FDA News

FDA advisory committee supports CTL019 for pediatric, young adult leukemia

An FDA advisory committee today unanimously expressed its support for the chimeric antigen receptor T-cell product tisagenlecleucel-T suspension for patients aged 3 to 25 years with relapsed/refractory B-cell acute lymphoblastic leukemia.

The Oncologic Drug Advisory Committee (ODAC) voted 10-0 in support of the favorability of the product’s benefit–risk profile.

If the FDA follows the committee’s guidance, tisagenlecleucel-T suspension (Novartis) — also known as CTL019 — would become the first approved chimeric antigen receptor (CAR) T-cell therapy.

The product is comprised of genetically modified T cells that target CD19, an antigen expressed on the surface of B cells.

“This is the most exciting advance I’ve seen in my lifetime, and since multiagent care — as it was once called — for childhood leukemia in the 1950s,” Timothy P. Cripe, MD, PhD, FAAP, CPI, voting member of ODAC and professor and chief in the division of hematology/oncology/bone marrow transplantation at Nationwide Children’s Hospital at The Ohio State University, said after the vote.

Stephan Grupp
Stephen Grupp

Efficacy

Tisagenlecleucel induced deep and durable remissions in this population of pediatric and young adult patients, for which there is a high unmet need, according to Stephan Grupp, MD, PhD, director of the cancer immunotherapy program, director of translational research for the Center for Childhood Cancer Research and medical director of the stem cell laboratory at Children’s Hospital of Philadelphia.

“Modern therapy serves many patients very well, but those who are left behind by modern therapy have very few treatment options,” Grupp, who has served as a researcher on CTL019 studies, said during the applicant presentations. “Getting relapsed patients back into remission is getting harder and harder. We do not transplant pediatric patients unless they are in remission. This means hitting them with very intensive chemotherapy over and over, requiring weeks and months in the hospital with extraordinarily levels of morbidity and some mortality. For that reason, the current treatment options are just not adequate.”

Results of the phase 2 ELIANA study formed the basis of Novartis’ application for tisagenlecleucel. Among 63 patients who received a single infusion of tisagenlecleucel, researchers reported an overall response rate of 82.5% (95% CI, 70.9-91). All responding patients showed no minimal residual disease.

However, FDA briefing materials indicated effectiveness of the product was not the “primary issue for consideration” by ODAC. Rather, the committee focused on manufacturing and safety issues.

Product quality, safety

The committee discussed the design of the CAR construct and viral vector, as well as the expression of CAR expression and T-cell activity through the number of transduced T cells per cell, vector copies per cell and antigen-specific T-cell function.

Several committee members expressed concern that heterogeneity of T-cell subpopulations in the final product could lead to varying safety and efficacy outcomes.

“I have concerns that you are not getting 100% CD3 T cells in your final product,” Catherine M. Bollard, MBChB, MD, chief of division of allergy and immunology, director of program for cell enhancement and technologies for immunotherapy at Children’s National Medical Center at The George Washington University, and voting member of ODAC, said during the committee discussion. “[Although] there are clearly some [natural killer] cells, what are the other cells remaining? What you’re starting with is a very heterogenous material. How can we increase that purity in terms of absolute T-cell numbers to 100%, if possible?”

The committee also discussed the potential safety concern of replication-competent retrovirus and insertional mutagenesis, which could cause secondary malignancies.

“If there are multiple batches of the vector, there is the potential for batch-to-batch variability for how that vector performs functionally,” Bollard said.

The problem of insertion mutagenesis relates to the importance of product purity, Bollard added. “We cannot guarantee that we’re transfusing mature T cells,” she said. “[Although] I do acknowledge that it is laudable that Novartis will look for vectors in individuals with secondary malignancies, we should extend that to patients who are relapsing with leukemia with a different immunophenotype or genotype.”

All 68 patients infused with tisagenlecleucel were included in the safety analysis of ELIANA. Grade 3 or grade 4 cytokine release syndrome occurred in 32 patients (47%), but no deaths occurred due to cytokine release syndrome.

Thirty patients experienced neurological toxicities, which included encephalopathy, delirium, hallucinations, somnolence, cognitive disorder, seizure, depressed level of consciousness, mental status changes, dysphagia, muscular weakness and dysarthria.

The conduct of this trial demonstrated that tisagenlecleucel can safely and effectively be used beyond just a single trial site, after additional centers have been trained on proper handling of the product and adverse event management, Grupp said.

“We’ve treated so many patients at this point that we have a pretty good understanding of the adverse events,” he said.

Although long-term safety concerns exist for generation of replication-competent retrovirus and new malignancies from insertional mutagenesis, safety assessments from ELIANA did not identify risks from clonal outgrowth and vector-mediated delayed adverse. Longer follow-up will be necessary to assess these risks, according to the FDA briefing documents.

Future implementation

Upon approval, Novartis would introduce tisagenlecleucel in 30 to 35 sites across the United States. The company plans to train each center on processes for cell collection, cryopreservation, transport, safety management and logistics.

Safety management would involve an algorithm for infusion reactions and cytokine release syndrome management — developed and refined during the trials of tisagenlecleucel — which involves risk mitigation measures and close monitoring to allow early intervention and use of supportive care measures.

Patients and caregivers would be required to stay within 2 to 3 hours of the treatment center for several weeks after treatment.

Novartis is also planning to conduct a long-term postmarketing study with an observational registry, and to collect and evaluate tissue samples from patients who develop a secondary malignancy.

“This is a high-risk approach for a disease with very few alternative options,” Bruce J. Roth, MD, ODAC chairman and professor of medicine in the division of oncology at Washington University School of Medicine, said after the vote. “I still have concerns about late toxicity, but a patient has to be a long-term survivor for late toxicity, and [long-term survival] is what this drug gives us.”

The FDA is not required to follow the opinion of the advisory committee when making its final decision, but the agency often does so. A decision is anticipated by late September. – by Alexandra Todak

Disclosure: Grupp reports research support from Novartis. HemOnc Today could not confirm the other committee members’ financial disclosures at the time of reporting.

An FDA advisory committee today unanimously expressed its support for the chimeric antigen receptor T-cell product tisagenlecleucel-T suspension for patients aged 3 to 25 years with relapsed/refractory B-cell acute lymphoblastic leukemia.

The Oncologic Drug Advisory Committee (ODAC) voted 10-0 in support of the favorability of the product’s benefit–risk profile.

If the FDA follows the committee’s guidance, tisagenlecleucel-T suspension (Novartis) — also known as CTL019 — would become the first approved chimeric antigen receptor (CAR) T-cell therapy.

The product is comprised of genetically modified T cells that target CD19, an antigen expressed on the surface of B cells.

“This is the most exciting advance I’ve seen in my lifetime, and since multiagent care — as it was once called — for childhood leukemia in the 1950s,” Timothy P. Cripe, MD, PhD, FAAP, CPI, voting member of ODAC and professor and chief in the division of hematology/oncology/bone marrow transplantation at Nationwide Children’s Hospital at The Ohio State University, said after the vote.

Stephan Grupp
Stephen Grupp

Efficacy

Tisagenlecleucel induced deep and durable remissions in this population of pediatric and young adult patients, for which there is a high unmet need, according to Stephan Grupp, MD, PhD, director of the cancer immunotherapy program, director of translational research for the Center for Childhood Cancer Research and medical director of the stem cell laboratory at Children’s Hospital of Philadelphia.

“Modern therapy serves many patients very well, but those who are left behind by modern therapy have very few treatment options,” Grupp, who has served as a researcher on CTL019 studies, said during the applicant presentations. “Getting relapsed patients back into remission is getting harder and harder. We do not transplant pediatric patients unless they are in remission. This means hitting them with very intensive chemotherapy over and over, requiring weeks and months in the hospital with extraordinarily levels of morbidity and some mortality. For that reason, the current treatment options are just not adequate.”

Results of the phase 2 ELIANA study formed the basis of Novartis’ application for tisagenlecleucel. Among 63 patients who received a single infusion of tisagenlecleucel, researchers reported an overall response rate of 82.5% (95% CI, 70.9-91). All responding patients showed no minimal residual disease.

However, FDA briefing materials indicated effectiveness of the product was not the “primary issue for consideration” by ODAC. Rather, the committee focused on manufacturing and safety issues.

PAGE BREAK

Product quality, safety

The committee discussed the design of the CAR construct and viral vector, as well as the expression of CAR expression and T-cell activity through the number of transduced T cells per cell, vector copies per cell and antigen-specific T-cell function.

Several committee members expressed concern that heterogeneity of T-cell subpopulations in the final product could lead to varying safety and efficacy outcomes.

“I have concerns that you are not getting 100% CD3 T cells in your final product,” Catherine M. Bollard, MBChB, MD, chief of division of allergy and immunology, director of program for cell enhancement and technologies for immunotherapy at Children’s National Medical Center at The George Washington University, and voting member of ODAC, said during the committee discussion. “[Although] there are clearly some [natural killer] cells, what are the other cells remaining? What you’re starting with is a very heterogenous material. How can we increase that purity in terms of absolute T-cell numbers to 100%, if possible?”

The committee also discussed the potential safety concern of replication-competent retrovirus and insertional mutagenesis, which could cause secondary malignancies.

“If there are multiple batches of the vector, there is the potential for batch-to-batch variability for how that vector performs functionally,” Bollard said.

The problem of insertion mutagenesis relates to the importance of product purity, Bollard added. “We cannot guarantee that we’re transfusing mature T cells,” she said. “[Although] I do acknowledge that it is laudable that Novartis will look for vectors in individuals with secondary malignancies, we should extend that to patients who are relapsing with leukemia with a different immunophenotype or genotype.”

All 68 patients infused with tisagenlecleucel were included in the safety analysis of ELIANA. Grade 3 or grade 4 cytokine release syndrome occurred in 32 patients (47%), but no deaths occurred due to cytokine release syndrome.

Thirty patients experienced neurological toxicities, which included encephalopathy, delirium, hallucinations, somnolence, cognitive disorder, seizure, depressed level of consciousness, mental status changes, dysphagia, muscular weakness and dysarthria.

The conduct of this trial demonstrated that tisagenlecleucel can safely and effectively be used beyond just a single trial site, after additional centers have been trained on proper handling of the product and adverse event management, Grupp said.

“We’ve treated so many patients at this point that we have a pretty good understanding of the adverse events,” he said.

Although long-term safety concerns exist for generation of replication-competent retrovirus and new malignancies from insertional mutagenesis, safety assessments from ELIANA did not identify risks from clonal outgrowth and vector-mediated delayed adverse. Longer follow-up will be necessary to assess these risks, according to the FDA briefing documents.

PAGE BREAK

Future implementation

Upon approval, Novartis would introduce tisagenlecleucel in 30 to 35 sites across the United States. The company plans to train each center on processes for cell collection, cryopreservation, transport, safety management and logistics.

Safety management would involve an algorithm for infusion reactions and cytokine release syndrome management — developed and refined during the trials of tisagenlecleucel — which involves risk mitigation measures and close monitoring to allow early intervention and use of supportive care measures.

Patients and caregivers would be required to stay within 2 to 3 hours of the treatment center for several weeks after treatment.

Novartis is also planning to conduct a long-term postmarketing study with an observational registry, and to collect and evaluate tissue samples from patients who develop a secondary malignancy.

“This is a high-risk approach for a disease with very few alternative options,” Bruce J. Roth, MD, ODAC chairman and professor of medicine in the division of oncology at Washington University School of Medicine, said after the vote. “I still have concerns about late toxicity, but a patient has to be a long-term survivor for late toxicity, and [long-term survival] is what this drug gives us.”

The FDA is not required to follow the opinion of the advisory committee when making its final decision, but the agency often does so. A decision is anticipated by late September. – by Alexandra Todak

Disclosure: Grupp reports research support from Novartis. HemOnc Today could not confirm the other committee members’ financial disclosures at the time of reporting.