Amtagvi
lifileucel
Species
no relevantMouse
Longest study
none
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
No animal studies with product; published murine and human TIL literature only
“No nonclinical studies were conducted with AMTAGVI. Instead, the applicant cited published nonclinical data evaluating similar murine and human tumor-derived T lymphocytes to provide support for AMTAGVI.”
Why that species
Omission of tox studies accepted given product characteristics and biological activity (autologous unmodified T cells)
“No toxicology studies were conducted for AMTAGVI. Given the characteristics and biological activity of AMTAGVI, this omission is acceptable.”
Surrogate molecule
Yes: published studies of similar murine (homologous) and human TILs used in lieu of product testing
“Instead, the applicant cited published nonclinical data evaluating similar murine and human tumor-derived T lymphocytes to provide support for AMTAGVI.”
Species: general tox
None; no toxicology studies conducted (omission accepted)
“No toxicology studies were conducted for AMTAGVI. Given the characteristics and biological activity of AMTAGVI, this omission is acceptable.”
Species: DART
Not conducted (product characteristics and biological activity)
“No DART studies were conducted for AMTAGVI. Given the characteristics and biological activity of AMTAGVI, this omission is acceptable.”
Species: carcinogenicity
Not conducted; expanded TIL cultures free of tumor cells and residual tumor cells controlled at release
“No tumorigenicity studies were conducted for AMTAGVI. This is acceptable since Studies #3 and #4 provided evidence that the expanded human TIL cultures in the studies were free of tumor cells.”
Surrogate used in
Yes: published data on similar murine and human tumor-derived lymphocytes used instead of product studies
“No nonclinical studies were conducted with AMTAGVI. Instead, the applicant cited published nonclinical data evaluating similar murine and human tumor-derived T lymphocytes to provide support for AMTAGVI.”
Study lengthopen answer page →
Longest pivotal study
0 (no in vivo tox study)
“No toxicology studies were conducted for AMTAGVI.”
Pivotal GLP studies
None; five published pharmacology papers (TIL prognosis, expansion, cytotoxicity, murine tumor models) submitted in Module 4
“No nonclinical pharmacology studies were performed for AMTAGVI.”
Route in tox
Not applicable; no in vivo studies with product
“No nonclinical studies were conducted with AMTAGVI.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (not warranted given product characteristics and biological activity)
“No genotoxicity studies were conducted for AMTAGVI. Given the characteristics and biological activity of AMTAGVI, this omission is acceptable.”
Carcinogenicity
Not conducted (expanded TILs free of tumor cells; residual tumor cell release controls; no clinical tumorigenicity signal)
“No tumorigenicity studies were conducted for AMTAGVI. This is acceptable since Studies #3 and #4 provided evidence that the expanded human TIL cultures in the studies were free of tumor cells.”
Reproductive & developmental
Not conducted (product characteristics and biological activity)
“No DART studies were conducted for AMTAGVI. Given the characteristics and biological activity of AMTAGVI, this omission is acceptable.”
Safety pharmacology
Not conducted; omission accepted
“No safety pharmacology studies were conducted for AMTAGV1. Given the characteristics and biological activity of AMTAGVI, this omission is acceptable.”
Genotox: Ames
Not conducted (not warranted for this product)
“No genotoxicity, carcinogenicity, and developmental and reproductive toxicity (DART) studies were conducted for AMTAGVI. These studies are not warranted based on the product characteristics, biological activity, and safety profile.”
Genotox: in vitro mammalian
Not conducted (not warranted for this product)
“No genotoxicity, carcinogenicity, and developmental and reproductive toxicity (DART) studies were conducted for AMTAGVI. These studies are not warranted based on the product characteristics, biological activity, and safety profile.”
Genotox: in vivo
Not conducted (not warranted for this product)
“No genotoxicity, carcinogenicity, and developmental and reproductive toxicity (DART) studies were conducted for AMTAGVI. These studies are not warranted based on the product characteristics, biological activity, and safety profile.”
Carcinogenicity model
Not conducted; TIL cultures shown tumor-cell free, release specs control residual tumor cells
“No tumorigenicity studies were conducted for AMTAGVI. This is acceptable since Studies #3 and #4 provided evidence that the expanded human TIL cultures in the studies were free of tumor cells.”
Carcinogenicity timing
Not required (product characteristics, biological activity, safety profile)
“No genotoxicity, carcinogenicity, and developmental and reproductive toxicity (DART) studies were conducted for AMTAGVI. These studies are not warranted based on the product characteristics, biological activity, and safety profile.”
hERG / QT
Not conducted (no safety pharmacology studies; omission accepted)
“No safety pharmacology studies were conducted for AMTAGV1. Given the characteristics and biological activity of AMTAGVI, this omission is acceptable.”
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 Amtagvi 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 cell therapies
FDA expects preclinical proof-of-concept and toxicology studies to identify active dose levels and support the choice of starting dose and escalation. The 2013 guidance gives no numeric formula or scaling rule for the starting dose.
“Selection of potential starting dose level, dose-escalation schedule, and dosing regimen for clinical trials.”
✓ VerifiedFDA 2013: Preclinical Assessment of Investigational Cellular and Gene Therapy…, p. 7Source ↗
This product's starting point
NOAEL / key findings: No NOAEL; no toxicology studies; no target-organ findings available (FDA pharmacology/toxicology review, p. 13)
NOAEL / key findings
No NOAEL; no toxicology studies; no target-organ findings available
“No toxicology studies were conducted for AMTAGVI. Given the characteristics and biological activity of AMTAGVI, this omission is acceptable.”
Risksopen answer page →
Immune & cytokine safety
No immunotox/cytokine studies; literature shows anti-CD3-activated TIL cytotoxicity specific to autologous tumor, not heterologous targets
“Compared to TILs expanded in 1000 U/ml of IL-2 alone, TILs activated with anti-CD3 + 50 U/ml of IL-2 demonstrated higher cytotoxicity against autologous tumor cells but not against Daudi, K562, or histologically matched heterologous tumor cells.”
Biodistribution & persistence
Not conducted; accepted based on known distribution of IV T cell products
“No nonclinical studies were conducted to evaluate distribution of AMTAGVI. Based on the available information on the in vivo distribution of intravenously administered T cell products, this omission is acceptable.”
Modality-specific risk
Residual tumor cell contamination/tumorigenicity of tumor-derived product; LD chemo and IL-2 toxicity deferred to approved labels
“AMTAGVI specifications also include measures to control residual tumor cell levels in the final drug product.”
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
Boxed warning: TREATMENT-RELATED MORTALITY, PROLONGED SEVERE CYTOPENIA, SEVERE INFECTION, CARDIOPULMONARY and RENAL IMPAIRMENT
- Treatment-Related Mortality
- Prolonged Severe Cytopenia
- Internal Organ Hemorrhage
- Severe Infection
- Cardiac Disorder
- Respiratory Failure
- Acute Renal Failure
- Hypersensitivity Reactions
NephrotoxicityCytopeniasInfectionsCardiovascularPulmonary toxicityBleedingHypersensitivity & infusion reactions
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 Amtagvi 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 cell therapies
FDA expects preclinical proof-of-concept and toxicology studies to identify active dose levels and support the choice of starting dose and escalation. The 2013 guidance gives no numeric formula or scaling rule for the starting dose.
“Selection of potential starting dose level, dose-escalation schedule, and dosing regimen for clinical trials.”
✓ VerifiedFDA 2013: Preclinical Assessment of Investigational Cellular and Gene Therapy…, p. 7Source ↗
This product's starting point
NOAEL / key findings: No NOAEL; no toxicology studies; no target-organ findings available (FDA pharmacology/toxicology review, p. 13)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (no toxicology studies conducted)
“No toxicology studies were conducted for AMTAGVI.”
Pivotal GLP studies
None; five published pharmacology papers (TIL prognosis, expansion, cytotoxicity, murine tumor models) submitted in Module 4
“No nonclinical pharmacology studies were performed for AMTAGVI.”
DART package
Species: DART
Not conducted (product characteristics and biological activity)
“No DART studies were conducted for AMTAGVI. Given the characteristics and biological activity of AMTAGVI, this omission is acceptable.”
Reproductive & developmental
Not conducted (product characteristics and biological activity)
“No DART studies were conducted for AMTAGVI. Given the characteristics and biological activity of AMTAGVI, this omission is acceptable.”
PPND / ePPND: when
Not conducted; acceptable given product characteristics and biological activity
“No DART studies were conducted for AMTAGVI. Given the characteristics and biological activity of AMTAGVI, this omission is acceptable.”
Carcinogenicity
Species: carcinogenicity
Not conducted; expanded TIL cultures free of tumor cells and residual tumor cells controlled at release
“No tumorigenicity studies were conducted for AMTAGVI. This is acceptable since Studies #3 and #4 provided evidence that the expanded human TIL cultures in the studies were free of tumor cells.”
Carcinogenicity model
Not conducted; TIL cultures shown tumor-cell free, release specs control residual tumor cells
“No tumorigenicity studies were conducted for AMTAGVI. This is acceptable since Studies #3 and #4 provided evidence that the expanded human TIL cultures in the studies were free of tumor cells.”
Carcinogenicity timing
Not required (product characteristics, biological activity, safety profile)
“No genotoxicity, carcinogenicity, and developmental and reproductive toxicity (DART) studies were conducted for AMTAGVI. These studies are not warranted based on the product characteristics, biological activity, and safety profile.”
Safety marginopen answer page →
Safety margin at NOAEL
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.
NOAEL / key findings
No NOAEL; no toxicology studies; no target-organ findings available
“No toxicology studies were conducted for AMTAGVI. Given the characteristics and biological activity of AMTAGVI, this omission is acceptable.”
Efficacy evidenceopen answer page →
Efficacy evidence
Published literature only: tumor-derived lymphocytes with Cy and IL-2 in murine colon adenocarcinoma and sarcoma metastasis models
“anti-tumor activity of tumor-derived lymphocytes, in combination with Cy and IL-2, in murine models of colon adenocarcinoma and sarcoma with lung and liver metastases.”
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: published TIL expansion methods differ from GEN2 process, so comparable cytotoxicity of AMTAGVI cannot be assessed
“The GEN2 manufacturing process for AMTAGV1 is different from the TILs expansion method in this publication. Therefore, this reviewer cannot comment on whether AMTAGV1 exhibits comparable cytotoxicity against autologous tumor cells as TILs in this publication.”
Flexibilityopen answer page →
Flexibility accepted
Efficacy modelQuestioned
No nonclinical pharmacology studies with the product; published data on similar murine and human tumor-derived T lymphocytes cited instead
“No nonclinical studies were conducted with AMTAGVI. Instead, the applicant cited published nonclinical data evaluating similar murine and human tumor-derived T lymphocytes to provide support for AMTAGVI.”
“The GEN2 manufacturing process for AMTAGV1 is different from the TILs expansion method in this publication. Therefore, this reviewer cannot comment on whether AMTAGV1 exhibits comparable cytotoxicity against autologous tumor cells as TILs in this publication.”
OtherAcceptedBeyond the letter
No toxicology studies of any kind
Why: Characteristics and biological activity of the product · Low-risk modality
“No toxicology studies were conducted for AMTAGVI. Given the characteristics and biological activity of AMTAGVI, this omission is acceptable.”
BiodistributionAcceptedBeyond the letter
No cell distribution studies
Why: Available information on in vivo distribution of intravenously administered T cell products · Class precedent
“No nonclinical studies were conducted to evaluate distribution of AMTAGVI. Based on the available information on the in vivo distribution of intravenously administered T cell products, this omission is acceptable.”
CarcinogenicityAcceptedBeyond the letter
No tumorigenicity studies
Why: Published studies showed expanded human TIL cultures were free of tumor cells · Weight of evidence
“No tumorigenicity studies were conducted for AMTAGVI. This is acceptable since Studies #3 and #4 provided evidence that the expanded human TIL cultures in the studies were free of tumor cells.”
DARTAcceptedBeyond the letter
No DART, genotoxicity or safety pharmacology studies
Why: Characteristics and biological activity of the product · Low-risk modality
“No DART studies were conducted for AMTAGVI. Given the characteristics and biological activity of AMTAGVI, this omission is acceptable.”
Similar precedents
AbecmaCell therapy · idecabtagene vicleucel · BCMA CAR-TNo relevant species · 12 wkAucatzylCell therapy · obecabtagene autoleucel · CD19 CAR-TNo relevant species · 2 wkBreyanziCell therapy · lisocabtagene maraleucel · CD19 CAR-TNo relevant species · 14 wkCarvyktiCell therapy · ciltacabtagene autoleucel · BCMA CAR-TNo relevant species · 14 wkKymriahCell therapy · tisagenlecleucel · CD19 CAR-TNo relevant species · 31 wkProvengeCell therapy · sipuleucel-T · PAP-GM-CSF (autologous APC)No relevant species · 6 wk