The U.S. Food and Drug Administration (FDA) placed partial clinical holds on five trials and a full clinical hold on one trial of the PD-L1 inhibitor durvalumab in combination with other immunomodulatory agents with or without chemotherapy in patients with multiple myeloma (MM), chronic lymphocytic leukemia (CLL), or lymphoma.
The decision was based on risks identified in trials evaluating another PD-1 inhibitor, pembrolizumab, also being studied in combination with immunomodulatory agents in patients with MM. Earlier this year, the FDA placed holds on three clinical trials of pembrolizumab after safety monitors reported more deaths in the treatment arms than in the control arms.
The following trials evaluating durvalumab were placed on partial clinical hold:
- MEDI4736-MM-001: durvalumab either as monotherapy or in combination with pomalidomide with or without low-dose dexamethasone in patients with relapsed/refractory MM
- MEDI4736-MM-003: durvalumab plus daratumumab in patients with relapsed/refractory MM
- MEDI4736-MM-005: durvalumab plus daratumumab in patients with relapsed/refractory MM that progressed during a treatment regimen containing daratumumab
- MEDI4736-NHL-001: only on the durvalumab, lenalidomide, and rituximab treatment arm in patients with lymphoma or CLL
- MEDI4736-DLBCL-001: durvalumab in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or with lenalidomide plus R-CHOP in patients with previously untreated, high-risk, diffuse large B-cell lymphoma (DLBCL)
The MEDI4736-MM-002 trial, which is investigating durvalumab in combination with lenalidomide with or without low-dose dexamethasone in patients with newly diagnosed MM, was placed on full clinical hold.
Patients enrolled in partially held trials and who are receiving clinical benefit may continue treatment, but treatment has been stopped for patients enrolled in the trial on full clinical hold. The trials are not enrolling any new patients.
One week before issuing the clinical holds on the durvalumab trials, Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, released a statement reiterating the safety risks associated with PD-1 and PD-L1 inhibitors in patients with MM: “Today’s alert underscores the importance of why new therapies are thoroughly studied to ensure the benefits of taking them outweigh the risks to patients, and we will continue to aggressively monitor clinical trials to ensure patients are protected when safety concerns arise. The FDA still believes the benefits of taking [pembrolizumab and other PD-1/PD-L1 inhibitors] for their approved uses and as indicated in the labels continue to outweigh their risks.”
Sources: AstraZeneca press release, September 7, 2017; U.S. Food and Drug Administration news release, August 31, 2017.