FDA Grants CTL019 Breakthrough Designation for DLBCL

April 18, 2017

The FDA has granted a breakthrough therapy designation to tisagenlecleucel-T (CTL019) for use as a treatment for adult patients with relapsed/refractory diffuse large B-cell lymphoma after the failure of at least 2 prior therapies.

Carl June, MD

The designation is based on results from the multicenter phase II JULIET study (NCT02445248). Novartis intends to present the trial findings at an upcoming medical meeting.

Breakthrough therapy designation is meant to expedite the development of promising medications that have shown preliminary signs of clinical efficacy. Under the program, the FDA will be more accessible, in order to provide advice on the design and conduct of the clinical development program.

“We are encouraged by the FDA's recognition in the potential of CTL019 for this indication, which follows our promising studies of this therapy for acute lymphoblastic leukemia (ALL) and the FDA filing by Novartis in pediatric and young adult ALL that received priority review,” said Carl June, MD, director of the Center for Cellular Immunotherapies in the Perelman School of Medicine at the University of Pennsylvania, where CTL019 was first developed. “Work with our collaborators at trial sites across the world is paving a path to bring personalized cell therapies to more patients with these devastating blood cancers.”

Tisagenlecleucel-T previously received a breakthrough therapy designation for the treatment of pediatric and young adult patients with relapsed/refractory B-cell ALL. Last month, the FDA granted a priority review designation to an application for tisagenlecleucel-T for use in this setting. Under the priority review program, the FDA will decide on the BLA for tisagenlecleucel-T within 6 months compared with the standard 10-month review.

The application is based primarily on findings from the global, phase II ELIANA study along with a multicenter trial conducted in the United States and a single institution trial. In findings presented at the 2016 ASH Annual Meeting for the first 50 patients enrolled in the ELIANA trial, the complete remission (CR) or CR with incomplete blood count recovery (CRi) rate was 82% with tisagenlecleucel-T, the 6-month overall survival rate was 89% (95% CI, 76-95), and the disease-free survival rate was 60%.

The ELIANA study enrolled patients at 25 centers in the United States, Europe, Asia, and Australia. At the time of the assessment, there were 81 participants in the study, of which 5 were awaiting infusion and 14 discontinued prior to infusion due to deaths (n = 5), manufacturing failures (n = 5), and adverse events (n = 3). The primary efficacy analysis was conducted after a median of 4.3 months of follow-up for the first 50 patients treated with tisagenlecleucel-T.

All patients received lymphodepleting chemotherapy prior to infusion of tisagenlecleucel-T. Fludarabine was administered at 30 mg/m2 daily for 4 doses and cyclophosphamide was given at 500 mg/m2 daily for 2 doses. The targeted dose of each tisagenlecleucel-T infusion was 2.0 to 5.0 x 106 kg for patients ≤50 kg and 1.0 to 2.5 x 108 for those >50 kg.

The CR rate was 68% with tisagenlecleucel-T, and 14% of patients had a CRi. All patients with a CR/CRi also tested negative for minimal residual disease (95% CI, 69-91; P <.0001).

Forty-four patients continue to be followed in the study at the time of the assessment. Eighteen discontinued follow-up due to deaths (n = 6), relapse (n = 5), starting a new therapy while in CR (n = 5), and patient or guardian decision (n = 2). There were 2 deaths within 30 days of treatment (1 from ALL and 1 from cerebral hemorrhage). There were no deaths related to cytokine release syndrome (CRS) and no cases of cerebral edema were reported.

Most adverse events (AEs) occurred during the first 8 weeks of treatment. Seventy-one percent of patients experienced AEs with tisagenlecleucel-T within the first 8 weeks of treatment, of which 68% were suspected to be related to treatment. After 8 weeks, the serious AE rate dropped to 17%, of which 2% were related to tisagenlecleucel-T. The rate of treatment-related grade 3/4 AEs dropped from 74% to 10%, before and after the 8-week mark, respectively.

Seventy-nine percent of patients experienced CRS, of which 21% was grade 3 and 27% was grade 4. CRS occurred within 3 days of treatment (range, 1-22) and lasted for a median of 8 days (range, 1-36). Fifty-nine percent of patients with CRS were admitted to the intensive care unit for a median of 8 days (range, 1-34). To resolve CRS, patients required treatment with anti-cytokine therapy (51%), high dose vasopressors (33%), invasive ventilation (20%), and dialysis (12%).

Other AEs of interest included cytopenias that did not resolve by day 28 (all-grades, 37%; grade 3, 11%; grade 4, 19%), infections (all-grades, 40%; grade 3, 23%; grade 4, 3%), transient neuropsychiatric events (all-grades, 45%; grade 3, 15%; grade 4, 0%), and tumor lysis syndrome (all-grades, 5%; grade 3, 5%; grade 4, 0%).

In a statement on the latest breakthrough designation for tisagenlecleucel-T, Vas Narasimhan, global head of drug development and chief medical officer, Novartis, said, “At Novartis, we are eager to unlock the full potential of CTL019, including the potential to help patients with relapsed/refractory DLBCL. We look forward to working closely with the FDA to help bring this potential new treatment option to patients as soon as possible."

Grupp SA, Laetsch TW, Buechner J, et al. Analysis of a global registration trial of the efficacy and safety of CTL019 in pediatric and young adults with relapsed/refractory acute lymphoblastic leukemia. 58th ASH Annual Meeting and Exposition; San Diego, California; December 2-6, 2016. Abstract 221.

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The median age of patients was 12 years (range, 3-23), and 55% were male. More than half (56%) had received a prior stem cell transplant, and the median number of prior lines of therapy was 3 (range, 1-8). Patients had primary refractory (10%), chemo refractory (11%), and relapsed ALL (79%).