Combined idelalisib, lenalidomide, and rituximab proved excessively toxic for the treatment of relapsed and refractory mantle cell and follicular lymphoma in two phase I trials conducted by the Alliance for Clinical Trials in Oncology.

The unexpected outcome, which led to early study termination, underscores the need for caution as new treatment combinations are proposed, Sonali M. Smith, MD , of the University of Chicago and her colleagues said in The Lancet Haematology.

In four of the first eight patients enrolled in the mantle cell lymphoma (A051201) and follicular lymphoma (A051202) phase I trials between July 9, 2013, and Sept. 30, 2014, unexpected dose-limiting toxicities occurred, including grade 4 sepsis syndrome, grade 4 hypotension with grade 3 rash and fevers, grade 4 aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation with fevers, and grade 3 pulmonary infection with grade 3 maculopapular rash.

The adverse events occurred between 9 and 20 days after treatment initiation and coincided with rituximab infusions, the researchers said. No treatment-related deaths occurred ( Lancet Haematol. 2017 Apr;4:e176-82 ).

Overall, 8 of 11 patients were removed from treatment because of an adverse event, and 3 of those required intensive care unit level of care.

Although rituximab was removed in both trials, two of the remaining three patients in the studies, including three with mantle cell lymphoma and eight with follicular lymphoma, experienced grade 3 rashes, and one had grade 3 AST elevations. In those with mantle cell lymphoma, the most common grade 3-4 adverse events were ALT elevations and rash. In those with follicular lymphoma, the most common grade 3-4 adverse events were neutropenia and rash.

“Given the inability to deliver treatment due to toxicity, both studies were permanently closed,” the researchers wrote, noting that the primary endpoint of safety and tolerability was not met.

The trials had the overall goal of developing targeted regimens to replace cytotoxic therapy.

“Both … trials were designed to capitalize on the clinical synergy of lenalidomide and rituximab observed in previous trials by adding the highly specific PI3K delta inhibitor, idelalisib, for patients with relapsed mantle cell lymphoma and follicular lymphoma,” they said.

Previously available data implied that lenalidomide plus rituximab would be a safe backbone for therapy, and there was clinical rationale for adding idelalisib to that combination, they explained.

“Overall, our brief experience underscores the limited knowledge regarding drug interactions and off-target effects and serves as a cautionary note in developing biological agents in combination and against ad-hoc combinations outside of carefully monitored clinical trials,” they said.

The researchers noted that the nature of the toxicities observed in these trials supports an immune-activated state characterized by excessive inflammation.

“A more detailed assessment of effect on cytokines, T-cell subsets, natural killer cells, and clinical features predictive of toxicity and response should be included in any further testing of these classes of agents, and they should never be combined outside of a carefully designed and diligently monitored clinical trial setting,” they concluded.

The study was funded by the National Cancer Institute. Dr. Smith received research funding and consulting fees from Gilead and Celgene.


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