Abecma
idecabtagene vicleucel · BCMA CAR-TCountry not stated; first-in-human dose-finding study in patients with relapsed/refractory multiple myeloma (CRB-401)
Yescarta: what was done before first-in-human, and what came after?
axicabtagene ciloleucel · CD19 CAR-T
Before first-in-human
First-in-human: where
Country not stated; initial dose-finding study NCI 09-C-0082 in patients with advanced B-cell malignancies
“Dosing of the conditioning chemotherapy agents and Yescarta was based on the results NCI study 09-C0082, a Phase 1 open label study of the safety and feasibility of anti-CD 19 CAR T-cells in subjects with advanced B-cell malignancies.”
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 Yescarta 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; surrogate mice: no overt toxicity, persistent on-target B-cell aplasia to Day 209 (FDA pharmacology/toxicology review, p. 16)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No toxicology studies with the product; surrogate mouse CAR-T pharmacology study only
“No toxicology studies with KTE-C19 were conducted.”
Pivotal GLP studies
No toxicology studies; published surrogate CAR-T study in lymphodepleted syngeneic tumor-bearing mice (Kochenderfer 2010)
“No toxicology studies with KTE-C19 were conducted.”
DART package
Species: DART
Not conducted
“Developmental and Reproductive Toxicology Studies (DART) No DART studies were conducted.”
Reproductive & developmental
Not conducted
“Developmental and Reproductive Toxicology Studies (DART) No DART studies were conducted.”
PPND / ePPND: when
No fertility/reproduction/development studies; acceptable given product type, target expression and lack of a relevant animal model
“No studies have been conducted to evaluate the effects of YESCARTA on fertility, reproduction and development. This is acceptable based on the type of product, the expression pattern of the target antigen and the lack of a relevant animal model.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“No in vitro and in vivo genotoxicity and carcinogenicity assessments for KTE-C19 were conducted.”
Carcinogenicity model
Not conducted; literature review suggests T cells relatively resistant to retroviral malignant transformation
“To address the risk of retroviral vector insertional mutagenesis and potential carcinogenicity/tumorigenicity the applicant performed a review of published nonclinical and clinical information reported for T cells transduced with retroviral vectors. The data suggest that T cells are relatively resistant to malignant transformation by retroviral vectors.”
Carcinogenicity timing
Not conducted; literature review on retroviral-vector T-cell transformation submitted instead
“No in vitro and in vivo genotoxicity and carcinogenicity assessments for KTE-C19 were conducted. To address the risk of retroviral vector insertional mutagenesis and potential carcinogenicity/tumorigenicity the applicant performed a review of published nonclinical and clinical information reported for T cells transduced with retroviral vectors.”
Same question, other cell therapies
Carvykti
ciltacabtagene autoleucel · BCMA CAR-TCountry not stated; first clinical trial in patients with relapsed/refractory multiple myeloma (LEGEND-2)
MACI
autologous cultured chondrocytes on porcine collagen membrane · Autologous chondrocytesOutside the United States: all clinical studies ex-US (countries not named)
Tecelra
afamitresgene autoleucel · MAGE-A4 TCR-TCountry not stated; first-in-human dose-escalation and expansion study in HLA-A*02 patients with MAGE-A4-positive advanced tumors
Zemcelpro
dorocubicel · UM171-expanded cord blood CD34+Canada: dose de-escalation study (Study 001) at 2 sites in patients needing allogeneic stem cell transplant
Alofisel
darvadstrocel · Allogeneic adipose MSCNot stated in public reviews
Amtagvi
lifileucel · TIL therapyNot stated in public reviews
Aucatzyl
obecabtagene autoleucel · CD19 CAR-TNot stated in public reviews
Breyanzi
lisocabtagene maraleucel · CD19 CAR-TNot stated in public reviews
ChondroCelect
characterised viable autologous cartilage cells · Autologous chondrocytesNot stated in public reviews
Ebvallo
tabelecleucel · EBV-specific allogeneic T cellsNot stated in public reviews
Encelto
revakinagene taroretcel · CNTF (encapsulated RPE cell implant)Not stated in public reviews
Gintuit
allogeneic cultured keratinocytes and fibroblasts in bovine collagen · Allogeneic keratinocytes + fibroblastsNot stated in public reviews
Holoclar
autologous corneal epithelial cells containing limbal stem cells · Autologous limbal stem cellsNot stated in public reviews
Kymriah
tisagenlecleucel · CD19 CAR-TNot stated in public reviews
Lantidra
donislecel · Allogeneic pancreatic isletsNot stated in public reviews
Laviv
azficel-T · Autologous fibroblastsNot stated in public reviews
Omisirge
omidubicel · Expanded cord blood HPCNot stated in public reviews
Provenge
sipuleucel-T · PAP-GM-CSF (autologous APC)Not stated in public reviews
Rethymic
allogeneic processed thymus tissue · Allogeneic thymus tissueNot stated in public reviews
Ryoncil
remestemcel-L · Allogeneic BM-MSCNot stated in public reviews
Spherox
spheroids of autologous matrix-associated chondrocytes · Autologous chondrocyte spheroidsNot stated in public reviews
StrataGraft
allogeneic cultured keratinocytes and dermal fibroblasts in murine collagen · Allogeneic keratinocytes + fibroblastsNot stated in public reviews
Tecartus
brexucabtagene autoleucel · CD19 CAR-TNot stated in public reviews
Tregzi
allogeneic Treg immunotherapy with HSPC and T cells (Orca-T) · Allogeneic Treg + HSPC + TconNot stated in public reviews
Zalmoxis
allogeneic T cells modified with HSV-TK / dLNGFR (nalotimagene carmaleucel) · HSV-TK suicide-gene T cellsNot stated in public reviews