Juno Therapeutics, Inc., announced on July 12, 2016, that the U.S. Food and Drug Administration (FDA) has removed the clinical hold on the phase II clinical trial of JCAR015 (known as the ROCKET trial; clinicaltrials.gov identifier NCT02535364) in adult patients with relapsed or refractory B-cell acute lymphocytic leukemia (ALL). Under the revised protocol, the ROCKET trial will continue enrollment using JCAR015, an investigational CD19-targeted chimeric antigen receptor (CAR) modified T-cell product, with cyclophosphamide preconditioning only.
Previous Clinical Hold
The company had received notice on July 7 from the FDA that a clinical hold had been placed on the ROCKET trial after two patient deaths, which followed the recent addition of fludarabine to the preconditioning regimen.
Juno proposed to the FDA to continue the ROCKET trial using JCAR015 with cyclophosphamide preconditioning alone. The FDA requested that Juno submit a revised patient informed-consent form, a revised investigator brochure, a revised trial protocol, and a copy of the presentation made to the agency.
Early Phase I Results
Encouraging early clinical data from the ROCKET trial were presented by Park et al at the 2016 ASCO Annual Meeting.1 In the phase I section of the study, 51 adult patients with relapsed or refractory acute lymphocytic leukemia were treated with either cyclophosphamide or fludarabine/cyclophosphamide followed by an infusion of JCAR015. At the time of treatment, 31 patients had morphologic disease burden and 20 patients had minimal disease burden. Median study follow-up was 8.5 months.
Complete response was observed in 23 of 30 patients (77%) with morphologic disease and in 18 of 20 patients (90%) with minimal disease. In patients who achieved complete response and had adequate evaluation for minimal residual disease by flow cytometry or polymerase chain reaction, complete molecular remission was observed in 19 of 21 patients (90%) with morphologic disease and in 14 of 18 patients (78%) with minimal disease.
Median overall survival for patients with minimal disease treated with JCAR015 was not reached and was 9 months for morphologic patients treated with JCAR015; median overall survival follow-up for all patients was 13 months. Durable responses and survival observed in patients who received JCAR015 were comparable between groups that received a subsequent stem cell transplant and those that did not.
Severe cytokine-release syndrome was observed in 14 of 51 patients (27%) and grade 3 or higher neurotoxicity was observed in 15 of 51 patients (29%). For patients with minimal disease, 1 of 20 patients (5%) experienced severe cytokine-release syndrome, and 4 of 20 patients (20%) had grade 3 or higher neurotoxicity.
Juno’s CAR and T-cell receptor (TCR) technologies genetically engineer T cells to recognize and kill cancer cells. The CAR T-cell technology inserts a gene for a particular CAR into the T cell, enabling it to recognize cancer cells based on the expression of a specific protein located on the cell surface. The TCR technology provides the T cells with a specific T-cell receptor to recognize protein fragments derived from either the surface or inside the cell. When either type of engineered T cell engages the target protein on the cancer cell, it initiates a cell-killing response against the cancer cell.
Juno’s trials and plans for its other CD19-directed CAR T-cell product candidates, including JCAR017, have not been affected by the FDA clinical hold. ■