Revtorpyk
gedatolisib
Species
RatDog
Longest study
13 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“Repeat-dose toxicity studies were conducted with gedatolisib in Sprague Dawley rats and Beagle dogs up to approximately 1-month duration using an every 4-day dosing schedule (8 total doses) and up to approximately 3-month duration using the clinical dosing schedule of once weekly for 3 weeks on followed by 1 week off; both durations were followed by a 12-week recovery period.”
Why that species
Not stated in public reviews
The reviews list the species but not why. For small molecules, ICH M3(R2) expects one rodent and one non-rodent species, chosen with in vitro metabolism, protein binding and exposure data compared with human.
“In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials.”
✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 11Source ↗
Surrogate molecule
No surrogate; the clinical compound was tested
“Repeat-dose toxicity studies were conducted with gedatolisib in Sprague Dawley rats and Beagle dogs up to approximately 1-month duration using an every 4-day dosing schedule (8 total doses) and up to approximately 3-month duration using the clinical dosing schedule of once weekly for 3 weeks on followed by 1 week off; both durations were followed by a 12-week recovery period.”
Species: general tox
Sprague Dawley rat and Beagle dog (1-month and 3-month IV studies)
“Repeat-dose toxicity studies were conducted with gedatolisib in Sprague Dawley rats and Beagle dogs up to approximately 1-month duration using an every 4-day dosing schedule (8 total doses) and up to approximately 3-month duration using the clinical dosing schedule of once weekly for 3 weeks on followed by 1 week off;”
Species: DART
Not conducted: fertility not required (advanced cancer); EFD waived as given with drugs known to cause EFD toxicity
“Fertility and early embryonic development studies are not required as gedatolisib is indicated for the treatment of patients with advanced cancer. In addition, embryo-fetal development studies were not conducted as gedatolisib will be administered in combination with palbociclib and fulvestrant, both of which are known to cause embryo-fetal developmental toxicities.”
Species: carcinogenicity
Not conducted (ICH S9)
“In accordance with ICH S9 on the Nonclinical Evaluation for Anticancer Pharmaceuticals, no carcinogenicity studies have been conducted with gedatolisib.”
Surrogate used in
No surrogate used; gedatolisib tested directly
“Repeat-dose toxicity studies were conducted with gedatolisib in Sprague Dawley rats and Beagle dogs up to approximately 1-month duration using an every 4-day dosing schedule (8 total doses)”
Study lengthopen answer page →
Longest pivotal study
13 (3-month rat and dog)
“Repeat-dose toxicity studies were conducted with gedatolisib in Sprague Dawley rats and Beagle dogs up to approximately 1-month duration using an every 4-day dosing schedule (8 total doses) and up to approximately 3-month duration using the clinical dosing schedule of once weekly for 3 weeks on followed by 1 week off; both durations were followed by a 12-week recovery period.”
Pivotal GLP studies
1-month (8 doses every 4 days) and 3-month (weekly, 3 weeks on/1 week off) rat and dog studies, 12-week recovery
“Repeat-dose toxicity studies were conducted with gedatolisib in Sprague Dawley rats and Beagle dogs up to approximately 1-month duration using an every 4-day dosing schedule (8 total doses) and up to approximately 3-month duration using the clinical dosing schedule of once weekly for 3 weeks on followed by 1 week off; both durations were followed by a 12-week recovery period.”
Route in tox
Intravenous (5-minute infusion)
“Administration of gedatolisib by 5-minute intravenous (IV) infusion for 8 doses (1 dose/4 days) at 10 mg/kg to male and female rats resulted in:”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, human lymphocyte chromosomal aberration and rat bone marrow micronucleus assays
“Gedatolisib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and not clastogenic in a human lymphocyte chromosomal aberration assay. Gedatolisib was not genotoxic in the in vivo rat bone marrow micronucleus assay.”
Carcinogenicity
Not conducted (advanced cancer indication, ICH S9)
“In accordance with ICH S9 on the Nonclinical Evaluation for Anticancer Pharmaceuticals, no carcinogenicity studies have been conducted with gedatolisib.”
Reproductive & developmental
Not conducted: no fertility or EFD studies (advanced cancer; given with drugs known to cause EFD toxicity)
“Fertility and early embryonic development studies are not required as gedatolisib is indicated for the treatment of patients with advanced cancer. In addition, embryo-fetal development studies were not conducted as gedatolisib will be administered in combination with palbociclib and fulvestrant, both of which are known to cause embryo-fetal developmental toxicities.”
Safety pharmacology
Dog CV study: 5 mg/kg raised heart rate (24%) and blood pressure (6%); no QTc or other ECG effects
“In a single dose safety pharmacology study, a 5 mg/kg IV dose of gedatolisib administered to dogs increased heart rate (24%) and arterial blood pressure (6%) compared to control 12- to 33-hours post-dose, without an effect on QTc prolongation or other ECG parameters.”
Genotox: Ames
Negative
“Gedatolisib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and not clastogenic in a human lymphocyte chromosomal aberration assay.”
Genotox: in vitro mammalian
Human lymphocyte chromosomal aberration: negative
“Gedatolisib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and not clastogenic in a human lymphocyte chromosomal aberration assay.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“Gedatolisib was not genotoxic in the in vivo rat bone marrow micronucleus assay.”
Carcinogenicity model
Not conducted (ICH S9, advanced cancer)
“In accordance with ICH S9 on the Nonclinical Evaluation for Anticancer Pharmaceuticals, no carcinogenicity studies have been conducted with gedatolisib.”
Carcinogenicity timing
Not required (ICH S9, advanced cancer)
“In accordance with ICH S9 on the Nonclinical Evaluation for Anticancer Pharmaceuticals, no carcinogenicity studies have been conducted with gedatolisib.”
hERG / QT
No hERG inhibition in vitro; no QTc prolongation or arrhythmias in dogs
“Gedatolisib produced no inhibition of human ether-a-go-go-related gene (hERG) potassium ion channel in vitro (RPT-76804/4.2.1.3), and no remarkable changes in electrocardiogram (ECG) parameters, including no evidence of QTc prolongation or arrhythmias at any dose in dogs (RPT-76613/4.2.1.3).”
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 Revtorpyk 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: Rat NOAEL 5 mg/kg (8-dose) and 1 mg/kg (4-cycle); mortality, body weight loss, skin ulceration, testicular degeneration at higher doses (FDA multi-discipline review, p. 61)
NOAEL / key findings
Rat NOAEL 5 mg/kg (8-dose) and 1 mg/kg (4-cycle); mortality, body weight loss, skin ulceration, testicular degeneration at higher doses
“The no-observed-adverse-effect level (NOAEL) was considered to be 5 mg/kg in the 8-dose study (based on mortality, adverse body weight changes, focal skin ulcerations, and testicular tubular degeneration), and 1 mg/kg in the 4-cycle study (based on histopathologic evidence).”
Risksopen answer page →
Immune & cytokine safety
Decreased white blood cells and lymphocytes, reduced bone marrow cellularity (rat) and lymphocyte depletion in thymus and spleen
“Hematological changes were generally more pronounced in rats than dogs and included decreases in absolute white blood cells, reticulocytes, lymphocytes, monocytes, eosinophils, and basophils with microscopic correlates of decreased hematopoietic cellularity in bone marrow (rat), decreased lymphocytes in thymus (rat and dog), and spleen (dog).”
Biodistribution & persistence
Prolonged retention in pigmented tissues of rats: up to 672 hours in uveal tract and 96 hours in pigmented skin
“Following IV administration of [14C] gedatolisib to pigmented male and female rats, radioactivity was highly concentrated and retained for a prolonged period for up to 672 hours and 96 hours in the uveal tract of the eye and pigmented skin, respectively.”
Modality-specific risk
Male and female reproductive organ toxicity (possible impaired fertility)
“Gedatolisib may impair fertility based on adverse effects on reproductive organs in the repeat-dose toxicity studies of up to 3-month duration.”
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
- Stomatitis
- Dermatologic Adverse Reactions
- Hyperglycemia
- Embryo-Fetal Toxicity
GastrointestinalSkin reactionsMetabolic & endocrineEmbryo-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 Revtorpyk 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: Rat NOAEL 5 mg/kg (8-dose) and 1 mg/kg (4-cycle); mortality, body weight loss, skin ulceration, testicular degeneration at higher doses (FDA multi-discipline review, p. 61)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
3-month rat and dog studies (weekly dosing, 3 weeks on/1 week off) with 12-week recovery
“Repeat-dose toxicity studies were conducted with gedatolisib in Sprague Dawley rats and Beagle dogs up to approximately 1-month duration using an every 4-day dosing schedule (8 total doses) and up to approximately 3-month duration using the clinical dosing schedule of once weekly for 3 weeks on followed by 1 week off; both durations were followed by a 12-week recovery period.”
Pivotal GLP studies
1-month (8 doses every 4 days) and 3-month (weekly, 3 weeks on/1 week off) rat and dog studies, 12-week recovery
“Repeat-dose toxicity studies were conducted with gedatolisib in Sprague Dawley rats and Beagle dogs up to approximately 1-month duration using an every 4-day dosing schedule (8 total doses) and up to approximately 3-month duration using the clinical dosing schedule of once weekly for 3 weeks on followed by 1 week off; both durations were followed by a 12-week recovery period.”
DART package
Species: DART
Not conducted: fertility not required (advanced cancer); EFD waived as given with drugs known to cause EFD toxicity
“Fertility and early embryonic development studies are not required as gedatolisib is indicated for the treatment of patients with advanced cancer. In addition, embryo-fetal development studies were not conducted as gedatolisib will be administered in combination with palbociclib and fulvestrant, both of which are known to cause embryo-fetal developmental toxicities.”
Reproductive & developmental
Not conducted: no fertility or EFD studies (advanced cancer; given with drugs known to cause EFD toxicity)
“Fertility and early embryonic development studies are not required as gedatolisib is indicated for the treatment of patients with advanced cancer. In addition, embryo-fetal development studies were not conducted as gedatolisib will be administered in combination with palbociclib and fulvestrant, both of which are known to cause embryo-fetal developmental toxicities.”
PPND / ePPND: when
Not conducted: no animal reproductive toxicity studies (advanced cancer)
“Animal reproductive toxicity studies have not been conducted with REVTORPYK.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S9)
“In accordance with ICH S9 on the Nonclinical Evaluation for Anticancer Pharmaceuticals, no carcinogenicity studies have been conducted with gedatolisib.”
Carcinogenicity model
Not conducted (ICH S9, advanced cancer)
“In accordance with ICH S9 on the Nonclinical Evaluation for Anticancer Pharmaceuticals, no carcinogenicity studies have been conducted with gedatolisib.”
Carcinogenicity timing
Not required (ICH S9, advanced cancer)
“In accordance with ICH S9 on the Nonclinical Evaluation for Anticancer Pharmaceuticals, no carcinogenicity studies have been conducted with gedatolisib.”
Safety marginopen answer page →
Safety margin at NOAEL
No margin: reproductive organ findings in rats and dogs at exposures ≤0.2x human AUC
“All findings occurred at exposure ≤ 0.2 times the human AUC at the recommended dose.”
NOAEL / key findings
Rat NOAEL 5 mg/kg (8-dose) and 1 mg/kg (4-cycle); mortality, body weight loss, skin ulceration, testicular degeneration at higher doses
“The no-observed-adverse-effect level (NOAEL) was considered to be 5 mg/kg in the 8-dose study (based on mortality, adverse body weight changes, focal skin ulcerations, and testicular tubular degeneration), and 1 mg/kg in the 4-cycle study (based on histopathologic evidence).”
Efficacy evidenceopen answer page →
Efficacy evidence
ER+ breast cancer PDX models and MCF7 orthotopic xenograft (triplet with palbociclib and fulvestrant)
“inhibited tumor cell growth in human patient-derived xenograft (PDX) ER+ breast tumors with or without PIK3CA and PTEN mutations. In the MCF7 orthotopic mouse xenograft model of PIK3CA-mutant breast cancer, the combination of gedatolisib with palbociclib and fulvestrant increased tumor growth inhibition compared to each treatment alone or doublet combinations.”
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: nonclinical data adequate to support approval
“The nonclinical data submitted to this NDA are adequate to support approval of Revtorpyk for the proposed indication.”
Flexibilityopen answer page →
Flexibility accepted
DARTAcceptedBeyond the letter
No embryo-fetal development studies; drug is given with palbociclib and fulvestrant, both known embryo-fetal toxicants
Why: Co-administered palbociclib and fulvestrant are known to cause embryo-fetal developmental toxicities · Other reason
“In addition, embryo-fetal development studies were not conducted as gedatolisib will be administered in combination with palbociclib and fulvestrant, both of which are known to cause embryo-fetal developmental toxicities.”
“The FDA’s Assessment: The FDA agrees with the Applicant.”
Safety marginVerdict not stated
Reproductive organ findings in rats and dogs at exposures at or below 0.2 times human AUC; no margin
“All findings occurred at exposure ≤ 0.2 times the human AUC at the recommended dose.”
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