Ibrutinib combined with bortezomib showed “durable efficacy” and safety in patients with relapsed or refractory mantle cell lymphoma (MCL), according to a study published in eClinicalMedicine.
The phase I/II trial, led by Urban Novak, MD, University Hospital of Bern in Switzerland, established the recommended phase II dose of ibrutinib combined with bortezomib and assessed its efficacy in patients with relapsed or refractory MCL.
The study included ibrutinib-naïve and bortezomib-naïve patients with relapsed or refractory MCL after receiving ≤two lines of chemotherapy. Fifty-five evaluable patients received six 21-day cycles of daily 560 mg ibrutinib and twice-weekly subcutaneous bortezomib at 1.3 mg/m2, followed by daily 560 mg ibrutinib maintenance until progression or unacceptable toxicity. The combination therapy was reduced to a minimum of four cycles to decrease possible toxicity.
The study also showed that the median time to best response for ibrutinib plus bortezomib treatment was 2.4 months, and the median number of combination cycles was six.
During the phase I study (n=9), researchers applied a standard 3+3 dose escalation design to determine the recommended phase II dose of ibrutinib combined with bortezomib. A fixed dose of bortezomib was used in combination with two dose levels of ibrutinib: 420 mg daily for 21 days (dose level one), and 560 mg (dose level two). The primary endpoint in phase I was the dose-limiting toxicities in cycle one.
Meanwhile, the phase II study (n=49) was an open-label, single-arm trial with a Simon’s two-stage min–max design with a primary endpoint of overall response rate (ORR). The ORR, assessed by computed tomography (CT) and magnetic resonance imaging (MRI) scan, increased with continued ibrutinib treatment over a median duration of 10.6 months (81.8% to 87.3%, respectively). In comparison, the current standard of care (SOC) with ibrutinib monotherapy achieves an ORR rate of 69.7%, researchers noted.
Researchers did not observe any new safety signals in phase II compared with phase I. All patients experienced (AEs), most commonly grade 1 or 2 diarrhea (36%), grade 3 infections (25%; mainly pulmonary), and grade 4 hematotoxicities (16.4%; mainly thrombocytopenia). 67.3% of patients experienced grade 3 AEs and 21.8% experienced grade 4 AEs.
“The two very well-established drugs have nonoverlapping toxicities, as well as regulatory approval in relapsed or refractory MCL,” researchers determined. “We propose this combination as a new and valid option especially for patients with MCL who have biological high-risk features, and as a comparator for future phase III trials incorporating appropriate biomarkers.”
Another phase I/II trial enrolled patients to assess the combination of ibrutinib with ixazomib, but results are not yet available.
Reference
Novak U, Fehr M, Schar S, et al. Combined therapy with ibrutinib and bortezomib followed by ibrutinib maintenance in relapsed or refractory mantle cell lymphoma and high-risk features: a phase 1/2 trial of the European MCL network (SAKK 36/13). 2023. eClinicalMedicine, https://doi.org/10.1016/j.eclinm.2023.102221