunotoxicity studies were conducted with capmatinib”
Biodistribution & persistence
Reversible melanin binding (eye choroid); highest accumulation in eye lens and adrenal medulla
“In pigmented rats, radioactivity was reversibly distributed into the melanin containing structures such eye choroid. The highest accumulation was observed in eye (lens) and adrenal (medulla).”
Modality-specific risk
Brain white matter vacuolation in rats at >=2.2x human AUC
“In rats, capmatinib administration resulted in vacuolation of white matter of the brain in both 4- and 13-week studies at doses ≥2.2 times the human exposure (AUC) at the 400 mg twice daily clinical dose.”
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
- Interstitial Lung Disease (ILD)/Pneumonitis
- Hepatotoxicity
- Pancreatic Toxicity
- Hypersensitivity Reactions
- Risk of Photosensitivity
- Embryo-Fetal Toxicity
Immune-mediated reactionsPulmonary toxicityHepatotoxicityGastrointestinalHypersensitivity & infusion reactionsSkin reactionsEmbryo-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 Tabrecta 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 40 (male) and 20 (female) mg/kg/day; monkey 30 mg/kg/day (EMA assessment report, p. 23)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week cynomolgus monkey with 8-week recovery (13-week rat study ties)
“Cynomolgus monkeys were administered with capmatinib (0, 10, 30 and 75 mg/kg/day) by oral gavage for 13 weeks, followed by an 8-week recovery period.”
Pivotal GLP studies
4- and 13-week rat and monkey studies
“Pivotal repeat dose toxicity studies were conducted in rats and monkeys for a 4- and 13-week dosing period.”
DART package
Species: DART
Rat and rabbit (EFD)
“To address the potential reproductive effects of capmatinib, Novartis conducted embryo-fetal development studies in rats and rabbits.”
Reproductive & developmental
Rat and rabbit EFD: malformations at maternal exposures below human AUC
“Oral administration of capmatinib to pregnant rats and rabbits during the period of organogenesis resulted in malformations at maternal exposures less than the human exposure based on AUC at the 400 mg twice daily clinical dose ( see Data ).”
PPND / ePPND: when
PPND not conducted, in line with ICH S9 (advanced cancer)
“In line with ICH guideline S9, neither fertility and early embryonic development nor pre- and postnatal toxicology studies have been conducted with capmatinib.”
Carcinogenicity
Species: carcinogenicity
Not conducted (advanced cancer indication)
“Carcinogenicity studies were not conducted for capmatinib or necessary for a drug intended for the treatment of patients with advanced cancer.”
Carcinogenicity model
Not conducted; not needed for advanced cancer
“Carcinogenicity studies were not conducted for capmatinib or necessary for a drug intended for the treatment of patients with advanced cancer.”
Carcinogenicity timing
Not required for advanced cancer indication
“Carcinogenicity studies were not conducted for capmatinib or necessary for a drug intended for the treatment of patients with advanced cancer.”
Safety marginopen answer page →
Safety margin at NOAEL
Small margins: NOAEL AUC in nonclinical species within the same range as human exposure
“It is noted that AUC ratio was within the same range, indicating small safety margins, when compared exposure in humans and NOAEL values established by the company in the nonclinical species (rat and dog).”
NOAEL / key findings
13-week NOAELs: rat 40 (male) and 20 (female) mg/kg/day; monkey 30 mg/kg/day
“The applicant established the NOAEL values (40 mg/kg/day for males and 20 mg/kg/day for females in the case of rat, and 30 mg/Kg/day for monkey species), based on the findings observed”
Efficacy evidenceopen answer page →
Efficacy evidence
Patient-derived NSCLC xenografts (MET exon 14 skipping or MET amplification) in nude mice
“Capmatinib demonstrated anti-tumor activity against patient-derived human lung cancer xenografts with either MET exon 14-associated skipping mutations or MET amplifications implanted into nude mice.”
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
FDA: studies support mechanism and activity in the patient population
“These studies support the proposed mechanism of action of capmatinib and its activity in the proposed patient population.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
NOAEL exposures in rat and dog within the range of human exposure; below 1 in female monkeys
“AUC ratio were within the same range when compared exposure in humans and NOAEL values established by the company in the nonclinical species (rat and dog). In the case of female monkeys, ratio value was below 1 (Table 9).”
Efficacy modelAcceptedBeyond the letter
Binding of capmatinib to mutated MET not thoroughly investigated nonclinically
Why: Clinical data could justify the absence of these studies · Human data
“Further, binding of capmatinib to mutated MET were not thoroughly investigated during the nonclinical development. At this point, clinical data could provide a justification for the absence of these studies.”
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