Source: FDA, National Drug Code (US) Revision Year: 2024
TECELRA is a genetically modified autologous T cell immunotherapy consisting of CD4 and CD8 positive T cells transduced with a self-inactivating LV to express an affinity-enhanced TCR specific for human MAGE-A4 on the cell surface.
The TCR recognizes an HLA-A*02 restricted MAGE-A4 peptide. MAGE-A4 is an intracellular cancer-testis antigen that has restricted expression in normal tissues and is expressed in synovial sarcoma. Antigen-specific activation of TECELRA via TCR-peptide-HLA-A*02 complex results in T cell proliferation, cytokine secretion, and killing of MAGE-A4/HLA-A*02 expressing synovial sarcoma cells.
In patients with synovial sarcoma who were treated with TECELRA, serum concentrations of cytokines and other soluble factors involved in cellular homeostasis, T cell activation, and inflammation (e.g. IFNγ, IL-6, IL-8, IL-15, and IL-2Rα) increased post-infusion, peaking between Days 3-8.
TECELRA exhibited an initial engraftment and expansion phase followed by contraction, and then persistence. High inter-individual variability was observed.
The pharmacokinetics of TECELRA in patients with synovial sarcoma are summarized in Table 3.
Table 3. Pharmacokinetics of Afamitresgene Autoleucel in SPEARHEAD-1 (Cohort 1)*:
| PK Parameter | N | Statistics | Value |
|---|---|---|---|
| tmax (day) | 44 | Median (range) | 7 (1-89) |
| Cmax (DNA copies/μg) | 44 | Geometric mean (CV%) | 189269 (109.1%) |
| AUC0-7D (day*DNA copies/μg) | 44 | Geometric mean (CV%) | 729653 (110.8%) |
| AUC0-28D (day*DNA copies/μg) | 41 | Geometric mean (CV%) | 3074205 (164.7%) |
| AUC0-3M (day*DNA copies/μg) | 35 | Geometric mean (CV%) | 4988965 (242.7%) |
| AUC0-6M (day*DNA copies/μg) | 33 | Geometric mean (CV%) | 6784047 (313.4%) |
* All patients received a dose within the range of 2.68 x 109 to 10 x 109 MAGE-A4 TCR positive T cells.
The pharmacokinetics of afamitresgene autoleucel (Cmax, AUC0-7D, AUC0-28D, AUC0-3M, AUC0-6M) were not impacted by body weight, body mass index, sex, age (range: 19 to 76 years), and baseline tumor sum of longest diameter (SLD).
Hepatic and renal impairment studies of TECELRA were not conducted.
No carcinogenicity or genotoxicity studies have been conducted with TECELRA.
A genomic insertion site analysis was performed on TECELRA products from five patients. There was no evidence for preferential integration near genes of concern. No studies have been conducted to evaluate the effects of TECELRA on fertility.
The efficacy of TECELRA was evaluated in a multicenter, single-arm, open-label clinical trial (SPEARHEAD-1, Cohort 1). The study enrolled HLA-A*02:01P, HLA-A*02:02P, HLA-A*02:03P, and HLA-A*02:06P allele positive patients with inoperable or metastatic synovial sarcoma who had received prior systemic therapy with either doxorubicin and/or ifosfamide and whose tumor expressed the MAGE-A4 tumor antigen. The study included patients with measurable disease according to RECIST v1.1, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and glomerular filtration rate (GFR) ≥60 mL/min. The study excluded patients with HLA-A*02:05P in either allele, patients on systemic corticosteroids for at least 14 days prior to leukapheresis and lymphodepletion, and recipients of allogeneic hematopoietic stem cell transplants.
Patients underwent high resolution HLA typing at a centralized testing site and had tumor samples tested for MAGE-A4 expression by an immunohistochemistry (IHC) clinical trial assay at a centralized testing site. Patients underwent leukapheresis for collection of autologous cells for processing and manufacture into TECELRA. Risk of manufacturing or delivery failure was 8% in the clinical trial (4/52) patients.
Patients received lymphodepleting chemotherapy with fludarabine 30 mg/m² for 4 days (Day -7 to Day -4) and cyclophosphamide 600mg/m²/day for 3 days (Day -7 to Day -5). Patients with GFR 60-79 mL/min received an adjusted fludarabine dose of 20 mg/m²/day. TECELRA was administered as a single intravenous (IV) infusion on Day 1.
Fifty-two (52) patients were enrolled and underwent leukapheresis, eight of whom did not receive TECELRA due to the following: death (n=3), loss of eligibility prior to lymphodepleting chemotherapy (n=3), withdrawal by patient (n=1), investigator decision (n=1). Forty-five (45) patients with synovial sarcoma received lymphodepletion and one patient withdrew consent before receiving TECELRA. There were 44 patients with synovial sarcoma who received a single infusion of TECELRA.
Among the efficacy analysis population demographic characteristics were as follows: median age was 41 years (range: 19 to 73 years), 50% were female, and 89% were White, and 96% were HLA-A*02:01P.
The median number of prior lines of systemic therapies was three (range: 1 to 12 lines). Prior therapies included ifosfamide (100%), doxorubicin (95%), pazopanib (48%), trabectedin (25%), dacarbazine (11%), and gemcitabine (11%). Between leukapheresis and initiation of lymphodepletion, 16 (36%) of the 44 patients received bridging therapy. The most commonly used bridging therapy was pazopanib (69%). The median dose of TECELRA was 8 x 109 MAGE-A4 TCR positive T cells (range: 2.68 x 109 to 9.99 x109).
The major efficacy outcome measure was overall response rate (ORR) according to RECISTv1.1 evaluated by independent review committee (IRC). Duration of response (DOR) was an additional outcome measure.The ORR results are presented in Table 4.
Table 4. Efficacy Results* for SPEARHEAD-1 (Cohort 1):
| Endpoint | TECELRA Treated population N=44 |
|---|---|
| Overall Response Rate (95% CI)† Complete response rate, n (%) Partial response rate, n (%) | 43.2% (28.4, 59.0) 2 (4.5%) 17 (38.6%) |
| Median Duration of Response‡ in months (95% CI)§ Min, Max Patients with DoR ≥6 months, %§ Patients with DoR ≥12 months, %§ | 6.0 (4.6, NR) 1.9, 36.1+ 45.6% 39.0% |
CI = confidence interval; NR = not reached.
* Efficacy assessment was by independent review committee according to Response Evaluation Criteria In Solid Tumors (RECIST) v1.1.
† Two-sided 95% confidence interval based on exact Clopper-Pearson (exact Binomial) method.
‡ Duration of response only applies to patients with a complete or partial response.
§ Two-sided 95% confidence interval and % of patients with response duration ≥6 and ≥12 months based on Kaplan-Meier method.
The median time to response from TECELRA treatment was 4.9 weeks (95% CI: 4.4 weeks, 8 weeks) by Kaplan Meier estimation.
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