All FDA panel members go thumbs up for CTL019 in relapsed/refractory childhood ALL

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CTL019 rollout will be gradual
Helen Heslop, MD

The unanimous recommendation by the Food and Drug Administration's Oncologic Drugs Advisory Committee means that the FDA is likely to approve CTL019 (tisagenlecleucel-T), and that approval may come quickly, possibly before the end of 2017. This approval was based on compelling data showing that 83% of children and young adults with refractory or relapsed acute lymphocytic leukemia (ALL) achieved remission with this therapy. This is exciting news for ALL patients as well as for the cell and gene therapy community. What remains to be determined are the labelling for CTL019, the cost of the therapy, and whether all patients who might benefit from this therapy will have the coverage to be able to access it.

While the response rates in patients treated in the trials presented to the FDA are very encouraging there are also concerns with the risks for cytokine release syndrome and neurotoxicity which can affect up to half of treated patients. As a result, Novartis, the manufacturer of CTL019, has proposed an extensive mitigation strategy and education process for the cell therapy centers that will offer the therapy. Initially, this is likely to be limited to around 30 centers that will be geographically distributed throughout the United States with gradual roll out to more centers as there is more experience with the use of CTL019.

Another issue for the centers is going to be operationalizing a new paradigm where CTL019 will be offered as a standard of care rather than in the context of a research study. Most of the initial pediatric centers will likely provide CTL019, within their transplant infrastructure since procurement, initial processing and infusion of cells will utilize their cell processing and collection facilities. The Foundation for Accreditation of Cell Therapy (FACT) has also anticipated this approval by publishing new standards for Immune Effectors earlier this year to promote quality practice in immune effector cell administration.

One other question is whether CTL019 will be transplant enabling or transplant replacing. While the initial response rates are very high and there are some well publicized patients who remain in remission over 5 years after CTL019 without other therapy, other responders proceeded to transplant and there is also a significant relapse rate. It is therefore an open question whether treating physicians will be happy to watch patients who attain remission after this therapy or whether they will still recommend transplant because there is not yet enough follow up on this product to know what the long-term cure rate is going to be.

Another CAR T-cell product is scheduled to come before an FDA advisory committee in October. The indication for KTE-C19 (axicabtagene ciloleucel) from Kite is for relapsed/refractory diffuse large B-cell lymphoma, a much bigger indication with a potentially much larger number of patients. The response rates for KTE-C19 in DLBCL (and indeed for CTL019 in DLBCL) are not as high as those for CTL019 in ALL and follow-up time is shorter, so it is not yet clear how many patients will have sustained long term responses. Nevertheless the response rate in patients who have failed all other therapies is high enough that this product will also likely be approved.

Helen Heslop, MD, is the Dan L. Duncan Chair and Professor of Medicine and Pediatrics at Baylor College of Medicine, Houston. She also is the Director of the Center for Cell and Gene Therapy at Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital. Dr. Heslop is a member of the editorial advisory board of Hematology News.


The answer to the billion dollar question – Does the chimeric antigen receptor T-cell (CAR T) construct CTL019 (tisagenlecleucel-T) have a favorable risk-benefit profile for the treatment of children and young adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia? – was a unanimous “yes” at a July 12 meeting of the Food and Drug Administration’s Oncologic Drugs Advisory Committee.

“This is the most exciting thing I have seen in my lifetime, and probably since the introduction of ‘multiagent total cancer care,’ as it was called then, for treatment of childhood leukemia,” remarked Timothy P. Cripe, MD, PhD, from Nationwide Children’s Hospital in Columbus, Ohio, and a temporary voting member of the ODAC.

Catherine M. Bollard, MD, MBChB, from the Children’s National Medical Center in Washington, also a temporary ODAC member, said that she voted “yes” because “this is a very poor-risk patient population, this is an unmet need in the pediatric population, and as you saw in the data [presented to ODAC] today, the clinical responses are remarkable. I think Novartis [the maker of CTL019] has done a great job putting together a plan for mitigating risk going forward.”

CTL019 was shown in a pivotal phase 2 clinical trial to induce an overall remission rate of 83% in children and young adults with relapsed/refractory ALL for whom at least two prior lines of therapy had failed. Based on these results, the FDA accepted a biologics license application for the agent from Novartis.

At the meeting, panel members initially seemed favorably disposed toward recommending approval but heard concerns from FDA scientists about the potential for severe or fatal adverse events such as the cytokine release syndrome (CRS); the possible generation of replication competent retrovirus (RCR); and the potential for secondary malignancies from insertional mutagenesis, the incorporation of portions of the lentiviral vector into the patient’s genome.

In his opening remarks, Wilson W. Bryan, MD, from the FDA’s Office of Tissue and Advanced Therapies and Center for Biologics Evaluation and Drug Research, commented that “the clinical development of tisagenlecleucel suggests that this is a life-saving product.”

He went on, however, to frame the FDA’s concerns: “Clinical trials are not always a good predictor of the effectiveness and safety of a marketed product,” he said. “In particular, we are concerned that the same benefit and safety seen in clinical trials may not carry over to routine clinical use.”

The purpose of the hearing was to focus on manufacturing issues related to product quality, including replicability of the product for commercial use and safety issues such as prevention of CRS and neurotoxicities.

“We are also concerned about the hypothetical risk of secondary malignancies. Therefore, we are asking for the committee’s recommendations regarding the nature and duration of follow-up of patients who would receive this product,” Dr. Bryan said.

“CTL019 is a living drug, which demonstrates activity after a single infusion,” said Samit Hirawat, MD, head of oncology global development for Novartis.

But the nature of CTL019 as a living drug also means that it is subject to variations in the ability of autologous T cells harvested via leukapheresis to be infected with the lentiviral vector and expanded into a population of CAR T cells large enough to have therapeutic value, said Xiaobin Victor Lu, PhD, a chemistry, manufacturing, and controls reviewer for the FDA.

Mitigation plan

Novartis’ proposed plan includes specific, long-term steps for mitigating the risk of CRS and neurologic events, such as cerebral edema, the latter of which caused the FDA to call for a clinical hold of the phase 2 ROCKET trial for a different CAR T-cell construct.

Among the proposed elements of the mitigation plan are a 15-year minimum pharmacovigilance program and long-term safety follow-up for adverse events related to the therapy, efficacy, immunogenicity, transgene persistence of CD19 CAR, and the incidence of second malignancies possibly related to insertional mutagenesis.

Novartis also will train treatment center staff on processes for cell collection, cryopreservation, transport, chain of identity, safety management, and logistics for handling the CAR T-cell product. The company proposes to provide on-site training of personnel on CRS and neurotoxicity risk and management, as well as to offer information to patients and caregivers about the signs and symptoms of adverse events of concern.

Dr. Cripe expressed his concerns that Novartis’ proposal to initially limit the mitigation plan to 30 or 35 treatment sites would create problems of access and economic disparities among patients, and could cause inequities among treatment centers even with the same city.

David Lebwohl, MD, head of the CAR T global program for Novartis, said that the planned number of sites for the mitigation program would be expanded after 6 to 12 months if the CAR T construct receives final approval and clinical implementation goes well.

There was nearly unanimous agreement among the panel members that the planned 15-year follow-up and other mitigation measures would be adequate for detecting serious short- and long-term consequences of CAR T-cell therapy.

Patient/advocate perspective

In the public comment section of the proceedings, panel members were urged to vote in favor of CTL019 by parents of children with ALL, including Don McMahon, whose son Connor received the therapy after multiple relapses, and Tom Whitehead, father of Emily Whitehead, the first patient to receive CAR T cells for ALL.

Both children are alive and doing well.

CTL019 is produced by Novartis.

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