The medications will be given in different ways – some as tablets taken by mouth and others through an intravenous infusion (given directly into a vein) or subcutaneous injection (given under the skin). The study will be conducted in two parts. The first part will determine the right dose of the drug combinations, while the second part will further study how well these doses work and what side effects they may cause.

Throughout the study, doctors will monitor patients’ health, check how well the treatment is working, and track any side effects. They will look at how many patients respond to treatment and how long the response lasts. For some patients, they will also measure the amount of cancer cells remaining in the blood or bone marrow after treatment.

The investigation is divided into two parts to first determine the most appropriate amount of the medicine to give and then to see how well it works. The medication is administered as a subcutaneous injection, which is a type of injection given into the fatty tissue just under the skin. Participants will receive the treatment for a series of cycles to monitor how the disease responds over time.

The study includes different groups of patients: those whose disease has returned or not responded to previous treatments (relapsed/refractory disease), those who couldn’t tolerate certain previous treatments, and those who haven’t received any treatment yet for their Waldenström Macroglobulinemia. During the study, participants will receive either sonrotoclax alone or in combination with zanubrutinib, depending on which study group they join.

Researchers will track how well patients respond to the treatment by measuring changes in their cancer. They will also monitor side effects, laboratory test results, and how the treatment affects patients’ quality of life and symptoms related to their disease.

Participants in the study will take acalabrutinib orally, meaning they will swallow the tablets or capsules. The study is designed to observe the effects of the medication over a period of time, with regular check-ups to monitor the participants’ health and response to the treatment. The study aims to understand the overall response rate, which refers to how well the cancer responds to the treatment, as assessed by the study investigators.

Throughout the study, researchers will also look at other important factors such as the duration of response, progression-free survival, and overall survival. These terms refer to how long the treatment continues to work, how long patients live without the disease getting worse, and the overall lifespan of the participants, respectively. Additionally, the study will assess the safety of acalabrutinib by monitoring any side effects and how they affect the participants’ quality of life. The study is open-label, meaning both the researchers and participants know which treatment is being administered.

Participants in the study will receive the treatment through an intravenous infusion, which means it is given directly into the bloodstream. The study will also involve other medications, including ibrutinib, a drug that helps block certain proteins that cancer cells need to grow, and cyclophosphamide, a type of chemotherapy. Additionally, supportive medications like mesna to protect the bladder, methylprednisolone and dexamethasone as corticosteroids to reduce inflammation, and fludarabine, another chemotherapy drug, may be used. Some participants may receive a placebo instead of certain medications to compare the effects.

The study will take place over several months, with regular check-ups to monitor the participants’ health and the effectiveness of the treatment. The goal is to see how well the treatment works in reducing the cancer and improving the patients’ condition. Participants will be closely monitored by healthcare professionals throughout the study to ensure their safety and well-being.