CTEP 10590, NORM: Nodular Lymphocyte Predominant Hodgkin Lymphoma Patients Treated in a Randomized Phase II Trial with Either Rituximab or Mosunetuzumab

Background: Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) expresses CD20 and is characterized by an indolent disease course, similar to indolent B-cell non-Hodgkin lymphoma (iNHL). NLPHL often affects young patients, who have an excellent prognosis irrespective of therapy and are frequently overtreated with cytotoxic therapies. Overall, 77% of causes of death of NLPHL patients treated in the trials HD7-HD15 were due to second malignancies and nonmalignant conditions possibly associated with radiotherapy (RT) and/or chemotherapy used for classical Hodgkin lymphoma (cHL). Mosunetuzumab is an anti-CD20/CD3 T-cell-dependent bispecific antibody with a complete response (CR) rate of 65.7% in relapsed/refractory iNHL (Budde et al. JCO 2024). The discovery of novel efficacious targeted therapies for NLPHL is essential to avoid overtreatment, decrease toxicities, and improve patient quality of life. Objectives: This study aims to compare the progression-free survival (PFS), safety and antitumor activity of mosunetuzumab versus rituximab in NLPHL patients. Methods: We are conducting a phase II, randomized, open label, multicenter trial NCT05886036 evaluating either rituximab or mosunetuzumab for patients 18 years or older with previously untreated NLPHL stage IB to IV or previously treated NLPHL of any stage, requiring systemic therapy. Patients with transformed NLPHL and patients previously treated with rituximab are excluded. Patients will receive either rituximab (375 mg/m2 IV on Cycle 1 Day 1, followed by rituximab 1400 mg/hyaluronidase 23,400 units SC on C1D8-C2D22, 2 cycles of weekly rituximab 4x, 8 weeks apart) or mosunetuzumab (SC with step-up dosing Cycle 1 Day 1, 8, and 15 and Day 1 of subsequent cycles (5/45/45 mg), up to 8 cycles). Consolidative RT based on disease response for patients with limited stage is allowed, if declared prior to randomization (30 Gy for patients with CR, 36-40 Gy for patients with partial response [PR]). PET-CT imaging will be performed to assess response according to the Lugano classification at 12 weeks (interim assessment) and at 25 weeks (end of treatment (EOT) assessment). For patients with disease progression at the time of the interim assessment, crossover to the opposite arm of the trial (start from cycle 1 day 1) is permitted if transformation is excluded and the treating physician estimates that there is potential clinical benefit to continuing therapy on the trial. The primary endpoint is the 2-year PFS. Secondary endpoints include the response rate at the interim and EOT, landmark survival outcomes and safety. Exploratory analyses include assessing molecular response by sequencing cell-free DNA, RNA-sequencing and whole exome sequencing and assessing the association of baseline FDG-PET/CT measurements including metabolic tumor volume (MTV) and maximum standardized uptake value (SUVmax), in combination with other risk factors, with PFS and overall survival. We based our sample size justification on a log rank test comparing PFS between the two treatment groups with assumed 2-year PFS rates of 50% (rituximab) versus 75% (mosunetuzunab) with a one-sided type I error rate of 10% and 85% power; accrual period of 3 years and maximum trial duration of 5 years. The expected sample size is 56.1 under the null hypothesis and 61.9 under the alternative hypothesis. Randomization will be 1:1 and the permuted block randomization will be used to balance the stratification factors of: disease stages I/II and III/IV, consolidative RT versus no RT (only for stages I/II patients) and frontline versus relapsed/refractory. The study is open for accrual in the US and Canada since 2024.