Zandelisib Plus Rituximab Under Study in Indolent Non-Hodgkin Lymphoma

Pipeline Report | <b>Pipeline Report: August 2021</b>

Zandelisib plus rituximab is being evaluated as a potentially chemotherapy-free treatment strategy vs standard chemoimmunotherapy in patients with indolent non-Hodgkin lymphoma in first relapse in the ongoing, phase 3 COASTAL trial.

Zandelisib plus rituximab (Rituxan) is being evaluated as a potentially chemotherapy-free treatment strategy vs standard chemoimmunotherapy in patients with indolent non-Hodgkin lymphoma (iNHL) in first relapse in the ongoing, phase 3 COASTAL trial (NCT04745832).1

Zandelisib is a potent, selective, and structurally unique, oral PI3Kδ inhibitor under development for the treatment of patients with B-cell malignancies.

A chemotherapy-sparing regimen may be of benefit to patients with iNHL whose disease relapsed after receiving chemoimmunotherapy in the frontline setting.

On March 31, 2020, the FDA granted zandelisib a fast track designation for the treatment of adult patients with relapsed/refractory follicular lymphoma who have received at least 2 prior systemic therapies.2

In an ongoing phase 1b single-arm, dose-escalation/-expansion study (NCT02914938), the agent elicited a response rate ranging from 83% to 89% and a median duration of response that was not reached in an intermittent schedule as monotherapy and in combination with rituximab in patients with chronic lymphocytic leukemia, small lymphocytic lymphoma, follicular lymphoma, and B-cell NHL.3

“Durable responses were achieved regardless of the number of prior chemotherapy lines or tumor bulk,” said lead study author Wojciech Jurczak, MD, PhD, of the Maria Sklodowska-Curie National Research Institute of Oncology in Krakow, Poland, in a virtual presentation of the study schema during the 2021 ASCO Annual Meeting.

Additionally, less than 10% of patients who were treated with the agent experienced grade 3 or greater immune-mediated adverse effects of special interest.

The COASTAL study is a multicenter, open-label, randomized, controlled, phase 3 trial investigating the safety and efficacy of zandelisib plus rituximab vs standard chemoimmunotherapy in patients with iNHL.

To be eligible for enrollment, patients must have relapsed/refractory follicular lymphoma or marginal zone lymphoma (MZL) and received at least 1 prior line of therapy, including an anti-CD20 antibody in combination with chemotherapy or lenalidomide (Revlimid); at least 1 bi-dimensionally measured lesion greater than 1.5 cm; adequate bone marrow and renal and hepatic function; and an ECOG performance status score of 0 or 1.

Patients will be excluded from enrollment if they have a histologically confirmed diagnosis of grade 3b follicular lymphoma or transformed disease; received 2 prior chemoimmunotherapy regimens; received prior PI3K inhibitor therapy; have ongoing or a history of drug-induced pneumonitis; known lymphomatous involvement of the central nervous system, or are seropositive for or have an active viral infection.

In the study, patients will be randomized 1:1 to receive zandelisib plus rituximab or physician’s choice of chemoimmunotherapy of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone (R-CHOP) or bendamustine plus rituximab. Patients will be stratified by type and number of prior treatment regimens, histology, and duration of treatment-free interval after last therapy.

Patients will receive zandelisib with rituximab for the first 6 cycles followed by 20 cycles of zandelisib alone. Rituximab will be given weekly in the first cycle followed by monthly administration for the remaining 5 cycles. Chemoimmunotherapy will be administered for a total of 6 cycles.

Zandelisib will be administered in a 28-day cycle consisting of daily dosing for the first 2 cycles followed by intermittent schedule dosing on days 1 through 7 of each of the 24, 28-day cycles thereafter for a duration of 2 years.

Disease response will be assessed by an Independent Response Review Committee according to the modified Lugano Classification. Radiographic tumor assessment will be performed approximately every 12 weeks for the first 9 months, every 16 weeks for the next 12 months, and every 24 weeks thereafter.

The primary end point is progression-free survival. Key secondary end points include objective response rate, complete response rate, overall survival, patient-reported outcomes, and safety.

The trial will enroll approximately 534 patients across 200 sites and 25 countries globally and will begin enrollment in mid-2021.

The open-label, phase 2 TIDAL study (NCT03768505) is also ongoing, which is evaluating zandelisib as third- or later-line therapy in patients with relapsed/refractory follicular lymphoma and MZL.

Pending the results of the TIDAL trial, Mei Pharma, the developer of the agent, is planning submissions with the FDA to support accelerated approval marketing applications.

The results of the COASTAL trial are intended to support full marketing applications in the United States and globally in patients with relapsed/refractory follicular lymphoma and MZL who have received at least 1 prior line of treatment. COASTAL is also intended to serve as the confirmatory trial for the potential FDA accelerated approval of zandelisib.4

References

  1. Jurczak W, Zinzani 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. 2021;39(suppl 15):TPS7573. doi:10.1200/JCO.2021.39.15_suppl.TPS7573
  2. MEI Pharma announces fast track designation granted by U.S. FDA for ME-401 for the treatment of adult patients with relapsed or refractory follicular lymphoma. News release. Mei Pharma. March 31, 2020. Accessed August 12, 2021. https://bit.ly/3ayo71X.
  3. Zelenetz AD, Reddy N, Jagadeesh D, et al. Tolerability and durable responses 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. doi:10.1200/JCO.2021.38.15_suppl.8016
  4. Zandelisib (ME-401). Mei Pharma. Accessed August 11, 2021. https://www.meipharma.com/pipeline/zandelisib