Study Evaluating the Efficacy and Tolerance of a Zanubrutinib and BGB-11417 Combination in Patients Previously Treated for Waldenström Macroglobulinemia

Inclusion Criteria:

1. Be ≥ 18-year-old.
2. Have received at least 1 prior line of treatment (excluding treatment with any BTKi or Bcl-2 antagonist, see non-inclusion criteria).
3. Provide written informed consent.
4. Have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 3.
5. Have adequate renal function defined as creatinine clearance ≥ 50 mL/min as determined by the Cockroft-Gault equation.
6. Have adequate hepatic function defined as:

   * total serum bilirubin ≤ 1.5 × ULN, unless bilirubin rise is due to Gilbert's syndrome or non-hepatic cause.
   * alanine aminotransferase (ALAT) \< 2 × ULN
   * aspartate aminotransferase (ASAT) \< 2 × ULN,
7. Have adequate BM function defined as:

   * absolute neutrophil count ≥ 1x109/L
   * platelet count ≥ 75 x109/L
8. For women of childbearing potential, a negative pregnancy test must be documented prior to enrollment.

   * A woman is considered of childbearing potential, ie, fertile, following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.
   * A post-menopausal state is defined as no menses for 12 months without an alternative medical cause.
9. Agree to use a highly effective form of contraception with sexual partners throughout study participation (for female and male patients who are fertile). Patients using hormonal contraceptives (eg, birth control pills or devices) must use a barrier method of contraception (eg, condoms) as well.
10. Ability to comply with study procedures, in the Investigator's opinion.
11. Patient covered by any social security system

Exclusion Criteria:

1. Have previously been treated with a BTK inhibitor.
2. Have been previously treated with a bcl-2 antagonist.
3. Have active central nervous system (CNS) disease as evidenced by cytology or pathology. In the absence of clinical signs of CNS disease, a lumbar puncture is not mandatory.
4. Have significant or active cardiovascular disease:

   * stage III to IV congestive heart failure (CHF) as determined by the New York Heart Association (NYHA) classification system for heart failure and/or with left ventricular ejection fraction \< 50%
   * myocardial infarction within 6 months before study treatment.
   * unstable angina within 6 months before study treatment.
   * uncontrolled atrial arrhythmia.
   * history of clinically significant ventricular arrhythmias (e.g sustained ventricular tachycardia, ventricular fibrillation, torsades de pointe).
   * uncontrolled hypertension.
   * history of stroke or intracranial hemorrhage within 180 days before the first dose of study drugs
   * QTcF interval \> 450 ms on screening electrocardiogram (ECG) evaluation.
5. Have a history of stroke or intracranial hemorrhage within 6 months before first dose of study drug, have a history of a severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention:

   * patients with constitutional hemophilia or von Willebrand's disease will be excluded.
   * patients with acquired hemophilia will be excluded.
   * Requires ongoing treatment with warfarin or warfarin derivatives.
   * patients with acquired von Willebrand's disease related to WM can be included. i) if bleeding manifestations are considered as non-clinically significant (i.e.grade 2 or below) ii) or if bleeding manifestations have been corrected by plasma exchange
6. Have received live vaccine within 4 weeks of inclusion.
7. Receive other concomitant investigational therapy.
8. Have a history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, or hepatic condition that, in the opinion of the Investigator, would adversely affect a subject's participation in the study.
9. Have currently active, clinically significant Child-Pugh Class B or C hepatic impairment.
10. Present an inability or difficulty swallowing capsules/tablets, malabsorption syndrome, or any disease or medical condition significantly affecting gastrointestinal function.
11. Have a known allergy to either xanthine oxidase inhibitors or rasburicase or zanubrutinib (patients at risk for G6PD deficiency may be screened before enrolment).
12. Are pregnant or lactating. Women of childbearing potential must agree to use highly effective contraception from the time of signing informed consent until end-of-treatment visit,

    ≥90 days after last dose of BGB-11417-101 and Zanubrutinib. Male patients must be abstinent, vasectomized, or agree to the use of barrier contraception in combination with other methods.
13. Have a history of other active malignancies requiring treatment within 3 years of study entry, with exception of (1) localized basal cell or squamous cell carcinoma of the skin, (2), adequately treated in situ endometrial carcinoma, (3) incidental histology finding of prostate carcinoma, (4) previous malignancy confined and treated locally (surgery or other modality) with curative intent.
14. Be known to be positive for HIV.
15. Present evidence of other clinically significant uncontrolled condition(s) including, but not limited to:

    * uncontrolled and/or active systemic infection (viral, bacterial or fungal) including COVID-19
    * chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface \[HBs\] antigen negative-, anti-HBs antibody positive and anti-hepatitis B core \[c\] antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate. Patients with serologic evidence of prior resolved infection can be included according to recommendations .
16. Suffer from any condition or illness that, in the opinion of the Investigator or medical monitor, would compromise patient safety or interfere with the evaluation of the safety of the study drugs.
17. Have received or consumed any of the following within 3 days prior to the first dose of study drugs:

    * grapefruit or grapefruit products.
    * Seville oranges (including marmalade containing Seville oranges).
    * star fruit.
18. Have received a treatment with any of the following prior to the first dose of study drugs:

    * ≤7 days steroid therapy with anti-neoplastic intent.
    * ≤ 7 days or 5 half-lives (whichever is longer) of any moderate or strong CYP3A4 inhibitor and ≤ 14 days or 5 half-lives, (whichever is longer) of moderate or strong CYP3A4 inducer before the first dose of study drugs.
    * allogeneic or autologous stem cell transplantation or CAR-T cell therapy less than 3 months before the first dose of study drugs.
19. Severe or debilitating pulmonary disease.
20. Major surgery within 4 weeks of the first dose of study drug.
21. Active and/or ongoing autoimmune anemia and/or autoimmune thrombocytopenia (eg, idiopathic thrombocytopenia purpura).
22. Ongoing alcohol or drug addiction or any psychiatric condition(s) which would compromise ability to comply with study procedures.