Three centers in the United States are recruiting patients with indolent non-Hodgkin lymphoma to receive the investigational selective PI3Kδ inhibitor zandelisib in combination with rituximab in a phase 3 clinical trial setting. The study aims to determine the efficacy and safety of zandelisib in combination with rituximab compared with standard immunochemotherapy.
Three centers in the United States are recruiting patients with indolent non-Hodgkin lymphoma (iNHL) to receive the investigational selective PI3Kδ inhibitor zandelisib (ME-401) in combination with rituximab (Rituxan) in a phase 3 clinical trial setting. The study aims to determine the efficacy and safety of zandelisib in combination with rituximab compared with standard immunochemotherapy.1
In today’s treatment landscape, standard immunochemotherapy consists of rituximab in combination with bendamustine or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).1 Investigators of the COASTAL trial (NCT04745832) hypothesize that patients with iNHL may benefit from having a chemotherapy-free treatment option.2
“Patients are commonly treated with chemotherapy-based regimens in the frontline. Especially when talking about diseases like follicular lymphoma [FL] or mantle cell lymphoma, they may get standard chemotherapy, they may even get that at the time they relapse,” John M. Pagel, MD, PhD, chief of hematologic malignancies at the Center for Blood Disorder and Stem Cell Transplantation in Seattle, told Targeted Oncology ™, in an interview.
To test this theory, patients enrolled in the COASTAL trial will receive zandelisib 60 mg capsules for 2 treatment cycles followed by an intermittent dosing schedule at cycle 3. Rituximab in the experimental arm will be administered intravenously (IV) at 375 mg/m2 for 6 cycles.
In the control arm, patients will receive the same dose and schedule of rituximab in combination with either bendamustine IV 90 mg/m2 or the CHOP regimen. Those who receive CHOP will be dosed with cyclophosphamide 750 mg/m2, hydroxydoxorubicin IV 50 mg/m2, vincristine IV 1.4 mg/m2, and prednisone 100 mg daily.
“We do know that patients will become more refractory to chemotherapy and not tolerate that as well over time and the durations of those remissions to immunochemotherapy can be quite limited with multiple relapses or other encounters for treatment. So, developing a novel approach that's well-tolerated, that's chemotherapy-free, and that has a different mechanism of killing these lymphoma cells, is highly valued and desired. I think that's why this regimen is appealing for patients with relapsed B -ell malignancies,” said Pagel.
COASTAL will enroll an estimated 534 patients with iNHL and randomize them 1:1 to receive either zandelisib with rituximab or immunochemotherapy. Being stratified by type and number of prior treatment regimens, histology, and duration of treatment-free interval after last therapy, patients will be assessed for the primary end point of progression-free survival. The secondary end points explored in the study include the overall response rate (ORR), complete response rate, overall survival, the number of patients with treatment-emergent adverse events (AEs), the number of serious AEs, and the number of laboratory abnormalities.
Patients aged 18 years or older are eligible to enroll given they have a histologically confirmed diagnosis of CD20-positive iNHL. Subtypes of iNHL in the study are limited to grade 1-3 FL, and marginal zone lymphoma. Patients are required to have relapsed or refractory disease and have received ≥1 prior lines of therapy. In addition, patients are required to have measurable disease and adequate renal, hepatic function, and cardiac function.
Previously, the phase 1 study of zandelisib demonstrated that the monotherapy can achieve durable objective responses in relapsed/refractory indolent B-cell malignancies, including FL.3
Fifty-seven patients were treated with zandelisib in the study, and of those treated, 35 had FL. The ORR in the FL group was 83% with zandelisib monotherapy. In addition, patients with FL were treated with zandelisib in combination with either rituximab or zanubrutinib (Brukinsa).
Safety results showed that zandelisib was well tolerated in patients with indolent B-cell lymphomas. Grade 3 AEs were reported in 7 patients, including diarrhea (3.5%), colitis (3.5%), rash (2%), alanine transferase increased (2%), and pneumonitis (2%).
In the interview with Targeted Oncology™, Pagel explained why toxicity is a concern with the PI3Kδ drug class. “I think the biggest thing that we learned early on with PI3Kδ inhibitors is that they disrupt the balance between T-cell regulation. That balance over time can lead to some very significant immune-mediated adverse events. Those can manifest as significant diarrhea or colitis. Sometimes, we see some inflammation of the liver, sometimes in the lungs with pneumonitis, or other adverse events like rashes.”
Regarding the COASTAL study’s overarching goal, Pagel stated, “This will be a very important study to help establish not only the combination of zandelisib with rituximab, but to look at its immune-mediated toxicities and hopefully see strong mitigation against those adverse events with the intermittent schedule.”
1. Phase 3 study of zandelisib (ME-401) in combination with rituximab in patients with iNHL - (COASTAL). Clinicaltrials.gov. Accessed August 18, 2021. https://clinicaltrials.gov/ct2/show/NCT04745832
2. Jurczak W, Znzani PL, Cunningham D, et al. Coastal: A phase 3 study of the PI3Kδ inhibitor zandelisib with rituximab (R) versus immunochemotherapy in patients with relapsed indolent non-Hodgkin’s lymphoma (iNHL). J Clin Oncol. 202;39(suppl 15). doi: 10.1200/JCO.2021.39.15_suppl.TPS7573
3. Zelentz AD, Reddy N, Jagadeesh D, et al. Tolerability and durable respones of the PI3Kδ inhibitor ME-401 administered on an intermittent schedule in relapsed/refractory (R/R) follicular lymphoma (FL) and other B-cell malignancies. J Clin Oncol. 2020; 38(suppl 15): 8016-8016. doi: 10.1200/JCO.2020.38.15_suppl.8016