SOUNDTRACK-F1: A phase 3, randomized, open-label study of surovatamig (AZD0486) plus rituximab versus chemotherapy plus rituximab in patients with previously untreated follicular lymphoma

Abstract

Abstract Background and Significance: Follicular lymphoma (FL) is the most common indolent lymphoma and advanced-stage disease is considered incurable despite recent advances. The current standard initial treatment for patients with FL and high tumor burden requiring therapy is chemoimmunotherapy in combination with a CD20 monoclonal antibody, which induces high response rates. However, these treatments are associated with chemotherapy-related toxicities; thus, there is need to develop more effective and better tolerated treatments. Surovatamig, formerly AZD0486, is a CD19xCD3 fully human IgG4 bispecific T-cell engager. In patients with heavily pretreated FL, surovatamig yielded high response rates (complete response [CR] rate of 85% for ≥2.4 mg). Surovatamig was well tolerated, with 50% (n=19/38) of patients who received double step-up dosing (2SUD) having cytokine release syndrome (all grade 1); 3% (n=1/38) had immune effector cell–associated neurotoxicity syndrome (grade 1; Hou JZ, et al. Blood. 2024;144:341). The SOUNDTRACK-F1 study (NCT06549595) is evaluating surovatamig plus rituximab versus chemotherapy plus rituximab in patients with previously untreated FL and high tumor burden. Study Design and Methods Theglobal, randomized, phase 3, multicenter, open-label SOUNDTRACK-F1 study consists of a safety run-in portion followed by a phase 3 portion. Key inclusion criteria include patients aged ≥18 years with previously untreated FL and high tumor burden requiring therapy, defined by Groupe D'Etude des Lymphomes Folliculaires criteria, and Eastern Cooperative Oncology Group performance status 0‒2. In the safety run-in portion, all disease stages and all Follicular Lymphoma International Prognostic Index (FLIPI) scores are allowed. The phase 3 portion is restricted to patients with Ann Arbor stage II–IV disease and FLIPI score 2‒5. Key exclusion criteria include follicular large B-cell lymphoma (WHO 2022 classification); active central nervous system (CNS) lymphoma; history or presence of clinically significant CNS pathology (eg, epilepsy, seizure, stroke); or major cardiac abnormalities. The safety run-in portion assesses 2 target dose levels of intravenous surovatamig (2.4 and 7.2 mg) to establish the recommended phase 3 dose (RP3D) of surovatamig in combination with rituximab, to be administered for 7 cycles followed by 17 cycles of surovatamig monotherapy in patients achieving partial response (PR) or CR after the first 7 cycles. In the phase 3 portion, patients will be randomized 1:1:1 to arms A, B, or C. Patients in arm A will receive surovatamig at the RP3D target dose plus rituximab for 7 cycles; those in arm B will receive the same therapy as arm A followed by 17 cycles of surovatamig monotherapy for patients who achieved PR or CR after the first 7 cycles; and patients in arm C will receive a preselected choice of chemoimmunotherapy (R-CHOP [rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone], R-CVP [rituximab-cyclophosphamide-vincristine-prednisone], or BR [bendamustine-rituximab]) followed by rituximab maintenance for patients achieving PR or CR with induction chemoimmunotherapy (arm C). In arms A and B and the safety run-in, in which 1 cycle (C) is 28 days, rituximab is administered at 375 mg/m2 on day (D) 1, 8, 15, and 22 of C1, then D1 of each cycle up to C7; surovatamig is delivered via a 2SUD schedule at 0.27 mg on C1D15, at 1.0 mg on C1D22, then at the RP3D target dose on D1 and D15 of subsequent cycles. Qualifying patients in arm B will receive 17 additional cycles of surovatamig monotherapy on D1 of each cycle. In arm C, standard chemoimmunotherapy is given for 6 cycles (21-day cycles for R-CHOP and R-CVP; 28-day cycles for BR), followed by rituximab maintenance every 8 weeks for 2 years. The safety run-in portion includes 40 patients, and approximately 975 patients will be recruited for the randomized phase 3 portion. The primary objective of the safety run-in portion is to assess the safety and tolerability of surovatamig to determine its RP3D in combination with rituximab. The primary objective of the phase 3 portion is to demonstrate the superiority of surovatamig plus rituximab versus chemoimmunotherapy, with dual primary endpoints of overall response rate at the end of induction and progression-free survival. The key secondary endpoint is overall survival. Minimal residual disease and safety will also be assessed. Enrollment in the study is ongoing.