FDA Grants RMAT/Fast Track Designations to C-CAR039 for Relapsed/Refractory DLBCL

The FDA has granted a regenerative medicine advanced therapy (RMAT) designation and a fast track designation to C-CAR039 for use as a potential therapeutic option in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).¹

A novel second-generation 4-1BB bispecific CAR T-cell therapy, C-CAR039 was designed to target both CD19 and CD20 antigens. The product has showcased in vitro antitumor activity against both single positive and double positive CD20/CD19-expressing tumors. Moreover, both in vitro and in vivo, C-CAR039 has demonstrated superior antitumor activity compared with an anti-CD20/CD19 bispecific CAR T product with Leu16-FMC63.

At the 2021 ASCO Annual Meeting, data from a phase 1 trial (NCT04317885; NCT04655677; NCT04696432; NCT04693676) showed that C-CAR039 elicited an overall response rate (ORR) of 92.6% with a complete response (CR) rate of 85.2% in all patients with relapsed/refractory non-Hodgkin lymphoma (NHL; n = 27).² The CAR T-cell therapy induced an ORR of 91.7% in those with DLBCL (n = 24), with a CR rate of 83.3%. Moreover, the ORRs were 100% in those with primary mediastinal large B-cell lymphoma (PMBCL; n = 1), follicular lymphoma (n = 1), and transformed follicular lymphoma (n = 1).

“This is great news for Cellular Biomedicine Group Inc. [CBMG] that the FDA has granted C-CAR039 both RMAT and fast track designations based on its potential to increase ORRs and CRs in relapsed/refractory DLBCL,” Tony (Bizuo) Liu, chairman and chief executive officer at CBMG, stated in a press release. “The clinical data based on our clinical trials in China continue to support the hypothesis that C-CAR039 is the best-in-class CAR T asset for patients in this indication.”

The open-label, dose-escalation and expansion trial was done at 4 clinical sites in China. To be eligible for enrollment, patients needed to have relapsed/refractory B-cell NHL, which could include DLBCL, follicular lymphoma, and mantle cell lymphoma. Patients also needed be between the ages of 18 years and 75 years, have either CD19- or CD20-positive disease, and have received anti-CD20 monoclonal antibodies. They could not have central nervous system involvement.

At day -28, participants underwent screening; this was followed by apheresis on day -21 and a baseline assessment on day -7, as the CAR T-cell therapy was being manufactured. From days -5 to -3, patients received fludarabine at a daily dose of 30 mg/m² and cytarabine at a daily dose of 300 mg/m². On day 0, they received an infusion of C-CAR039 at the following dose levels (DL): 1.0 x 10⁶/kg (DL1), 2.5 x 10⁶/kg (DL2), and 5.0 x 10⁶/kg (DL3). The first clinical response assessment was done at week 4.

The key efficacy end points of interest for the trial were ORR, duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

Investigators also assessed the incidence and severity of treatment-emergent adverse effects (TEAEs).

As of April 20, 2021, a total of 40 patients underwent leukapheresis in 4 clinical centers, and 34 patients were infused with the CAR T-cell product. Of the 34 patients, 28 were safety evaluable and 27 were efficacy evaluable. In the efficacy set, 4 patients received DL1, 15 received DL2, and 8 received DL3.

The median manufacturing time was 6 days (range, 5-11) and the median vein to vein time was 19 days (range, 12-67). At the time of the presentation, 28 patients had at least 1 month of data available.

Among these patients, the median age was 55.5 years (range, 28-71) and 28.6% of patients were aged 65 years or older. Moreover, 67.9% of patients were male, 64.3% had an ECOG performance status of 0, 25.0% had an IPI score of 3 or 4, 75.0% had Ann Arbor stage III or IV disease, and 28.6% had double-expressor lymphoma.

Most patients had DLBCL (89.3%), and others had PMBCL (3.6%), transformed follicular lymphoma (3.6%), and follicular lymphoma (3.6%). The median number of prior lines of therapy received was 3 (range, 1-5); 3.6% had 1 prior line, 35.7% had 2 prior lines, 14.3% had 3 prior lines, 25.0% had 4 prior lines, and 21.4% had 5 prior lines.

Moreover, 17.9% previously underwent transplant, 28.6% received a BTK inhibitor, and 32.1% had received lenalidomide (Revlimid). Notably, 28.6% of patients never achieved a CR to previous treatment, and 17.9% received bridging therapy.

Additional data showed that the median time to the first response was 1 month (range, 0.9-1.6) and the median time to CR was also 1 month (range, 0.9-6.0). At a median follow-up of 7.0 months (range, 1.9-7.12), the median DOR had not yet been reached.

One patient experienced no significant CAR expansion and achieved no clinical response, and another patient developed a second malignancy and dropped out of the trial. Additionally, 4 patients experienced relapse after achieving a CR, at 3, 6, 8, and 9 months, respectively. CR rates proved to be consistent across key subgroups analyzed.

The PFS rate at 6 months with the CAR T-cell product was 83.2% (95% CI, 69.1%-100.0%).

Regarding safety, 92.9% of 28 patients reported cytokine release syndrome (CRS) with only 1 effect (3.6%) being grade 3 in severity. Moreover, 14.3% of patients received single-agent tocilizumab (Actemra), 3.6% were given corticosteroids alone, and 3.6% of patients received both.

Additionally, 7.1% of patients experienced grade 1 immune effector cell–associated neurotoxicity syndrome (ICANS); both patients were in the highest dose group. One of the 2 patients received corticosteroids to manage the toxicity.

“We are working toward initiating 1b/2 trials for C-CAR039 in the United States soon. And we will work closely with the FDA to seek the best path forward to deliver the drug to patients in the United States and the European Union,” Liu added.

References

1. CBMG receives FDA regenerative medicine advanced therapy and fast track designations for bi-specific anti-CD19/CD20 CAR-T cell therapy for relapsed/refractory B-cell non-Hodgkin lymphoma. News release. Cellular Biomedicine Group, Inc.; January 12, 2022. Accessed January 12, 2022. https://prn.to/3GoBy4q
2. Liang A, Zhou L, Li P, et al. Safety and efficacy of a novel anti-CD20/CD19 bi-specific CAR T-cell therapy (C-CAR039) in relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). J Clin Oncol. 2021;39(suppl 15):2507. doi:10.1200/JCO.2021.39.15_suppl.2507