Sonic: Escalated inpatient ramp-up of sonrotoclax in CLL/SLL and MCL Free

Background: Bcl-2 inhibitors have well-established efficacy in the treatment of chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL), and mantle cell lymphoma (MCL). Sonrotoclax (BGB-11417) is a promising next generation Bcl-2 inhibitor with better potency and specificity than venetoclax, a first generation Bcl-2 inhibitor, in pre-clinical studies. A challenge of using venetoclax is the need for a gradual and slow medication ramp-up strategy due to risk of life-threatening tumor lysis syndrome (TLS). Since many patients with CLL/SLL and MCL experience bulky or progressive disease requiring immediate and urgent treatment, there is a critical need for safe but rapid Bcl-2 inhibitor treatment.

Treatment with sonrotoclax in a phase I study did not result in clinical TLS among patients with CLL/SLL or MCL who received sonrotoclax in combination with zanubrutinib after a long ramp-up period. No patients met the criteria for laboratory TLS. Thus, sonrotoclax is an excellent Bcl-2 candidate for a rapid up-strategy.

This study will seek to identify the optimal strategy for an escalated inpatient ramp-up of sonrotoclax after initial debulking with zanubrutinib or rituximab.

Study Design and Methods: SONIC is a single-institution, single-arm phase 2 clinical trial (NCT06839053) conducted at Fred Hutch Cancer Center/University of Washington in Seattle, WA.

Major Eligibility Criteria: Patients (≥ age 18) with CLL/SLL who meet indication for treatment per the iwCLL criteria or with MCL. Patients with CLL/SLL can either be treatment-naïve or have relapsed/refractory (R/R) disease to at least 1 prior line of therapy, and patients with MCL must have R/R disease. Patients with active central nervous system involvement of disease or Richter's syndrome are excluded. Patients may not have a history of progression on a Bcl-2 inhibitor and no history of exposure to a Bcl-2 inhibitor in the previous 12 months. Patients must have an ECOG status of 0-2 and have adequate organ function. Patients with a prior other malignancy within the past 2 years are excluded.

Objectives: Primary Objectives:

To examine the safety and tolerability of an escalated ramp-up of sonrotoclax (BGB-11417) following initial debulking with zanubrutinib or rituximab in patients with treatment-naïve or R/R CLL/SLL and patients with R/R MCL.

To assess safety by measuring the frequency of adverse events (AEs), including episodes of laboratory and clinical TLS.

To evaluate the feasibility of reaching a target dose of sonrotoclax 320mg daily on day 12 +/- 2 days following a 4-day inpatient ramp-up of sonrotoclax.

Secondary Objective:

To estimate the efficacy of an escalated ramp-up of sonrotoclax followed by 1 year of combination therapy (with either zanubrutinib or rituximab) by assessing the overall response rate (ORR), time to response, overall survival (OS), progression-free survival (PFS), rate of complete response (CR), and time to CR.

Treatment Schedule: Patients in Cohort A (BTK inhibitor non-refractory) will undergo debulking with zanubrutinib 320mg daily for 3 cycles (28-day cycles), and patients in Cohort B (BTK inhibitor refractory) will debulk with 4 weekly cycles of rituximab 375 mg/m2. After debulking, patients will be admitted for rapid sonrotoclax ramp-up, receiving 2mg on Day 1, 5mg on Day 2, 20mg on Day 3, and 80mg on Day 4. Patients will be discharged on Day 5 and start taking sonrotoclax 160mg daily on that day. The last dose ramp-up will occur on Day 12 (+/-2 days) and the dose will be increased to 320mg daily. Patients will be treated with sonrotoclax for a total of 1 year, along with either 1 year of zanubrutinib (Cohort A) or 6 months of rituximab (Cohort B).

Statistical Considerations: Goal enrollment will be 20 patients. Analysis of primary and secondary endpoints will be descriptive and incorporate the appropriate analysis set. Binary outcomes will be estimated as simple proportions with corresponding exact confidence intervals. Time-to-event outcomes (eg. OS and PFS) will be summarized using the method of Kaplan and Meier. Continuous measures will be summarized using means/medians, standard deviations, and ranges.

Summary: The SONIC trial evaluates the safety, tolerability, and feasibility of a rapid inpatient ramp-up of sonrotoclax for patients with treatment-naïve or relapsed/refractory CLL/SLL or relapsed/refractory MCL. The trial is actively enrolling participants at Fred Hutch Cancer Center/University of Washington.