information: Presentation of results at a congress
Announcement: presentation of results at the European Hematology Association (EHA) Annual Meeting
Company: Novartis (Switzerland)
Product: CTL019 - tisagenlecleucel-T
mechanism: cell therapy/gene therapy/CAR-T cell therapy. CTL019 is an investigational, personalized T cell therapy, which was pioneered by Carl June and his team at Penn. In a CTL019 treatment cycle, immune cells (T cells) are drawn from a patient's blood. Then, using CAR technology, the T cells are reprogrammed to "hunt" cancer cells that express specific proteins, called CD19. CD19 is associated with a number of B-cell malignancies including ALL, CLL, diffuse large B-cell lymphoma, follicular lymphoma and mantle cell lymphoma. When the T cells are re-introduced into the patient's blood, the cells proliferate and bind to the targeted cancer cells and destroy them. These autologous T cells transduced with lentiviral vector containing a chimeric antigen receptor directed against CD19 were previously known as CART19.
In July 2014, the FDA designated CTL019 as a Breakthrough Therapy for the treatment of pediatric and adult patients with r/r ALL under the Penn IND. Novartis and Penn have an exclusive global agreement to research, develop and commercialize personalized CAR T cell therapies for the treatment of cancers. Novartis holds the worldwide rights to CARs developed through the collaboration for all cancer indications, including the lead program CTL019.
Disease: B-cell acute lymphoblastic leukemia
area: Cancer - Oncology
Country: Australia, Austria, Belgium, Canada, France, Germany, Italy, Japan, Norway, Spain, USA
- ELIANA 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.
- 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.(NCT02435849)
- • On June 23, 2017, 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). These 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. Results from this study of CTL019 will be presented at the European Hematology Association (EHA) Annual Meeting (Abstract #S476).
- 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. 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.
- A pooled data analysis from two multicenter trials of CTL019 in pediatric and young adult patients with r/r B-cell ALL, including ELIANA and ENSIGN (NCT02228096), will also be highlighted in a presentation at the meeting. This research is aimed to identify any new safety issues with CTL019 as a result of its use in multicenter trials, which included 25 sites across 11 countries. Study authors concluded that there were no new safety issues and that CRS and neurologic events were effectively managed. Prolonged follow-up will be required to determine the long-term safety of B-cell aplasia (Abstract #P517; Saturday, June 24, 5:30 PM CEST).
An oral presentation will feature pooled analyses from two multicenter trials of CTL019 in pediatric and young adult patients with r/r B-cell ALL, including ELIANA and ENSIGN, observing response analysis and impact of intrinsic/extrinsic and manufacturing factors on CTL019 expansion and persistence (Abstract #S477; Saturday, June 24, 4:15 PM CEST).
- • On December 4, 2016, Novartis has presented results from first global registration trial (ELIANA) of CTL019 in pediatric and young adult patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (ALL) at the 58th American Society of Hematology (ASH) annual meeting (Abstract #221, December 3, 4:00-5:30 p.m.). The global Phase II study found that 82% (41 of 50) of infused patients achieved complete remission or complete remission with incomplete blood count recovery at three months post CTL019 infusion. For all patients with complete remission, no minimal residual disease was detected. In addition, the estimated relapse-free rate among responders was 60% (95% CI: 36, 78) six months after infusion with CTL019. The results set the stage for filing CTL019 with the FDA in early 2017 for pediatric and young adult patients with r/r B-cell ALL.
ELIANA is the first pediatric global CAR T cell registration trial with study enrollment having occurred across 25 centers in the US, EU, Canada, Australia and Japan. Forty-eight 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 on a global scale using prior site education with implementation of the CRS treatment algorithm. There were no deaths due to CRS. Fifteen percent of patients experienced grade 3 neurological and psychiatric events including encephalopathy and delirium, with no grade 4 events seen.
In addition to filing CTL019 for approval with the FDA in early 2017, Novartis plans to file with the European Medicines Agency (EMA) later in 2017. The investigational therapy received PRIME (PRIority MEdicines) designation from the EMA.