ALLG NHL43: An open-label multi-centre international phase 2 trial to evaluate the safety and efficacy of two years fixed duration therapy with sonrotoclax in combination with the BGB-16673 and rituximab in patients with treatment naïve or BTKi naïve/intolerant Waldenström Macroglobulinemia (WM).

Exclusion Criteria33

• Prior therapy with a Bruton Tyrosine Kinase (BTK) inhibitor, unless the BTK inhibitor was ceased within six months of commencing treatment due to intolerance.
• Prior therapy with BGB-16673 or another BTK degrader, Sonrotoclax or another B-cell lymphoma 2 (BCL2) inhibitor.
• Any immunoglobulin M (IgM) monoclonal gammopathy of clinical significance without unequivocal evidence of bone marrow (BM) involvement with clonal lymphoplasmacytic infiltrate. This includes, but is not limited to, patients with associated cold agglutinin disease, type I and II cryoglobulinemia, IgM-associated peripheral neuropathy, Schnitzler syndrome, and IgM-associated amyloid light-chain (AL) amyloidosis.
• Active malignancy (other than Waldenström Macroglobulinemia [WM]) within the past two years, except for curatively treated skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast, or localised Gleason score less than or equal to six prostate cancer.
• Clinically significant cardiovascular disease including the following:
• a. Myocardial infarction less than or equal to six months before the date screening commences.
• b. Unstable angina less than or equal to three months before the date screening commences.
• c. History of cardiovascular arrhythmias including sustained ventricular tachycardia, ventricular fibrillation, and Torsades de Pointes.
• d. New York Heart Association (NYHA) class III or IV congestive heart failure.
• e. Uncontrolled hypertension as deemed by the treating investigator.
• f. History of or active Mobitz II second- or third-degree heart block without a permanent pacemaker in place.
• g. Heart rate-corrected QT interval based on Fridericia’s formula (QTcF) greater than 480 milliseconds.
• Underlying medical conditions that, in the investigator’s opinion, will render the administration of trial drug hazardous or obscure the interpretation of safety or efficacy results.
• Women who are pregnant or lactating.
• Patient has toxicities from previous anti-cancer therapies that have not resolved to baseline levels or to grade 1 or less, except for alopecia, peripheral neuropathy, and haematologic toxicity.
• Transformation to aggressive lymphoma, such as diffuse large B-cell lymphoma. If transformation is suspected, a biopsy of the suspected area is required to exclude transformation.
• History of stroke or intracranial haemorrhage within six months of first dose of the trial drugs.
• Active infection (viral, bacterial, or fungal) requiring systemic anti-microbial treatment at the time of screening or within the previous two weeks prior to the first dose of trial treatment. Note that prophylactic anti-microbials (e.g., valaciclovir for herpes simplex virus [HSV]/varicella zoster virus [VZV] or entecavir for a history of hepatitis B) are allowed.
• Positive serology for human immunodeficiency virus (HIV).
• Active hepatitis B infection (defined as the presence of detectable hepatitis B virus [HBV] deoxyribonucleic acid [DNA] or hepatitis B surface antigen [HBsAg]). Patients who are hepatitis B core antibody (HBcAb) positive but are HBV DNA and HBsAg negative are eligible. These patients will have monthly monitoring of HBV DNA for the duration of the trial and receive appropriate anti-viral prophylaxis, with entecavir or similar, according to advice from the infectious disease service. Please note that patients who have received intravenous immunoglobulin (IVIG) may have false positive HBcAb results. In such patients, if HBV DNA and HBsAg are negative, prophylaxis may be omitted if deemed unnecessary by the infectious disease service, but monitoring of HBV DNA levels is still required.
• Active hepatitis C, defined by the detection of hepatitis C ribonucleic acid (RNA) in plasma by polymerase chain reaction (PCR). Patients who have received treatment for hepatitis C that was intended to eradicate the virus may participate if hepatitis C RNA levels are undetectable.
• Uncontrolled intercurrent illness, such as ongoing or active infection requiring intravenous antibiotic treatment at the time of enrolment.
• Received a live, attenuated vaccine within 28 days prior to initiation of trial treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live, attenuated vaccines and are not allowed. Experimental and/or non-authorized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinations are not allowed.
• Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of the trial drugs.
• Receiving treatment with any moderate or strong cytochrome P450 3A4 (CYP3A4) inhibitor or moderate or strong CYP3A4 inducer less than or equal to 14 days or five half-lives (whichever is shorter) before the first dose of Sonrotoclax or requiring ongoing treatment with a moderate or strong CYP3A inhibitor or a moderate or strong CYP3A inducer.
• Use of the following substances prior to the first dose of the study drug:
• a. Systemic chemotherapy or radiation – less than or equal to 14 days (or five half-lives, whichever is shorter) before the first dose of the trial drug.
• b. Corticosteroid given with antineoplastic intent (symptom control will not be considered as antineoplastic intent) – less than or equal to seven days before the first dose of the trial drug.
• c. Any biologic and/or immunologic-based anticancer therapy – less than or equal to 28 days (or five half-lives, whichever is shorter).
• Requires ongoing systemic (defined as greater than or equal to 10 milligrams per day [mg/day] of prednisone or equivalent) corticosteroid treatment. Systemic corticosteroids must be discontinued greater than or equal to seven days before the first day of trial treatment.
• History of a severe bleeding disorder such as haemophilia A, haemophilia B, or von Willebrand disease (patients with acquired von Willebrand syndrome due to WM are eligible), or history of spontaneous bleeding requiring blood transfusion or other medical intervention.
• Patients requiring therapeutic anticoagulation with warfarin or another vitamin K antagonist.
• Patient has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the patient, or that could prevent, limit, or confound the protocol-specified assessments.