A Phase Ib/II Study of Trovocabtagene Autoleucel (C-CAR088), an Anti-BCMA CAR T-Cell Therapy in Relapsed or Refractory Multiple Myeloma

Background:

Trovocabtagene autoleucel (trovo-cel, C-CAR088), is a novel 2^nd generation 4-1BB CAR-T cell therapy targeting BCMA. As previously reported, trovo-cel at a dose level of 3.0-6.0 × 10⁶ cells/kg demonstrated good efficacy and safety in patients with relapsed/refractory multiple myeloma (R/R MM) (Qu X, et al. Journal for ImmunoTherapy of Cancer 2022;10). The phase Ib/II IND study (NCT05521802) of trovo-cel in R/R MM was approved in 2022. Here, we present the results of the phase Ib part of this study.

Methods:

R/R MM patients who have been treated with ≥ 3 prior lines of therapy (LOT), including at least one proteasome inhibitor (PIs) and one immunomodulatory drug (IMiDs) were eligible.

Total 12 subjects received lymphodepletion with fludarabine (30 mg/m²/day) and cyclophosphamide (300 mg/m²/day) for 3 days, followed by a single infusion of trovo-cel. The first 6 subjects were administered trovo-cel at a dose of 3.0×10⁶ cells/kg, and the rest infused at 6.0×10⁶ cells/kg.

The primary endpoint was the incidence and severity of adverse events (AEs), and the secondary endpoints included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS) and minimal residual disease (MRD) negativity rate, etc. by 2016 IMWG Response Criteria.

Results:

As of April 10^th, 2024, all 12 subjects were included in efficacy, safety and pharmacokinetics (PK) analysis.

The median age was 58.5 years (range 52-70) with 58.3% were male. With a median of 4 prior LOT, all subjects had been exposed to PIs and IMiDs, 91.7% had been treated with daratumumab, 41.7% were penta-exposed and 41.7% had undergone ASCT. At baseline, 100%, 33.3%, and 25% of the subjects were DS III, ISS III, and R-ISS III, respectively. Eight subjects (66.7%) had at least one high-risk cytogenetic abnormality. Three subjects had extramedullary diseases, and 1 subject progressed to plasma cell leukemia (PCL) at baseline.

The ORR was 91.7%, with a ≥CR rate of 75.0% and a ≥VGPR rate of 83.3%. The MRD negative rate was 88.9% in subjects achieved ≥CR. The ORR and ≥CR rate were 100% and 83.3% respectively in 6.0 dose cohort, and 83.3% and 66.7% in 3.0 dose cohort. With a median follow-up of 7.95 months, the median DOR, PFS, and OS had not been reached in each dose cohort. Ten subjects (83.3%) maintained response and under follow-up. Two subjects from 3.0 dose cohort withdrew from the study due to disease progression, one died from progression soon after, another remained alive. To date, three subjects with extramedullary diseases reached sCR, PR and SD, respectively; the subject who progressed to PCL reached sCR.

The most common AEs were hematologic toxicities and cytokine release syndrome (CRS).

All subjects experienced CRS. Two subjects from 6.0 dose cohort developed grade 3 CRS, which manifested as transient hypotension quickly corrected with dopamine. Other CRS events were grade 1-2. All CRS events resolved. The median time to CRS onset was 3 days, with a median duration of 4.5 days. No ICANS events were noted.

Four subjects (33.3%) reported grade 3 infections, including pneumonia and sepsis which were recovered or improved by the cutoff date. Long-term cytopenia, defined as grade ≥3 ANC count decrease, platelet count decrease, or anemia at day 30 post trovo-cel infusion, was observed in 41.7%, 41.7%, and 8.3% of subjects.

One 59-year-old male subject was diagnosed with lung adenocarcinoma after the data cutoff date, which was considered not related to trovo-cel. He had a 16-year smoking history, lung cancer family history, occupational dust exposure. His pulmonary nodules (tumor sites) were first detected in 2017 and gradually enlarged within 2 years before infusion with suspicious malignant imaging signs. The level of CAR transgene DNA copy number in tumor was consistent with that in peripheral blood. No CAR gene genome insertion hot spots were detected, and RCL were negative in both blood and tumor tissues.

In all subjects, Trovo-cel showed robust proliferation and expansion. qPCR analysis revealed a median C_max of 292,092 copies/μg gDNA, an AUC_0-28day of 4,030,778 copies/μg gDNA·day, a T_max of 13 days, and a T_last exceeding 183 days. No significant differences were observed between the two dose cohorts.

Conclusion:

Trovo-cel has a manageable safety profile, with no neurotoxicity event and low SPM rate. Deep and durable responses were observed in both dose cohort and 6.0x10⁶ cells/kg reached a relatively higher CR rate.

Huang:Shanghai AbelZeta Ltd.: Current Employment. Li:Shanghai AbelZeta Ltd.: Current Employment. Zhang:Shanghai AbelZeta Ltd.: Current Employment. Lan:Shanghai AbelZeta Ltd.: Current Employment.