FDA Grants RMAT Designation to CTX110 for Relapsed/Refractory CD19+ B-Cell Malignancies

The FDA has granted a Regenerative Medicine Advanced Therapy (RMAT) designation to the allogeneic CAR T-cell therapy CTX110 for the treatment of patients with relapsed or refractory, CD19-positive B-cell malignancies, according to a news release from CRISPR Therapeutics.¹ 

“This RMAT designation is based on the encouraging clinical data we have presented thus far, and it is an important milestone that recognizes the transformative potential of CTX110 for the treatment of hematological malignancies,” Samarth Kulkarni, PhD, chief executive officer of CRISPR Therapeutics, said.¹ “We look forward to working closely with the FDA as we continue our efforts to bring this important new therapeutic modality to patients.”

CTX110, a healthy donor-derived gene-edited allogeneic CAR-T therapy targeting CD19, is currently under investigation in the ongoing phase 1 CARBON trial (NCT04035434). The single-arm, multicenter, open-label clinical trial will assess the safety and efficacy of the agent at several dose levels for the treatment of patients with relapsed or refractory CD19-positive B-cell malignancies, including non-Hodgkin lymphoma (NHL), B-cell lymphoma, and adult B-cell acute lymphoblastic leukemia (ALL), who have received at least 2 prior lines of therapy.^2,3 

At a data cutoff of August 26, 2021, 30 patients with large B-cell lymphoma (LBCL) had been enrolled on the trial, 26 of whom had received treatment with CTX110 with at least 28 days of follow-up. One patient did not receive CTX110 treatment, and 3 patients were not evaluable.

Patients underwent a single infusion of CTX110 after 3 days of a standard lymphodepletion with fludarabine (at a dose of 30mg/m² per day) and cyclophosphamide (at a dose of 500mg/m² per day). Re-dosing with CTX110 is permitted following disease progression. 

Early results from the trial showed that in the intent-to-treat (ITT) population (n=24), CTX110 induced an overall response rate (ORR) of 58% (n = 14) at dose level 2 (100 x 106) or above; the ORR was comprised of 9 complete responses (CRs; 38%).² In the modified ITT population (n = 23), the ORR was 61% (n = 14) for those treated with dose level 2 or above; the ORR was comprised of 9 CRs (38%). Moreover, the 6-month CR rate was 21%, potentially showing that CTX110 can elicit durable remissions.

In terms of safety, CTX110 was found to be well tolerated at all dose levels, with no cases of graft-vs-host disease or infusion-related reactions to lymphodepleting chemotherapy or CTX110 reported. Among patients who received an infusion at dose level 2 or above (n = 23), 13 experienced cytokine release syndrome, although all cases were grades 1/2 in severity. Immune effector cell-associated neurotoxicity syndrome was reported by 2 patients, with one case that was grade 1/2 in severity, and the other that was grade 3/4. Furthermore, grade 3/4 infections were reported in 2 patients.

The study is expected to enroll up to 143 patients, and recruitment is ongoing, with an expected completion date of August 2026.³ 

Patients eligible to enroll are those 18 years or older with NHL, or 18 to 70 years old with B-cell ALL. Those in the NHL cohort must have relapsed or refractory disease, as evidenced by 2 or more prior lines of therapy, and those in the B-cell ALL cohort must have histologically confirmed relapsed or refractory disease. Additionally, those enrolled on the study must have an ECOG performance status of 0 or 1, as well as adequate renal, liver, cardiac, and pulmonary organ function. 

Those who have undergone any prior gene therapy, including prior CAR T-cell therapy, will not be allowed to enroll on the study. Furthermore, patients with NHL who have undergone prior allogeneic hematopoietic stem cell transplantation (allo-HSCT), or patients with B-cell ALL who have received an allo-HSCT within 6 months, are ineligible for enrollment.

The study is divided into 2 parts: part A is a dose-escalation portion, and part B is a cohort-expansion portion. The primary end point of part A is to examine the incidence of adverse effects in all disease cohorts, defined as dose limiting toxicities from the time if CTX110 infusion to 28 days after infusion. The primary end point of part B is the ORR for those enrolled to the NHL cohort. 

Secondary end points include duration of response for those who achieve either a complete or partial response, duration of clinical benefit, progression-free survival, overall survival, and ORR for those in the B-cell ALL cohort.

References

1. CRISPR Therapeutics announces FDA regenerative medicine advanced therapy (RMAT) designation granted to CTX110™ for the treatment of relapsed or refractory CD19+ B-cell malignancies. News release. CRISPR Therapeutics. November 22, 2021. Accessed November 23, 2021. https://bit.ly/3r1nJEf 
2. CRISPR Therapeutics reports positive results from its phase 1 CARBON trial of CTX110™ in relapsed or refractory CD19+ B-cell malignancies. News release. CRISPR Therapeutics. October 12, 2021. Accessed November 23, 2021. https://bit.ly/2ZhkrBl 
3. A safety and efficacy study evaluating CTX110 in subjects with relapsed or refractory B-cell malignancies (CARBON). ClinicalTrials.gov. Updated October 6, 2021. Accessed November 23, 2021. https://clinicaltrials.gov/ct2/show/NCT04035434