FDA Pushes Pause on 2 Regeneron Lymphoma Trials for Cytokine Release Syndrome
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Regeneron Pharmaceuticals reported that it is pausing enrollment in two of its clinical trials for odronextamab for lymphoma. The U.S. Food and Drug Administration (FDA) placed a partial clinical hold on the trials, requesting Regeneron modify protocols to decrease the occurrence of cytokine release syndrome in patients.
Cytokine release syndrome is a massive, rapid inflammatory overreaction by the immune system where it releases cytokines. It can potentially be fatal.
Regeneron indicated that the FDA decision also impacts an early-stage trial of odronextamab in B-cell non-Hodgkin lymphomas (B-NHL) and chronic lymphocytic leukemia. They have also paused enrollment in another Phase II trial of the drug in sub-types of B-NHL. It plans to submit the modified protocols to the agency in the first quarter of 2021.
Odronextamab is a CD20xCD3 bispecific antibody.
The company stated, “Patient safety is of the utmost concern to Regeneron.”
On December 5, the company reported updated data for REGN5458, its BCMAxCD3 bispecific antibody, from the Phase I part of a Phase I/II trial of relapsed or refractor (r/r) multiple myeloma. The company also updated results from the Phase I odronextamab clinical trial in r/r follicular lymphoma, diffuse large B-cell lymphoma and other B-cell NHLs. Both REGN5458 and odronextamab were developed using the company’s proprietary VelocImmune technology and its Veloci-Bi platform. The platforms let the company create bispecific antibodies that closely resemble natural human antibodies without the use of linkers or artificial sequences. It also allows for manufacturing using similar approaches as those used for human monoclonal antibody therapies, such as the company’s antibody cocktail against COVID-19.
BCMA is usually over-expressed on multiple myeloma cells. REGN5458 is engineered to bind to BCMA on MM cells and the CD3 receptor on T-cells to bridge them together and activate T-cells to kill the cancer cells.
In the trial, the 49 patients had a median of five previous lines of therapy with 100% being triple-refractory and 57% being penta-refractory. All patients were refractory to anti-CD38 therapy. The median follow-up was 2.6 months, and responses typically occurred by week 4.
“REGN5458 continues to show early, deep and durable anti-tumor responses in patients with relapsed and refractory multiple myeloma across all dose levels,” said Deepu Madduri, assistant professor of Medicine at the Icahn School of Medicine at Mount Sinai in New York and a trial investigator. “This is particularly encouraging given that a majority of patients were heavily pretreated and had few options remaining. All patients were triple-refractory, with 57% being penta-refractory. As these data continue to mature, we look forward to assessing whether responses will further deepen and remain durable with ongoing REGN5458 treatment.”
As with the odronextamab trials, the most common adverse events were cytokine release syndrome, as well as anemia, fatigue, nausea, pyrexia and back pain.
At the time, Andres Sirulnik, senior vice president, Translational & Clinical Sciences, Hematology at Regeneron, said, “REGN5458 is the second CD3 bispecific in our oncology portfolio to show clinically meaningful results. Alongside our CD20xCD3 bispecific odronextamab, REGN5458 offers additional evidence to support the potential of our bispecific platform to transform the treatment of diverse blood cancers for patients.”
Data on odronextamab’s Phase I trial was presented at the 2020 ASH Annual Meeting & Exposition. Data demonstrated that in patients who previously received CAR T-cell therapy, the objective response rate (ORR) was 33% and the complete response (CR) was 21%. CRs seemed durable, with 100% of CRs still ongoing. One patient maintained a CR for 20 months, which as of December 6 was still ongoing.
“Odronextamab is a novel CD20xCD3 bispecific antibody which offers an off-the-shelf, primarily outpatient treatment option for patients with relapsed/refractory B-NHL,” said Rajat Bannerji, chief of Hematologic Malignancies at Rutgers Cancer Institute of New Jersey, in a virtual presentation at the meeting. “In this first-in-human Phase I trial, odronextamab has demonstrated compelling antitumor activity, including durable complete responses in heavily pretreated patients with follicular lymphoma and DLBCL.”
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