FDA Halts Multiple Immunotherapy Trials


Clinical holds placed on Keytruda, Opdivo trials due to adverse event concerns.

PD-1/PD-L1 inhibitors are under increased FDA scrutiny following risks observed in Keytruda clinical trials, which lead to multiple clinical trial holds.

Yesterday, Bristol-Myers Squibb (BMS) announced the FDA placed a partial clinical hold on the CheckMate-602, CheckMate-039, and CA204142 trials, which are all investigating nivolumab (Opdivo) combinations in patients with relapsed or refractory (r/r) multiple myeloma, according to a press release.

The trials are exploring combinations of nivolumab plus other drugs—such as elotuzumab, pomalidomide, dexamethasone, daratumumab—in both previously-treated and treatment-naïve patients with r/r multiple myeloma.

The partial hold on nivolumab trials is the result of risks identified in studies of pembrolizumab (Keytruda), another anti-PD-1 drug being tested in patients with multiple myeloma.

The FDA reviewed data from the KEYNOTE-183 and KEYNOTE-185 trials, which evaluated pembrolizumab as part of a combination therapy for multiple myeloma. On July 3, 2016, the FDA halted the clinical trials due to evidence that suggests pembrolizumab plus an immunomodulatory agent can result in an increased risk of death compared with the control group, according to the FDA.

The FDA determined that the risks of pembrolizumab for this population outweighed the potential benefits of treatment.

In response to this determination, the FDA began looking into other PD-1 inhibitors being explored as a combination therapy for multiple myeloma.

The FDA ruled that data from these studies indicates that PD-1/PD-L1 therapy plus pomalidomide or lenalidomide and PD-1/PD-L1 drugs as a monotherapy or in combination may be harmful to these patients, according to BMS.

Under the partial hold, patients enrolled in the 3 nivolumab clinical trials who are benefiting from the therapy may continue treatment, but BMS may not enroll any new patients, according to the release. BMS said that other clinical trials of nivolumab will continue as planned.

Celgene also announced that the FDA placed a partial clinical hold on 5 trials and a full clinical hold on 1 trial exploring durvalumab (Imfinizi), an anti-PD-L1 drug, in combination with immunomodulatory and chemotherapy agents in multiple myeloma and other blood cancers, such as chronic lymphocytic leukemia and diffuse large B cell lymphoma.

Thus far, Celgene has not determined any increased risk, according to a press release. The clinical hold allows the company to further investigate the potential risk of PD-L1 combinations in multiple myeloma.

Patients enrolled in the trials on partial hold may continue treatment if they are achieving clinical benefits, while patients in the trial on full hold will be discontinued, according to Celgene.

The trials on partial clinical hold are: MEDI4736-MM-001, MEDI4736-MM-003, MEDI4736-MM-005, MEDI4736-NHL-001, and MEDI4736-DLBCL-001. These studies explore durvalumab as a monotherapy or in combination with pomalidomide, dexamethasone, daratumumab, R-CHOP, or lenalidomide.

A full clinical hold was placed on MEDI4736-MM-002, which is examining durvalumab plus lenalidomide and dexamethasone in multiple myeloma patients.

Celgene reports that other studies of durvalumab will continue to enroll patients.

It is likely that other clinical trials exploring PD-1/PD-L1 agents may be placed on hold.

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