Vectibix
panitumumab
Species
Monkey
Longest study
26 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey only
“Repeated dose general toxicity studies were conducted using intravenous administration of panitumumab to male and female cynomolgus monkeys.”
Why that species
Cross-reactivity supported the cynomolgus monkey as the toxicology species
“Cross reactivity supported the choice of the cynomolgus monkey for safety testing.”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkeys
“Repeated dose general toxicity studies were conducted using intravenous administration of panitumumab to male and female cynomolgus monkeys.”
Species: general tox
Cynomolgus monkey only (4-week to 6-month weekly IV studies)
“Repeated dose general toxicity studies were conducted using intravenous administration of panitumumab to male and female cynomolgus monkeys. These studies had a dosing duration from 4 weeks to 6 months, and all used once-a-week dosing.”
Species: DART
Cynomolgus monkey (embryo-fetal study dosed during organogenesis, GD 20-50)
“Pregnant cynomolgus monkeys were treated weekly with panitumumab during the period of organogenesis (gestation day [GD] 20-50).”
Species: carcinogenicity
Not conducted
“No carcinogenicity or mutagenicity studies of panitumumab have been conducted.”
Surrogate used in
No surrogate used; panitumumab itself tested in cynomolgus monkeys
“Repeated dose general toxicity studies were conducted using intravenous administration of panitumumab to male and female cynomolgus monkeys.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“These studies had a dosing duration from 4 weeks to 6 months, and all used once-a-week dosing.”
Pivotal GLP studies
Monkey IV studies of 4 weeks to 6 months, once-weekly dosing
“These studies had a dosing duration from 4 weeks to 6 months, and all used once-a-week dosing.”
Route in tox
Intravenous
“Repeated dose general toxicity studies were conducted using intravenous administration of panitumumab to male and female cynomolgus monkeys.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted
“Panitumumab has not been evaluated in genotoxicity studies.”
Carcinogenicity
Not conducted
“No carcinogenicity or mutagenicity studies of panitumumab have been conducted.”
Reproductive & developmental
Monkey EFD: embryolethality and abortions at 1.25-5x human dose, no teratogenicity
“There were no fetal malformations or other evidence of teratogenesis noted in the offspring; however, significant increases in embryolethality and abortions occurred at doses of approximately 1.25 to 5 times the recommended human dose (based on body weight).”
Safety pharmacology
Single-dose monkey telemetry study (CV, respiratory, CNS): no clinical signs, no CNS or respiratory effects, no ECG effects
“In this study, no clinical signs related to panitumumab were observed. Neuro-behavioural tests did not reveal any effect on the central nervous system.”
Genotox: Ames
Not conducted
“Panitumumab has not been evaluated in genotoxicity studies.”
Genotox: in vitro mammalian
Not conducted
“Panitumumab has not been evaluated in genotoxicity studies.”
Genotox: in vivo
Not conducted
“Panitumumab has not been evaluated in genotoxicity studies.”
Carcinogenicity model
Not conducted
“No carcinogenicity or mutagenicity studies of panitumumab have been conducted.”
Carcinogenicity timing
No carcinogenicity studies conducted
“No carcinogenicity studies have been conducted.”
hERG / QT
No test-article effects on PR, QRS, RR or QTc intervals or blood pressure
“There were neither test-article –related effects on PR interval, QRS interval, RR interval or QTc interval nor on systolic, diastolic or mean blood pressure.”
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 Vectibix 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: Skin toxicity and diarrhoea were the primary toxicities, severe enough to cause unscheduled deaths (EMA assessment report, p. 9)
NOAEL / key findings
Skin toxicity and diarrhoea were the primary toxicities, severe enough to cause unscheduled deaths
“Toxicity to skin and diarrhoea was the primary toxicity of panitumumab in monkeys. These effects were severe enough to cause a significant number of unscheduled deaths.”
Risksopen answer page →
Immune & cytokine safety
Anti-panitumumab antibodies (MAHA) in 9/10 low-dose, 2/10 mid-dose and 1/10 high-dose monkeys
“Nine of ten monkeys in the low dose group were MAHA positive (Monkey anti-human antibody defined as anti-panitumumab antibody); frequency for MAHA positive was 2/10 and 1/10 in the mid and high dose groups.”
Biodistribution & persistence
No panitumumab binding in human or monkey cardiac tissue in formal tissue cross-reactivity studies
“Further, no binding of panitumumab was noted in human or monkey cardiac tissue in a formal tissue cross-reactivity studies which utilised optimised immunohistochemical techniques to assess specific panitumumab binding.”
Modality-specific risk
Skin toxicity and diarrhoea from EGFR signalling inhibition; embryo-fetal loss
“It is considered directly related to the pharmacological action of drugs that inhibit EGFR signalling.”
Anti-drug antibodies: animals
Anti-panitumumab antibodies in 9/10 low-, 2/10 mid- and 1/10 high-dose monkeys; ADA-positive monkeys cleared drug faster
“Nine of ten monkeys in the low dose group were MAHA positive (Monkey anti-human antibody defined as anti-panitumumab antibody); frequency for MAHA positive was 2/10 and 1/10 in the mid and high dose groups. Monkeys that developed MAHA were noted to have more rapid elimination of panitumumab.”
Anti-drug antibodies: patients
Anti-panitumumab antibodies in 5.2% (74/1417); 18.9% of these neutralizing
“the incidence of anti-panitumumab antibodies was 5.2% (74/1417). Of the 74 patients who tested positive for anti-panitumumab antibodies, 18.9% (14/74) had neutralizing antibodies against panitumumab.”
Label warnings
Boxed warning: Dermatologic toxicity
- Dermatologic and Soft Tissue Toxicity
- Increased Tumor Progression, Increased Mortality, or Lack of Benefit in Patients with RAS-Mutant mCRC Receiving Vectibix Monotherapy or in Combination with Oxaliplatin-based Chemotherapy
- Electrolyte Depletion/Monitoring
- Infusion Reactions
- Acute Renal Failure
- Pulmonary Fibrosis/Interstitial Lung Disease (ILD)
- Photosensitivity
- Ocular Toxicities
- Increased Mortality and Toxicity with Vectibix in Combination with Bevacizumab and Chemotherapy
- Embryo-fetal Toxicity
Skin reactionsSecondary malignancyMetabolic & endocrineHypersensitivity & infusion reactionsNephrotoxicityPulmonary toxicityOcular toxicityEmbryo-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 Vectibix 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: Skin toxicity and diarrhoea were the primary toxicities, severe enough to cause unscheduled deaths (EMA assessment report, p. 9)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
6-month cynomolgus monkey (IV, once weekly); recovery phase not stated
“These studies had a dosing duration from 4 weeks to 6 months, and all used once-a-week dosing.”
Pivotal GLP studies
Monkey IV studies of 4 weeks to 6 months, once-weekly dosing
“These studies had a dosing duration from 4 weeks to 6 months, and all used once-a-week dosing.”
DART package
Species: DART
Cynomolgus monkey (embryo-fetal study dosed during organogenesis, GD 20-50)
“Pregnant cynomolgus monkeys were treated weekly with panitumumab during the period of organogenesis (gestation day [GD] 20-50).”
Reproductive & developmental
Monkey EFD: embryolethality and abortions at 1.25-5x human dose, no teratogenicity
“There were no fetal malformations or other evidence of teratogenesis noted in the offspring; however, significant increases in embryolethality and abortions occurred at doses of approximately 1.25 to 5 times the recommended human dose (based on body weight).”
PPND / ePPND: when
No pre- and postnatal development study conducted
“No pre- and post-natal development animal studies have been conducted with panitumumab.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“No carcinogenicity or mutagenicity studies of panitumumab have been conducted.”
Carcinogenicity model
Not conducted
“No carcinogenicity or mutagenicity studies of panitumumab have been conducted.”
Carcinogenicity timing
No carcinogenicity studies conducted
“No carcinogenicity studies have been conducted.”
Safety marginopen answer page →
Safety margin at NOAEL
No NOAEL margin stated; monkey EFD embryolethality/abortions at 1.25-5x human dose (no NOAEL)
“There were no fetal malformations or other evidence of teratogenesis noted in the offspring; however, significant increases in embryolethality and abortions occurred at doses of approximately 1.25 to 5 times the recommended human dose (based on body weight).”
NOAEL / key findings
Skin toxicity and diarrhoea were the primary toxicities, severe enough to cause unscheduled deaths
“Toxicity to skin and diarrhoea was the primary toxicity of panitumumab in monkeys. These effects were severe enough to cause a significant number of unscheduled deaths.”
Efficacy evidenceopen answer page →
Efficacy evidence
Tumour cell xenotransplants in mice: inhibition of tumour cell growth in vivo
“Panitumumab was also shown to inhibit cell growth in vitro and in vivo (xenotransplants in mice) in the same cell line.”
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: rationale for EGFR inhibition well established; specific EGFR binding and signalling inhibition shown
“The rationale for EGFR inhibition in metastatic colorectal cancer is well established. The applicant has shown that panitumumab specifically binds to epidermal growth factor receptors and inhibits signalling through this receptor.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
No NOAEL in the monkey embryo-fetal study: abortions or fetal death and maternal toxicity at the lowest dose
“There was no NOAEL in this study, as even the lowest dose was associated with foetal abortions or death and with significant maternal toxicity.”
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