Harmonized case report forms for clinical trials on a broad range of immunotherapies (including monoclonals, CAR-T cell therapies and T-cell engagers) should be used to better track the rates of cytokine release syndrome—and to distinguish CRS from other adverse events related to the use of the new therapies, according to a white paper from an industry-academia-regulator group convened by Friends of Cancer Research.
A dedicated case report form would be key to getting investigators to “commit to harmonized data collection” for “newer” immunotherapies, the group says. “A standardized approach is needed for diagnosing and reporting CRS [cytokine release syndrome] and its manifestations in clinical trials, published literature, and in clinical practice.”
“More importantly,” the white paper says, “there is a need to distinguish CRS from other clinical entities, such as acute infusionrelated reactions (IRR).”
The effort to find common ground in the active and highly competitive area of oncology research is an ambitious endeavor: side effect profiles with the different types of novel immunotherapies may be key areas of differentiation among products.
The six firms participating in the working group bought into the need to “enable a more precise evaluation of the therapeutic riskbenefit profile” of the new therapies. The six firms represented on the working group were Amgen, Bristol Myers, Genentech, Gilead/Kite, Regeneron, and Xencor. Novartis, marketer of the first FDA approved CAR-T therapy, did not have a representative listed on the group.
Genentech Group Medical Director-Safety Science Bruce McCall pointed out during a February 11 webinar tied to the release of the white paper that the “explosion of development” among immunotherapies is highlighting the need to coordinate systems for collecting safety data and rating scales for severity. He noted that three difference severity rating systems were used on the four recently approved novel immunotherapies (three CAR-Ts and one T-cell engager).
The white paper lists six grading systems that have evolved for CRS and notes some coalescence around a scale from the American Society for Transplantation and Cellular Therapy. “An informal sponsor survey,” the white paper says, “indicated that out of eight sponsors, seven are utilizing/planning to utilize ASTCT criteria for new protocols.”
Amgen VP-Global Development PK Morrow said that immune-oncology field is “still in adolescence” and there is a continuing development in “understanding of cytokine release syndrome and other complications of IO therapies.”
She pointed out that “it can be increasingly difficult to adequately compare safety across programs, making sure that we are comparing apples-to-apples, given the differences in the CRS criteria and the data capture elements. Thus, it is really, really critical that we arrive at a harmonized approach for grading CRS. That highly impacts the potential for appropriate CRS mitigation and prevention, ultimately, and it can affect dosing.”
UnitedHealthcare Senior Medical Director-Oncology and Genetics Jennifer Malin pointed out the complications for providers from the varying descriptions of adverse events associated with different immunotherapies, especially CRS syndrome. She noted that the cost of recovery from an immunotherapy treatment is part of the coverage decision for a payer. There is a need for comparability of data on safety and extent of reactions to different products, she suggested.
Duke-Margolis Director Mark McClellan looked at the commercial dynamics around immunotherapies from a different perspective, suggesting that hospitals are likely to learn to compete on the ability to manage the reactions to specific treatments, creating a “race to the top” among providers. However, he said that still puts pressure on collecting more standardized data on the adverse effects associated with immunotherapies.
The white paper outlines an approach for recording symptoms as separate adverse events and making sure that the symptoms are eventually designated to a correct syndrome if they fit as part of a broader diagnosis.
The paper urges development of “a comprehensive method to capture all the events and link those AEs that are signs and symptoms of CRS to the CRS event. Such that CRS is the AE, but the symptoms (fever, LFT [liver function tests] increase, seizure) that are AEs in themselves are attributable to CRS and are linked to the CRS event.”
FDA Office of Oncology Drugs Acting Associate Director of Safety Meredith Chuk described the appeal of both broadly collecting symptoms and then pulling them together into appropriate syndromes.
“One of the elements of the white paper that stood out most to me,” Chuk said, “was the call to collect data to the granular level enough that you could both uncover the individual components of a syndrome such as CRS but then be able to collapse them down at the end once you have more robust data to essentially call it that syndrome. I think it is really critical to be able to capture the fever, the hypoxia, the hypotension and then be able to link that back to the CRS event.” She also said it is “critical” to be “able to link in interventions under clinical trials for patients and link the outcomes for those interventions.”
Chuk was one of the five FDA representatives in the working group. She joined Marc Theoret (a deputy director of the Oncology Center of Excellence), Bindu George (CBER, clinical hematology branch chief), Nicole Gormley (acting director of the Division of Hematologic Malignancies 2), and Ke Liu (an associate director at OCE for cell and gene therapy and CBER oncology branch chief).
FDA’s Center for Biologics Evaluation and Research Director Peter Marks also participated in the webinar, although he focused on a different emerging issue for CAR-T therapies: the need to streamline regulatory processes to permit evolution of cell production technologies. (See our related Feb. 17 note, CAR-T Manufacturing Changes: FDA Drafting Policy To Streamline Process, Wants To Avoid Stifling Innovation.)
Chuk recently has been assigned on detail to HHS to advise on monoclonals for COVID – an example of the continuing staff reallocations caused by the COVID response. In this case, HHS is taking a senior staff person from the oncology area to deal with the issues of slow uptake of the three FDA authorized monoclonal antibody cocktails for COVID. The white paper identifies the minimum signs and symptoms to be collected as including “fever, nausea, chills, vomiting, diarrhea, confusion, dizziness, dyspnea, tachycardia, headache, hypotension, [and] hypoxia” but also calls for the case report form to “allow an investigator to enter any symptom thought to be a CRS symptom.” Information on interventions that should be collected as part of the harmonized data would address hypotension and hypoxia management, the level of care (hospital, ICU), and drugs to treat the reactions: “Tocilizumab or other cytokine-directed therapy administered for management, as well as corticosteroids other supportive care, such as antipyretics, and type of prophylaxis, if any.” Chuk said that the collection of discrete data elements would be helpful as FDA is “developing risk mitigation strategies” and will permit those strategies to “be data driven.” FDA would like to “be able to build a story from the data that we are collecting in the clinical trials. If we do that in a robust way, we will address the ultimate goal that everyone is striving for to maximize patient safety is to build predictive models,” Chuk said.
“We want to be able to know which patients are most likely not only to benefit from therapy but to have the toxicity so that we can potentially tailor some of the mitigation strategies for those particular patients. We are never going to get there unless we do very detailed and granular data collection early on in the development program,” Chuk added.
Chuk also highlighted the advice in the white paper to sponsors to begin collecting CRS and IRR data in a coordinated form from the earliest clinical trials.
The white paper suggests that “for therapeutic classes that are known to be associated with CRS or at particularly high risk for inducing CRS based on mechanism of action or preclinical data, the implementation of a dedicated clinical and safety monitoring plan may be required from the onset. The potential risks of IRR and CRS should be defined in the Investigator Brochure and protocol for the first-in-human trial,” with a dedicated case report form (CRF) for IRR/CRS that collects the associated signs and symptoms.
Chuk said from a regulatory perspective it is critical to be collecting the safety data aimed at CRS and IRR “in those early phase taking preclinical information and from similar drugs in the class and trying to anticipate what the toxicities might be and then designing protocols, patient management, mitigation strategies, and collecting the data that really allows those interventions to be data driven.” The early focus in made more important because of the number of “expedited development programs that we are seeing, where those early phase trials often become the registration trials.”
What ends up in the approved product label, Chuk pointed out, “is what was done in those early trials. We are trying to standardize those common elements among the drugs in class.” That will also help to “get some evidence-based driven modification strategies – dose modification strategies – to put in the label so that patients and providers are really able to adequately access the benefits and risks.”