Breyanzi
lisocabtagene maraleucel
Species
no relevantMouse
Longest study
14 wk
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 relevant species; in vitro and NSG mouse xenograft only
“In particular, suitable animal models are not available for accurately assessing the non-clinical characteristics of a human cell-based product such as JCAR017.”
Why that species
FMC63 scFv binds human CD19 only; no mouse or NHP cross-reactivity
“The results support that JCAR017 is specific for human CD-19 binding and lacks species cross-reactivity, in particular towards mouse and non-human primate.”
Surrogate molecule
No surrogate; human product tested in immunodeficient xenograft mice
“The lack of conventional in vivo studies and the use of immune-deficient Raji Burkitt’s lymphoma-bearing NOD/SCID IL-2Rγnull mice model are justified and appropriate to investigate autologous cell-based products.”
Species: general tox
None; single and repeat-dose toxicity studies not conducted (negligible utility)
“In this light, traditional toxicity, including single and repeat-dose toxicity, genotoxicity, carcinogenicity, reproductive and developmental toxicity, and local tolerance studies were deemed of negligible utility and thus were not conducted.”
Species: DART
Not conducted (no survival in immunocompetent rodents; GvHD in immunocompromised mice)
“JCAR017 does not survive in immunocompetent rodents and induces graft-versus-host disease in immunocompromised mice; therefore, traditional DART studies were not conducted.”
Species: carcinogenicity
Not conducted (ICH S9)
“Consistent with regulatory guidance under “Nonclinical Evaluation for Anticancer Pharmaceuticals” (ICH S9, 2009) carcinogenicity studies were not conducted.”
Surrogate used in
No surrogate used; human JCAR017 tested in Raji lymphoma-bearing immunodeficient mice
“The lack of conventional in vivo studies and the use of immune-deficient Raji Burkitt’s lymphoma-bearing NOD/SCID IL-2Rγnull mice model are justified and appropriate to investigate autologous cell-based products.”
Study lengthopen answer page →
Longest pivotal study
14 weeks
“periods (0-100 days), in contrast with the control group (died by day 10-11).”
Pivotal GLP studies
None; traditional single/repeat-dose, genotox, carcinogenicity, DART and local tolerance studies not conducted
“In this light, traditional toxicity, including single and repeat-dose toxicity, genotoxicity, carcinogenicity, reproductive and developmental toxicity, and local tolerance studies were deemed of negligible utility and thus were not conducted.”
Route in tox
Intravenous (xenograft pharmacology)
“JCAR017 is an autologous cell-based product administered by intravenous infusion.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (traditional); lentiviral integration site mapping instead
“Traditional genotoxicity assays and carcinogenicity assessments were not performed for JCAR017.”
Carcinogenicity
Not conducted (ICH S9); GLP in vitro 60-day IL-2-independent growth study instead
“Consistent with regulatory guidance under “Nonclinical Evaluation for Anticancer Pharmaceuticals” (ICH S9, 2009) carcinogenicity studies were not conducted.”
Reproductive & developmental
Not conducted (no survival in immunocompetent rodents; GvHD in immunodeficient mice)
“JCAR017 does not survive in immunocompetent rodents and induces graft-versus-host disease in immunocompromised mice; therefore, traditional DART studies were not conducted.”
Safety pharmacology
Not conducted (no species cross-reactivity)
“The autologous cell-based JCAR017 T products lack species cross-reactivity thus in all NC studies performed safety pharmacology was deemed not practical and of negligible utility.”
Genotox: Ames
Not conducted (negligible utility for this product)
“In this light, traditional toxicity, including single and repeat-dose toxicity, genotoxicity, carcinogenicity, reproductive and developmental toxicity, and local tolerance studies were deemed of negligible utility and thus were not conducted.”
Genotox: in vitro mammalian
Not conducted; genome-wide lentiviral integration site analysis across 54 products from 34 patients instead
“An unbiased, genome-wide, assay assessed viral integration events across 54 CAR T cell products derived from 34 patients that were transduced with vector to produce JCAR017.”
Genotox: in vivo
Not conducted (negligible utility for this product)
“In this light, traditional toxicity, including single and repeat-dose toxicity, genotoxicity, carcinogenicity, reproductive and developmental toxicity, and local tolerance studies were deemed of negligible utility and thus were not conducted.”
Carcinogenicity model
Not conducted; in vitro GLP IL-2-independent growth study assessed oncogenic transformation risk
“An in vitro GLP-compliant study evaluated the IL-2 independent growth of JCAR017 to assess the risk of oncogenic transformation following transduction.”
Carcinogenicity timing
Not required (ICH S9)
“Consistent with regulatory guidance under “Nonclinical Evaluation for Anticancer Pharmaceuticals” (ICH S9, 2009) carcinogenicity studies were not conducted.”
hERG / QT
Not conducted (no safety pharmacology studies)
“No safety pharmacology studies were conducted.”
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 Breyanzi 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; long-term safety in animals limited; tissue cross-reactivity showed off-target recognition of low concern (FDA pharmacology/toxicology review, p. 2)
NOAEL / key findings
No NOAEL; long-term safety in animals limited; tissue cross-reactivity showed off-target recognition of low concern
“Animal studies to assess the long-term safety of JCAR017 were limited because the JCAR017 does not survive in immunocompetent rodents and induces graft-versus-host disease in immunocompromised mice.”
Risksopen answer page →
Immune & cytokine safety
In vitro CD19-specific IFN-γ, IL-2, TNF-α release; EGFRt allows cetuximab-mediated CAR-T depletion
“These data provide support for administration of commercially available antibodies targeting the truncated EGFR domain on the surface of JCAR017 to reduce/eliminate the CAR T cells in vivo, if necessary.”
Biodistribution & persistence
No biodistribution studies; persistence assessed in xenograft PD study
“No biodistribution studies with JCAR017 were conducted.”
Modality-specific risk
Insertional mutagenesis/oncogenic transformation from lentiviral transduction; no preferential integration found
“The risk of insertional mutagenesis with lentiviral transduction of the T cells, leading to malignant transformation, was studied using unbiased, genome-wide bioinformatics methods.”
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
Treatment-induced or boosted anti-product antibodies 1% to 24% across studies (11% in LBCL cohort); no overall incidence
“Treatment-induced or treatment-boosted anti-product antibodies were detected in 11% (27/257) in Study 3 - LBCL Cohort, 1% (1/89) in Study 1, 2% (1/49) in Study 2, 7% (6/84) in Study 4, 24% (25/103) in Study 5 - FL Cohort, 18% (15/85) in Study 3 - MCL Cohort, and 20% (13/66) in Study 5 - MZL Cohort of patients.”
Label warnings
Boxed warning: Cytokine release syndrome, neurologic toxicities, and secondary hematological malignancies
- Cytokine Release Syndrome
- Neurologic Toxicities
- Hypersensitivity Reactions
- Serious Infections
- Prolonged Cytopenias
- Hypogammaglobulinemia
- Secondary Malignancies
- Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome (IEC-HS)
CytopeniasCytokine release syndromeNeurotoxicitySecondary malignancyHypersensitivity & infusion reactionsInfectionsImmune-mediated 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 Breyanzi 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; long-term safety in animals limited; tissue cross-reactivity showed off-target recognition of low concern (FDA pharmacology/toxicology review, p. 2)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (no species cross-reactivity; deemed of negligible utility)
“In this light, traditional toxicity, including single and repeat-dose toxicity, genotoxicity, carcinogenicity, reproductive and developmental toxicity, and local tolerance studies were deemed of negligible utility and thus were not conducted.”
Pivotal GLP studies
None; traditional single/repeat-dose, genotox, carcinogenicity, DART and local tolerance studies not conducted
“In this light, traditional toxicity, including single and repeat-dose toxicity, genotoxicity, carcinogenicity, reproductive and developmental toxicity, and local tolerance studies were deemed of negligible utility and thus were not conducted.”
DART package
Species: DART
Not conducted (no survival in immunocompetent rodents; GvHD in immunocompromised mice)
“JCAR017 does not survive in immunocompetent rodents and induces graft-versus-host disease in immunocompromised mice; therefore, traditional DART studies were not conducted.”
Reproductive & developmental
Not conducted (no survival in immunocompetent rodents; GvHD in immunodeficient mice)
“JCAR017 does not survive in immunocompetent rodents and induces graft-versus-host disease in immunocompromised mice; therefore, traditional DART studies were not conducted.”
PPND / ePPND: when
Not conducted; no survival in immunocompetent rodents and GvHD in immunocompromised mice
“JCAR017 does not survive in immunocompetent rodents and induces graft-versus-host disease in immunocompromised mice; therefore, traditional DART studies were not conducted.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S9)
“Consistent with regulatory guidance under “Nonclinical Evaluation for Anticancer Pharmaceuticals” (ICH S9, 2009) carcinogenicity studies were not conducted.”
Carcinogenicity model
Not conducted; in vitro GLP IL-2-independent growth study assessed oncogenic transformation risk
“An in vitro GLP-compliant study evaluated the IL-2 independent growth of JCAR017 to assess the risk of oncogenic transformation following transduction.”
Carcinogenicity timing
Not required (ICH S9)
“Consistent with regulatory guidance under “Nonclinical Evaluation for Anticancer Pharmaceuticals” (ICH S9, 2009) carcinogenicity studies were not conducted.”
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; long-term safety in animals limited; tissue cross-reactivity showed off-target recognition of low concern
“Animal studies to assess the long-term safety of JCAR017 were limited because the JCAR017 does not survive in immunocompetent rodents and induces graft-versus-host disease in immunocompromised mice.”
Efficacy evidenceopen answer page →
Efficacy evidence
Raji Burkitt's lymphoma-bearing NOD/SCID IL-2Rγnull xenograft mice
“The lack of conventional in vivo studies and the use of immune-deficient Raji Burkitt’s lymphoma-bearing NOD/SCID IL-2Rγnull mice model are justified and appropriate to investigate autologous cell-based products.”
Why that model
JCAR017 binds human CD19 only, with no cross-reactivity to mouse or non-human primate
“The results support that JCAR017 is specific for human CD-19 binding and lacks species cross-reactivity, in particular towards mouse and non-human primate.”
Reviewer's view of the efficacy data
EMA: primary pharmacodynamic studies provide adequate evidence of CD19 specificity, T-cell activation and antitumour effects
“Specifically, primary pharmacodynamic studies provide adequate evidences on the affinity and specificity of JCAR017 towards CD19-target cells and on their activation in terms of proliferation, cytokine production and lysis of target cells as well as on JCAR017 antitumour effects.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesAccepted
No pharmacologically relevant species; no conventional single- or repeat-dose toxicity, local tolerance or other traditional studies
Why: No species cross-reactivity; immunodeficient xenograft mouse models judged appropriate for autologous cell products · No relevant species · Within the guideline
“JCAR017 T product is an autologous T-cell based treatment characterised by the lack of species cross-reactivity. In this light, traditional toxicity, including single and repeat-dose toxicity, genotoxicity, carcinogenicity, reproductive and developmental toxicity, and local tolerance studies were deemed of negligible utility and thus were not conducted.”
“The lack of conventional in vivo studies and the use of immune-deficient Raji Burkitt’s lymphoma-bearing NOD/SCID IL-2Rγnull mice model are justified and appropriate to investigate autologous cell-based products.”
GenotoxicityAcceptedBeyond the letter
No traditional genotoxicity assays; lentiviral integration site mapping and long-term growth assays used instead
Why: Lentivirus does not preferentially integrate at oncogenic sites; insertional events carry minimal risk of oncogenic transformation · Weight of evidence
“The risk of insertional mutagenesis with lentiviral transduction of the T cells, leading to malignant transformation, was studied using unbiased, genome-wide bioinformatics methods.”
“These data support the conclusion that any insertional events resulting from lentiviral transduction methods used to generate JCAR017 have minimal risk for oncogenic transformation.”
CarcinogenicityAccepted
No carcinogenicity studies; non-conventional 60-day in vitro IL-2-independent proliferation study instead
Why: ICH S9 for anticancer products; cell counts below LLOQ without IL-2 after 60 days · Within the guideline · Weight of evidence
“Consistent with regulatory guidance under “Nonclinical Evaluation for Anticancer Pharmaceuticals” (ICH S9, 2009) carcinogenicity studies were not conducted.”
“Taken together, the applicant provided data supporting the absence of a carcinogenicity potential of JCAR017 T cells, since most samples in the absence of IL-2, after 60 days of culture, resulted below the LLOQ for cell concentration.”
DARTVerdict not stated
No developmental and reproductive toxicity studies
Why: No survival in immunocompetent rodents; graft-versus-host disease in immunocompromised mice · No relevant species
“JCAR017 does not survive in immunocompetent rodents and induces graft-versus-host disease in immunocompromised mice; therefore, traditional DART studies were not conducted.”
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