Herceptin
trastuzumab
Species
Monkey
Longest study
26 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rhesus and cynomolgus monkey
“The repeated-dose toxicity evaluation of trastuzumab is based on a four-week study in rhesus monkeys and 12- and 26-week studies in cynomolgus monkeys.”
Why that species
Monkey HER2 recognized (high homology, similar tissue binding); rodent p185neu not recognized
“rodent p185neu (corresponding receptor protein to human p185HER2) is not recognised, whereas in non-human primates trastuzumab recognises a receptor (as yet uncharacterised) in epithelial cells.”
Surrogate molecule
Yes: surrogate antibody specific for rat c-erbB2, used for rat doxorubicin cardiotoxicity model
“Enhanced cardiotoxicity was not observed in a rat model of doxorubicin cardiotoxicity following addition of a surrogate antibody specific for rat c-erbB2.”
Species: general tox
Rhesus monkey (4-week) and cynomolgus monkey (12- and 26-week)
“The repeated-dose toxicity evaluation of trastuzumab is based on a four-week study in rhesus monkeys and 12- and 26-week studies in cynomolgus monkeys.”
Species: DART
Cynomolgus monkey (fertility, embryo-fetal, peri/postnatal); rat and rabbit unsuitable
“Owing to the lack of suitability of the species used conventionally (rat, rabbit), studies were undertaken in the cynomolgus monkey.”
Species: carcinogenicity
Not conducted
“Herceptin has not been tested for carcinogenic potential.”
Surrogate used in
Yes: rat c-erbB2-specific surrogate antibody in a rat doxorubicin cardiotoxicity model
“Enhanced cardiotoxicity was not observed in a rat model of doxorubicin cardiotoxicity following addition of a surrogate antibody specific for rat c-erbB2.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“The repeated-dose toxicity evaluation of trastuzumab is based on a four-week study in rhesus monkeys and 12- and 26-week studies in cynomolgus monkeys.”
Pivotal GLP studies
4-week rhesus monkey; 12- and 26-week cynomolgus monkey repeat-dose studies
“The repeated-dose toxicity evaluation of trastuzumab is based on a four-week study in rhesus monkeys and 12- and 26-week studies in cynomolgus monkeys.”
Route in tox
IV
“In intravenous embryo-fetal development studies in cynomolgus monkeys after repeated administration, the fetal serum levels were 10-33% of the respective maternal concentrations.”
Skipped studiesopen answer page →
Genotoxicity
Conducted: Ames, E. coli, human lymphocyte chromosome aberration and mouse micronucleus; all negative
“The in-vivo test was a mouse micronucleus assay involving single iv injection of trastuzumab at 29.5, 59 and 118 mg/kg. All tests gave clearly negative results.”
Carcinogenicity
Not conducted
“Herceptin has not been tested for carcinogenic potential.”
Reproductive & developmental
Cynomolgus monkey fertility, embryo-fetal and peri/postnatal studies: no effects on menstrual cycles, embryo-fetal or neonatal toxicity
“Reproductive function: No effects on menstrual cycles or sex hormone profiles Embryotoxicity: No maternal toxicity, embryotoxicity or teratogenicity Peri-/Post-natal toxicity: No maternal, foetal or neonatal toxicity”
Safety pharmacology
ECG assessed in rhesus monkey combination study with chemotherapy; no significant findings
“A study of the administration of trastuzumab together with Taxol, Adriamycin, or Cytoxan/Adriamycin in rhesus monkeys did not elicit significant findings on parameters like mortality and clinical observations, body weights, electrocardiograms, clinical pathology including hematology, serum chemistry and urinalysis.”
Genotox: Ames
Negative (Ames, up to 5000 mcg/mL)
“No evidence of mutagenic activity was observed when trastuzumab was tested in the standard Ames bacterial and human peripheral blood lymphocyte mutagenicity assays at concentrations of up to 5000 mcg/mL.”
Genotox: in vitro mammalian
Human peripheral blood lymphocyte assay: negative up to 5000 mcg/mL
“No evidence of mutagenic activity was observed when trastuzumab was tested in the standard Ames bacterial and human peripheral blood lymphocyte mutagenicity assays at concentrations of up to 5000 mcg/mL.”
Genotox: in vivo
Mouse bone marrow micronucleus: negative up to 118 mg/kg IV
“In an in vivo micronucleus assay, no evidence of chromosomal damage to mouse bone marrow cells was observed following bolus intravenous doses of up to 118 mg/kg of trastuzumab.”
Carcinogenicity model
Not conducted
“Herceptin has not been tested for carcinogenic potential.”
Carcinogenicity timing
Not conducted (carcinogenic potential not tested)
“Herceptin has not been tested for carcinogenic potential.”
hERG / QT
No hERG assay; no significant ECG findings in rhesus monkeys given trastuzumab with chemotherapy
“A study of the administration of trastuzumab together with Taxol, Adriamycin, or Cytoxan/Adriamycin in rhesus monkeys did not elicit significant findings on parameters like mortality and clinical observations, body weights, electrocardiograms, clinical pathology including hematology, serum chemistry and urinalysis.”
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 Herceptin 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 monoclonal antibodies (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: Minimal toxicity in all repeat-dose studies; only injection-site trauma in rhesus monkey (EMA assessment report, p. 8)
NOAEL / key findings
Minimal toxicity in all repeat-dose studies; only injection-site trauma in rhesus monkey
“In all three studies there was a minimal toxic response, with the only noteworthy observations concerning injection-site trauma in the rhesus monkey.”
Risksopen answer page →
Immune & cytokine safety
Anti-drug antibodies rare: 1/84 animals in repeat-dose studies
“This represents an incidence of 1/84 animals in repeated-dose studies in which antibodies to trastuzumab were detected.”
Biodistribution & persistence
TCR in monkey and human tissue showed no localisation to heart tissue
“Tissue cross reactivity studies with trastuzumab in monkey and human tissue did not reveal localisation to heart tissue.”
Modality-specific risk
Cardiotoxicity, enhanced in combination with anthracyclines such as doxorubicin
“Preclinical studies have been undertaken in an attempt to elucidate the mechanism for the enhanced cardiotoxicity observed in some clinical-trial patients receiving trastuzumab in combination with an anthracycline-based cytotoxic such as doxorubicin.”
Anti-drug antibodies: animals
1/84 monkeys in repeat-dose studies; neutralising antibodies in one low-dose cynomolgus female (weeks 5-26)
“Neutralising antibodies were detected from weeks 5-26 in one low-dose female cynomolgus monkey. This represents an incidence of 1/84 animals in repeated-dose studies in which antibodies to trastuzumab were detected.”
Anti-drug antibodies: patients
Anti-trastuzumab antibodies (HAHA) in 1 of 903 women with metastatic breast cancer; no allergic reaction
“Among 903 women with metastatic breast cancer, human anti human antibody (HAHA) to Herceptin was detected in one patient using an enzyme linked immunosorbent assay (ELISA). This patient did not experience an allergic reaction.”
Label warnings
Boxed warning: CARDIOMYOPATHY, INFUSION REACTIONS, EMBRYO-FETAL TOXICITY, and PULMONARY TOXICITY
- Cardiomyopathy
- Infusion Reactions
- Embryo-Fetal Toxicity
- Pulmonary Toxicity
- Exacerbation of Chemotherapy-Induced Neutropenia
Hypersensitivity & infusion reactionsCardiovascularEmbryo-fetal toxicityPulmonary toxicityMusculoskeletalCytopenias
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 Herceptin 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 monoclonal antibodies (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: Minimal toxicity in all repeat-dose studies; only injection-site trauma in rhesus monkey (EMA assessment report, p. 8)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week cynomolgus monkey; recovery phase not stated
“The repeated-dose toxicity evaluation of trastuzumab is based on a four-week study in rhesus monkeys and 12- and 26-week studies in cynomolgus monkeys.”
Pivotal GLP studies
4-week rhesus monkey; 12- and 26-week cynomolgus monkey repeat-dose studies
“The repeated-dose toxicity evaluation of trastuzumab is based on a four-week study in rhesus monkeys and 12- and 26-week studies in cynomolgus monkeys.”
DART package
Species: DART
Cynomolgus monkey (fertility, embryo-fetal, peri/postnatal); rat and rabbit unsuitable
“Owing to the lack of suitability of the species used conventionally (rat, rabbit), studies were undertaken in the cynomolgus monkey.”
Reproductive & developmental
Cynomolgus monkey fertility, embryo-fetal and peri/postnatal studies: no effects on menstrual cycles, embryo-fetal or neonatal toxicity
“Reproductive function: No effects on menstrual cycles or sex hormone profiles Embryotoxicity: No maternal toxicity, embryotoxicity or teratogenicity Peri-/Post-natal toxicity: No maternal, foetal or neonatal toxicity”
PPND / ePPND: when
Peri-/postnatal study in cynomolgus monkey: completed before the marketing application; no maternal, fetal or neonatal toxicity
“studies were undertaken in the cynomolgus monkey. Reproductive function: No effects on menstrual cycles or sex hormone profiles Embryotoxicity: No maternal toxicity, embryotoxicity or teratogenicity Peri-/Post-natal toxicity: No maternal, foetal or neonatal toxicity”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Herceptin has not been tested for carcinogenic potential.”
Carcinogenicity model
Not conducted
“Herceptin has not been tested for carcinogenic potential.”
Carcinogenicity timing
Not conducted (carcinogenic potential not tested)
“Herceptin has not been tested for carcinogenic potential.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey fertility study: no impaired fertility at up to 25x the weekly human dose of 2 mg/kg
“A fertility study was conducted in female Cynomolgus monkeys at doses up to 25 times the weekly recommended human dose of 2 mg/kg of trastuzumab and has revealed no evidence of impaired fertility, as measured by menstrual cycle duration and female sex hormone levels.”
NOAEL / key findings
Minimal toxicity in all repeat-dose studies; only injection-site trauma in rhesus monkey
“In all three studies there was a minimal toxic response, with the only noteworthy observations concerning injection-site trauma in the rhesus monkey.”
Efficacy evidenceopen answer page →
Efficacy evidence
Human HER2-overexpressing tumour xenografts (BT-474) in vivo; trastuzumab plus paclitaxel gave greatest regression
“The combination with paclitaxel produced the greatest tumour regression in vivo with the BT-474 cell line.”
Why that model
Trastuzumab does not recognise rodent p185neu; monkeys bind but do not overexpress HER2
“Since trastuzumab is a humanised MAb, significant species differences in pharmacokinetics are to be expected: rodent p185neu (corresponding receptor protein to human p185HER2) is not recognised, whereas in non-human primates trastuzumab recognises a receptor (as yet uncharacterised) in epithelial cells. However, unlike humans these primate species do not overexpress p185HER2 or produce shed antigen.”
Reviewer's view of the efficacy data
EMA: pharmacology and toxicology thoroughly examined in more than 50 studies, the large majority of very good quality
“The toxico-pharmacological properties of trastuzumab were thoroughly examined in Part III of the dossier, which comprises more than 50 studies, of which the large majority was of very good quality.”
Flexibilityopen answer page →
Flexibility accepted
OtherAccepted with a conditionBeyond the letter
No animal model of trastuzumab-anthracycline cardiotoxicity; only a rat surrogate antibody study in a doxorubicin model
Why: Species specificity and immunogenicity in mice and dogs; ill-defined cardiotoxic dosing in monkeys; mechanistic studies ongoing · No relevant species
“Potential models of anthracycline-induced cardiotoxicity in mice and dogs using trastuzamab were unsuitable due to species specificity of trastuzumab and in consideration of potential immunogenic responses to a humanised protein. Possible anthracycline models in the monkey were considered unsuitable based on ill-defined dose requirements to produce cardiotoxicity.”
“Further mechanistic studies on the mode of action and impact of trastuzumab on the enhanced cardiotoxicity are being performed for which the results will be submitted on an ongoing basis.”
SpeciesVerdict not stated
Animal species used do not express human HER2 receptor on normal tissues, limiting extrapolation to humans
“Extrapolation of these results to humans is compromised by the fact that the animals used do not express human p185HER2 on normal tissues.”
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