Xpovio
selinexor
Species
MonkeyRat
Longest study
13 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Partial / alternative Partly stated
Speciesopen answer page →
Species
Rat and cynomolgus monkey
“Rats were chosen as the rodent species and cynomolgus monkeys as the non-rodent species.”
Why that species
Both species pharmacologically relevant
“Based on available data, both species were determined to be pharmacologically relevant for toxicology studies.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Thirteen-week repeat-dose oral toxicity and toxicokinetic studies were conducted in the rat (0, 0.25, 1, or 4 mg/kg selinexor; 5 total doses given every 2-week period) and monkey (0, 0.1, 0.3, 1 mg/kg selinexor; 2 to 3 times/week) to support the NDA.”
Species: general tox
Rat and cynomolgus monkey (13-week oral studies)
“Thirteen-week repeat-dose oral toxicity and toxicokinetic studies were conducted in the rat (0, 0.25, 1, or 4 mg/kg selinexor; 5 total doses given every 2-week period) and monkey (0, 0.1, 0.3, 1 mg/kg selinexor; 2 to 3 times/week) to support the NDA.”
Species: DART
Rat (EFD only); no fertility study and no second species
“No carcinogenicity study was conducted, and only maternal and embryo-foetal development toxicity were carried out, indicating a NOAEL value at 0.25 mg/Kg/day for rats. No data for a second species were provided.”
Species: carcinogenicity
Not conducted
“Carcinogenicity studies were not conducted to support the use of selinexor for the proposed indication.”
Surrogate used in
No surrogate used
“Based on available data, both species were determined to be pharmacologically relevant for toxicology studies.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat and monkey)
“Thirteen-week repeat-dose oral toxicity and toxicokinetic studies were conducted in the rat (0, 0.25, 1, or 4 mg/kg selinexor; 5 total doses given every 2-week period) and monkey (0, 0.1, 0.3, 1 mg/kg selinexor; 2 to 3 times/week) to support the NDA.”
Pivotal GLP studies
13-week oral studies in rat (5 doses per 2 weeks) and monkey (2-3 times/week)
“Thirteen-week repeat-dose oral toxicity and toxicokinetic studies were conducted in the rat (0, 0.25, 1, or 4 mg/kg selinexor; 5 total doses given every 2-week period) and monkey (0, 0.1, 0.3, 1 mg/kg selinexor; 2 to 3 times/week) to support the NDA.”
Route in tox
Oral
“Thirteen-week repeat-dose oral toxicity and toxicokinetic studies were conducted in the rat (0, 0.25, 1, or 4 mg/kg selinexor; 5 total doses given every 2-week period) and monkey (0, 0.1, 0.3, 1 mg/kg selinexor; 2 to 3 times/week) to support the NDA.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro human lymphocyte cytogenetic and in vivo rat micronucleus assays
“Selinexor was not mutagenic in vitro in a bacterial reverse mutation (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay in human lymphocytes or in the in vivo rat micronucleus assay.”
Carcinogenicity
Not conducted
“Carcinogenicity studies were not conducted to support the use of selinexor for the proposed indication.”
Reproductive & developmental
Rat EFD: reduced fetal weight and delayed or incomplete ossification at >=0.75 mg/kg/day
“Adverse developmental outcomes occurred at ≥ 0.75 mg/kg/day and included alterations to growth (e.g., fetal weights in the 0.75 and 2 mg/kg/day groups were 13.5% and 32.4% lower than controls) and structural abnormalities (such as incomplete or delayed ossification of sternebra(e) and/or vertebral arches, and/or unossified and bent ribs).”
Safety pharmacology
hERG IC50 20.6 μM (HEK293 patch clamp)
“Selinexor was evaluated for its ability to inhibit the hERG channel (IC50 = 20.6 μM) using whole cell patch clamp in stably-transfected HEK293 cells (Study: KS-0055).”
Genotox: Ames
Negative (bacterial reverse mutation)
“Selinexor was not mutagenic in vitro in a bacterial reverse mutation (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay in human lymphocytes or in the in vivo rat micronucleus assay.”
Genotox: in vitro mammalian
Human lymphocyte cytogenetic (chromosomal aberration) assay: negative
“Selinexor was not mutagenic in vitro in a bacterial reverse mutation (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay in human lymphocytes or in the in vivo rat micronucleus assay.”
Genotox: in vivo
Rat micronucleus assay: negative
“Selinexor was not mutagenic in vitro in a bacterial reverse mutation (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay in human lymphocytes or in the in vivo rat micronucleus assay.”
Carcinogenicity model
Not conducted; not needed for the proposed indication
“Carcinogenicity studies were not conducted to support the use of selinexor for the proposed indication.”
Carcinogenicity timing
Not required for the proposed indication
“Carcinogenicity studies were not conducted to support the use of selinexor for the proposed indication.”
hERG / QT
hERG IC50 20.6 µM; >250x human free Cmax at 80 mg; no ECG effects in monkeys
“The IC50 for the inhibitory effect of selinexor on hERG potassium current was 20.6 µM (Hill coefficient=1.1). The Applicant estimated >250 times safety margins based on the human free unbound Cmax following an 80 mg dose”
First doseopen answer page →
First-in-human starting dose
3 mg/m2 starting dose in Phase 1 3+3 dose escalation
“Study treatment on Arm 1 during the dose escalation phase followed a standard 3+3 design with a starting dose of selinexor 3 mg/m2.”
NOAEL / key findings
Rat: hematopoietic/lymphoid hypoplasia, reproductive organ toxicity; monkey: GI effects, lymphoid/hematologic depletion
“Rats exhibited toxicological sequalae due to hematopoietic/lymphoid hypoplasia and male/female reproductive organ effects. Female rats also exhibited higher liver weights and/or centrilobular hepatocellular hypertrophy and/or increased mitotic figures. Monkeys exhibited gastrointestinal effects and lymphoid/hematologic depletion.”
Risksopen answer page →
Immune & cytokine safety
Mild grade II dermal contact sensitivity response
“Selinexor was also identified as non-phototoxic and to induce mild-grade II dermal contact sensitivity response at 24 and 48 hours.”
Biodistribution & persistence
Highest in kidney, liver and small intestine; no specific binding to pigmented tissues
“The highest concentrations of radioactivity were observed in the kidneys, liver, and small intestine. There was no specific binding to pigmented tissues.”
Modality-specific risk
High toxicity: reproductive organs, CNS-mediated GI effects, reduced food intake and body weight, mortality
“Non-clinical safety program revealed a high toxicity of selinexor. Some tissues were mainly affected (reproductive systems, CNS-mediated gastrointestinal system…) and clinical findings reported (food consumption and body weight reduction, mortality).”
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
- Thrombocytopenia
- Neutropenia
- Gastrointestinal Toxicity
- Hyponatremia
- Serious Infection
- Neurological Toxicity
- Embryo-Fetal Toxicity
- Cataract
ThrombocytopeniaCytopeniasGastrointestinalInfectionsNeurotoxicityEmbryo-fetal toxicityOcular 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
3 mg/m2 starting dose in Phase 1 3+3 dose escalation
“Study treatment on Arm 1 during the dose escalation phase followed a standard 3+3 design with a starting dose of selinexor 3 mg/m2.”
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week (13-cycle) oral rat study with 4-week recovery; 13-week cynomolgus monkey study with 4-week recovery ties
“Study title/ number: A 13-Week (13-Cycle) Oral Gavage Toxicity and Toxicokinetic Study of KPT-330 in Sprague Dawley Rats with a 4-Week Recovery Period/ KNC-G-13-001”
Pivotal GLP studies
13-week oral studies in rat (5 doses per 2 weeks) and monkey (2-3 times/week)
“Thirteen-week repeat-dose oral toxicity and toxicokinetic studies were conducted in the rat (0, 0.25, 1, or 4 mg/kg selinexor; 5 total doses given every 2-week period) and monkey (0, 0.1, 0.3, 1 mg/kg selinexor; 2 to 3 times/week) to support the NDA.”
DART package
Species: DART
Rat (EFD only); no fertility study and no second species
“No carcinogenicity study was conducted, and only maternal and embryo-foetal development toxicity were carried out, indicating a NOAEL value at 0.25 mg/Kg/day for rats. No data for a second species were provided.”
Reproductive & developmental
Rat EFD: reduced fetal weight and delayed or incomplete ossification at >=0.75 mg/kg/day
“Adverse developmental outcomes occurred at ≥ 0.75 mg/kg/day and included alterations to growth (e.g., fetal weights in the 0.75 and 2 mg/kg/day groups were 13.5% and 32.4% lower than controls) and structural abnormalities (such as incomplete or delayed ossification of sternebra(e) and/or vertebral arches, and/or unossified and bent ribs).”
PPND / ePPND: when
No PPND conducted; only rat embryo-fetal development study performed (advanced-cancer program)
“No carcinogenicity study was conducted, and only maternal and embryo-foetal development toxicity were carried out, indicating a NOAEL value at 0.25 mg/Kg/day for rats.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Carcinogenicity studies were not conducted to support the use of selinexor for the proposed indication.”
Carcinogenicity model
Not conducted; not needed for the proposed indication
“Carcinogenicity studies were not conducted to support the use of selinexor for the proposed indication.”
Carcinogenicity timing
Not required for the proposed indication
“Carcinogenicity studies were not conducted to support the use of selinexor for the proposed indication.”
Safety marginopen answer page →
Safety margin at NOAEL
No margin: monkey 13-week NOAEL exposure below human exposure at 80 mg
“The exposure levels at the identified NOAEL in the 13-week study in monkeys is less than the measured exposure at the clinical dose of 80 mg.”
NOAEL / key findings
Rat: hematopoietic/lymphoid hypoplasia, reproductive organ toxicity; monkey: GI effects, lymphoid/hematologic depletion
“Rats exhibited toxicological sequalae due to hematopoietic/lymphoid hypoplasia and male/female reproductive organ effects. Female rats also exhibited higher liver weights and/or centrilobular hepatocellular hypertrophy and/or increased mitotic figures. Monkeys exhibited gastrointestinal effects and lymphoid/hematologic depletion.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse xenograft models of multiple myeloma (selinexor alone and with dexamethasone)
“The in vivo antitumor activity of selinexor was evaluated alone and in combination with dexamethasone in mouse xenograft models of multiple myeloma.”
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: tumour growth the only endpoint; methodology concerns in a pivotal study; xenograft models of limited clinical relevance
“The only endpoint investigated in these studies was tumour growth and therefore it is unclear if the effects on tumour growth translate into increased survival.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
No safety margin: toxicity in rats and monkeys at exposures below clinical exposure
“Non-clinical safety program revealed a high toxicity of selinexor. Some tissues were mainly affected (reproductive systems, CNS-mediated gastrointestinal system…) and clinical findings reported (food consumption and body weight reduction, mortality). No safety margin could be established for human studies.”
DARTVerdict not stated
Embryo-fetal development studied in rat only (NOAEL at 0.02x clinical exposure); no second species and no fertility study
Why: Findings in rats make a second species unnecessary (applicant)
“In an embryofoetal developmental toxicity study in rats the NOAEL value for maternal toxicity and embryo-foetal development was established at 0.25 mg/Kg/day and the resultant exposures measured represent a margin of exposure of 0.02 from the clinical dose. The Applicant has suggested that based on the findings in rats that studies in a second species are not warranted.”
OtherQuestioned
Rat 13-week NOAEL set by the applicant considered poorly justified given severity of findings
“As such, NOAEL was reported to be 0.25 mg/Kg/day for males and 1 mg/Kg/day for females, which was hardly justified given the severity of the findings reported in the study report.”
Impurity or metaboliteAccepted with a conditionBeyond the letter
Metabolite structures only partly characterised; confirmation study committed post-authorisation
“As of metabolites, partial information was provided. Therefore, the applicant committed to conduct additional post-authorisation studies to confirm the structure of the metabolites.”
“The Applicant has committed to submit results from a metabolite characterisation study, by Q1 2021 (CHMP Recommendation).”
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