The review of the Biologics License Application for idecabtagene vicleucel has been put on hold. The FDA issued a Refusal to File letter due to the need for additional data from the developer of the drug.
The FDA issued a Refusal to File letter regarding the Biologics License Application (BLA) for the chimeric antigen receptor (CAR) T-cell agent, idecabtagene vicleucel (ide-cel), which was submitted in March 2020 as a potential treatment for patients with heavily pretreated relapsed or refractory multiple myeloma.1
A preliminary review was carried out by the FDA, but it was realized that the Chemistry, Manufacturing, and Control (CMC) module of the BLA required more information before the review could be completed. The other modules of the BLA appear to be thorough considering that no additional clinical or non-clinical data were requested.
FDA approval for ide-cel is being sought by Bristol Myers Squibb based on data from the phase II KarMMa trial (NCT03361748), which is a multicenter study ongoing in Japan to evaluate the safety and efficacy the drug in patients with relapsed or refractory multiple myeloma.
Topline results from KarMMa reported in 2019 showed that the study met its primary end point of overall response rate and demonstrated a safety profile consistent with previously reported information from the CRB-401 study. The key secondary end points of the study, duration of response (DOR), and progression-free survival (PFS) were also reached.2
Of the 140 patients included in the study and followed for a median of 11.3 months, 94 patients achieved an objective response. Responses differed across the four-dose level arms, which included 150 x 106 , 300 x 106, or 450 x 106 CAR T cells. Specifically, the ORR was 50% for patients treated at the lowest CAR T-cell dose level, 68.6% for those given 300 x 106 CAR T cells, 81.5% for patients who received 450 x 106 CAR T cells. The ORR was 73.4% in the overall population. In each dose group, respectively, complete responses (CR) were seen in 25%, 28.6%, and 35.2% patients. The median DOR was not reached in the 150 x 106 treatment arm. The median DOR was 9.9 months in the 300 x 106 arm, 11.3 months in the 450 x 106 arm. The overall DOR was 10.6 months.
The median PFS was not reached in the 150 x 106 arm. In the 300 x 106 and 450 x 106 arms the median PFS was 5.8 months and 11.3 months, respectively.
In terms of safety, 5.5 % of patients experienced grade higher cytokine release syndrome (CRS), one of which was a fatal event. Grade 3 or higher neurotoxicity events occurred in 3.1% of patients. Less than 6% of patients among each dose level of CAR T-cell therapy had grade 3 or higher CRS or neurotoxicity events. Overall, CRS occurred in 83.6% of patients (n = 107), and neurotoxicity occurred in 18% (n = 23).
To be eligible for the trial, patients must be at least 18 years of age with a documented diagnosis of multiple myeloma, an ECOG performance status of 0 or 1, and measurable disease. The study excluded individuals with known central nervous system (CNS) involvement with myeloma, active or prior plasma cell leukemia, solitary plasmacytomas or non-secretory myeloma without other evidence of measurable disease, inadequate organ function, evidence of infection related to human immunodeficiency virus, evidence of active viral infection with hepatitis B virus or hepatitis C virus, history of class III or IV congestive heart failure, hypersensitivity to any component of ide-cel, a second malignancy in addition to myeloma, and those who known CNS involvement with myeloma or a history of CNS pathology.
The study is actively recruiting patients with relapsed/refractory multiple myeloma who meet the eligibility requirements for enrollment.
1. Bristol Myers Squibb and bluebird bio provide regulatory update on idecabtagene vicleucel (ide-cel, bb2121) for the treatment of patients with multiple myeloma [news release]. Princeton, New Jersey and Cambridge Massachusetts: Bristol Myers Squibb; May 13, 2020. https://bwnews.pr/3cpgJa1. Accessed May 13, 2020.
2. Bristol-Myers Squibb and bluebird bio announce positive top-line results from the pivotal phase 2 karmma study of ide-cel in relapsed and refractory multiple myeloma [news release]. Princeton, New Jersey and Cambridge Massachusetts: Bristol Myers Squibb; December 6, 2019. https://bit.ly/3dIQSdu. Accessed May 13, 2020.