CTL019 Highly Effective in Global Phase II ALL Study, FDA Submission Anticipated

Stephan Grupp, MD, PhD

The CAR T-cell therapy CTL019 demonstrated an 82% complete remission (CR) or CR with incomplete blood count recovery (CRi) rate for pediatric and young adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL), according to findings from the global, phase II ELIANA study presented at the 2016 ASH Annual Meeting.

The phase II study enrolled patients at 25 centers in the United States, Europe, Asia, and Australia. In the first 50 patients enrolled, the CR rate was 68% and the CRi rate was 14%. All patients with a CR/CRi also tested negative for minimal residual disease (95% CI, 69-91; P <.0001). The 6-month overall survival rate was 89% (95% CI, 76-95) and the disease-free survival rate was 60%.

"There was high efficacy, with the primary endpoint met. All complete remissions were MRD-negative and durable," said lead investigator Stephan Grupp, MD, PhD, the Yetta Deitch Novotny Professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania. "These global multicenter trial data build on earlier encouraging research conducted at a single trial site, and advance the case for CTL019 as a potential treatment for children and young adults with relapsed or refractory B-cell ALL.”

Novartis, the company developing the CAR T-cell therapy, plans to submit regulatory applications to the FDA and European Medicines Agency (EMA) for CTL019 as a treatment for pediatric and young adult patients with relapsed/refractory B-cell ALL, based on findings from ELIANA. The company expects to complete the submissions in early 2017.

"We are committed to advancing CTL019 and look forward to working closely with the FDA and EMA in the coming months," Bruno Strigini, CEO, Novartis Oncology, said in a statement. "This first-of-its-kind trial represents exciting progress toward our goal of helping children and young adults with relapsed or refractory B-cell ALL, a patient population with an urgent need for new treatment options."

The ELIANA study enrolled 81 patients, of which 5 are 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 CTL019.

All patients received lymphodepleting chemotherapy prior to infusion of CTL019. 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 CTL019 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 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%).

Forty-four patients continue to be followed in the study. 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 CTL019 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 CTL019. 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%).

"There were no new safety findings compared to prior CTL019 data,” said Grupp. “The single center data was confirmed in a worldwide multicenter trial,” he concluded.

CTL019 has received a breakthrough therapy designation from the FDA and a PRIME designation from the EMA. Both designations are meant to speed up the development of promising new therapies for unmet needs. Under these programs, Novartis will be eligible for a rolling submission of data for the CTL019 regulatory application.

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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CTL019 was manufactured in the United States at a Novartis facility for all patients, even those in Europe and Asia Pacific. In some instances, 41 days elapsed from the time of enrollment to infusion. "This was a global trial, with most eligible patients able to receive CTL019 in a timely manner utilizing central manufacturing," Grupp noted.