On October 15, 2014 Novartis and the University of Pennsylvania’s Perelman School of Medicine (Penn) reported preliminary results from two pilot clinical trials published in The New England Journal of Medicine (NEJM) evaluating the efficacy and safety of CTL019 in patients with relapsed/refractory acute lymphoblastic leukemia (r/r ALL) (Press release Novartis, OCT 15, 2014, View Source [SID:1234500834]). The studies, conducted by Penn, demonstrated that 27 of 30 pediatric and adult patients, or 90%, experienced complete remissions with the investigational chimeric antigen receptor (CAR) therapy CTL019.

“These interim results, which supported the recent FDA Breakthrough Therapy designation, reinforce the potential CTL019 has as a life-saving therapy for patients with relapsed/refractory ALL,” said Usman Azam, Global Head, Cell & Gene Therapies Unit, Novartis Pharmaceuticals. “These studies are another promising development in CTL019’s history. With each new CTL019 milestone, we are one step closer to potentially offering these seriously ill patients an additional treatment option.”

These data build on earlier research findings and are part of two pilot clinical studies that demonstrated sustained remissions of up to two years in pediatric and adult patients with r/r ALL. Median follow-up was just over six months, with event-free survival of 67% and overall survival of 78%. Probability of six-month CTL019 persistence was 68% and CTL019-modified T cells were detectable in the blood by flow cytometry for up to 11 months. Sustained remissions were seen in 15 patients and were associated with CAR T cell persistence and B cell aplasia. Updated results have been submitted for presentation at a medical congress taking place later in 2014.

“We are excited by these results, which indicated how effective CTL019 may be in fighting ALL, a leading cause of childhood cancer deaths,” said lead investigator Stephan Grupp, MD, PhD, the Yetta Deitch Novotny Professor of Pediatrics in the Perelman School of Medicine at the University of Pennsylvania and director of Translational Research in the Center for Childhood Cancer Research at the Children’s Hospital of Philadelphia (CHOP), where 25 pediatric patients were treated in the study cohort[1]. “This represents the largest experience to date of CD19-CAR T cells and demonstrates the ability of this approach to achieve sustained complete responses in a patient population with few other treatment options. We are especially hopeful for those patients who remain in remission for 1-2 years without further therapy.”

In July 2014, the FDA designated CTL019 as a Breakthrough Therapy under the Penn IND, which is intended to expedite the development and review of drugs that treat serious or life-threatening conditions if the therapy has demonstrated substantial improvement over an available therapy on at least one clinically significant endpoint[3].

Novartis holds the worldwide rights to CARs developed through the collaboration with Penn for all cancer indications, including the lead program, CTL019.

About These Studies
Twenty-five patients enrolled in the pediatric pilot trial at CHOP and 5 patients enrolled in the adult pilot trial at Penn from April 2012 to February 2014. The patients were infused with autologous T cells transduced with a CD19-directed CAR (CTL019) lentiviral vector at doses of 0.7-20.6×106 CTL019 cells/kg. The study found that 27 of 30 pediatric and adult patients with r/r ALL (90%) experienced complete remissions, including two blinatumomab-refractory patients and 15 with prior stem cell transplant.

Of the 27 patients who achieved a complete remission, five went off-study for alternate therapy, three of whom proceeded to allogeneic SCT in remission. Fifteen patients remain in remission with a median follow-up of seven months. Sustained remissions were achieved up to two years with six-month event-free survival 67% (95% CI, 51% to 88%) and overall survival 78% (95% CI, 65% to 95%). The probability of six-month CTL019 persistence was 68% (95% CI, 50 to 92%) and relapse-free B cell aplasia was 73% (95% CI, 57 to 97%). CTL019-modified T cells were detectable in the blood by flow cytometry for up to 11 months, and CTL019 sequences remained detectable by quantitative PCR (Q-PCR) in patients with sustained remissions for up to two years.

All patients experienced cytokine release syndrome (CRS). Of the 30 patients, 74% (n=22) experienced mild to moderate CRS. Severe CRS, seen in 27% of patients (n=8), was associated with higher disease burden and effectively treated with the IL-6 receptor antibody tocilizumab. Several patients experienced neurologic toxicities, which fully resolved without further intervention or apparent long-term implications.