An Evaluation of Ibrutinib and Ixazomib in Patients With Relapsed/Refractory Mantle Cell Lymphoma: PrE0404

Management of relapsed mantle cell lymphoma (MCL) has included Bruton's tyrosine kinase (BTK) inhibitors for more than 10 years, but finding an optimal combination partner that meaningfully improves outcomes while limiting toxicity has been difficult. We conducted a phase 1/2 trial of ibrutinib and the proteasome inhibitor, ixazomib, in patients with relapsed/refractory MCL.

Patients and Methods: The primary endpoint for the phase 1 study was to determine the recommended phase 2 dose (RP2D), and for the phase 2 study was the complete response (CR) rate, compared with the previously reported single-agent CR rate of ibrutinib. After the phase 1 portion of the study identified a recommended phase 2 dose of ixazomib 4 mg days 1, 8, and 15, of a 28-day cycle combined with ibrutinib 560 mg daily until progression or unacceptable toxicity.

We enrolled 35 BTK-naïve patients to the phase 2 portion of the study. Overall response rate was 77%, and 37% of patients achieved a CR. The 2-year progression-free survival is 44%, and the duration of response is 47%. Treatment-related adverse events were common, resulting in treatment discontinuation for 37% of patients.

Given that the progression-free survival (PFS) was not significantly improved compared to historical reports for single-agent BTK inhibitors and the high rate of treatment-related toxicity, this combination does not merit further study in this setting. Additional trials evaluating newer BTK inhibitors and alternative combination partners are warranted.