Novartis announced updated results from the ELIANA clinical trial demonstrating CTL019 (tisagenlecleucel) remission rates are maintained at six months in relapsed/refractory (r/r) pediatric and young adult patients with B-cell acute lymphoblastic leukemia (ALL).
Data from this pivotal trial of CTL019 show that 83% (52 of 63; 95% confidence interval [CI]: 71%-91%) of patients achieved complete remission (CR) or CR with incomplete blood count recovery within three months of infusion. No minimal residual disease (MRD) was detected among responding patients. MRD, which measures the elimination of residual disease in the blood and bone marrow at the molecular level following treatment, is important because it may be an indicator of potential relapse.
The ELIANA study also showed that the relapse-free probability was 75% (95% CI, 57%-87%; median duration of response not reached) at six months and 64% (95% CI, 42%-79%) at 12 months among responders. In addition, the probability of survival was 89% (95% CI, 77%-94%) at six months and 79% (95% CI, 63%-89%) at 12 months. The median time from infusion to data cutoff was 8.8 months.
"The updated CTL019 ELIANA data illustrating early observed response rates that have held steady over six months' time are exciting findings. Durability is an important measure for children and young adults with relapsed or refractory B-cell ALL, and we are truly encouraged by the results of this study," 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 (Penn), and Director of the Cancer Immunotherapy Frontier Program at the Children's Hospital of Philadelphia (CHOP).
Forty-seven percent of patients in ELIANA experienced grade 3 or 4 cytokine release syndrome (CRS), a known complication of the investigational therapy that may occur when the engineered cells become activated in the patient's body. CRS was managed globally using prior site education on implementation of the CRS treatment algorithm. There were no deaths due to refractory CRS and no incidents of cerebral edema were reported. Fifteen percent of patients experienced grade 3 neurologic events, with no grade 4 events seen.
The ELIANA trial enrolled 88 patients. Of the 88, 16 patients discontinued before infusion and the majority (nine patients) did so due to rapid progression of their disease or deterioration in their clinical status. This reflects the acute and progressive nature of this disease. Of the 16 patients who weren't infused, seven were a result of insufficiently formulated CAR-T cell product. Additionally, five infused patients had not reached three-month follow-up and four patients were pending infusion at the time of data cutoff.
ELIANA (NCT02435849) is the first pediatric global CAR-T cell therapy registration trial, with study enrollment having occurred across 25 centers in the US, Canada, EU, Australia and Japan. The single-arm, open-label, multicenter Phase II study included patients aged three to 23 years who were primary refractory, refractory to chemotherapy after their first relapse, relapsed after second line therapy or ineligible for an allogeneic stem cell transplant (SCT). Patients in the trial received a median of three prior lines of therapy and 59% of patients had a prior SCT.
CTL019 was first developed by Penn and uses the 4-1BB costimulatory domain to enhance cellular responses. In 2012, Novartis and Penn entered into a global collaboration to further research, develop and then commercialize CAR-T cell therapies, including CTL019, for the investigational treatment of cancers.
CTL019 was granted Priority Review from the FDA earlier this year in the treatment of r/r pediatric and young adult patients with B-cell ALL, and Novartis plans to file with the European Medicines Agency (EMA) later in 2017. The investigational therapy received PRIME (PRIority MEdicines) designation from the EMA in 2016. The FDA also granted Breakthrough Therapy designation to CTL019 for the treatment of adult patients with r/r DLBCL, whose disease has progressed on or after two or more prior therapies.
CAR-T is manufactured for each individual patient using their own cells. During the treatment process, T cells are drawn from a patient's blood and reprogrammed in the laboratory to create T cells that are genetically coded to hunt the patient's cancer cells and other B-cells expressing a particular antigen. In March 2017, Novartis announced that the FDA granted Priority Review for the company's Biologics License Application for CTL019 in the treatment of r/r pediatric and young adult patients with B-cell ALL.
Because CTL019 is an investigational therapy, the safety and efficacy profile has not yet been established. Access to investigational therapies is available only through controlled and monitored clinical trials. These trials are designed to better understand the potential benefits and risks of the therapy. Because of the uncertainty of clinical trials, there is no guarantee that CTL019 will ever be commercially available anywhere in the world.
Acute lymphoblastic leukemia makes up approximately 25% of cancer diagnoses among children under 15 years old and is the most common childhood cancer in the US. Patients with r/r ALL have limited treatment options, and the chance of survival for children with the disease who relapse or fail to attain remission is between 16% to 30.1%.