A Trial to Evaluate the Efficacy and Safety of a Fitness-adapted Thera-py Approach With Either Continuous Zanubrutinib Monotherapy or Time-limited Zanubrutinib + Sonrotoclax in Older and/or Frail Patients With Treatment-naïve CLL

Laborértékek

• 1\. Pprevious CLL-directed therapies. 2. Transformation of CLL to aggressive NHL (Richter's transformation or pro-lymphocytic leu-kaemia).
  • 3\. Patients with a history of confirmed progressive multifocal leukoencephalopathy (PML).
  • 4\. Uncontrolled autoimmune condition. 5. Malignancies other than CLL currently requiring systemic therapies (unless the malignant dis-ease is in a stable remission at the discretion of the treating physician).
  • 6\. Uncontrolled infection currently requiring systemic treatment. 7. Any serious medical condition or abnormality in clinical laboratory tests that, in the investiga-tor's judgment, precludes the patient's safe participation in and completion of the study.
  • 8\. Requirement of therapy with strong CYP3A4 inhibitors/ inducers. 9. Requirement of therapy with phenprocoumon or other vitamin K antagonists. 10. Known active infection with HIV, or serologic status reflecting active hepatitis B or C infection as follows:
  • Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Patients with presence of HBcAb, but absence of HBsAg, are eligible if hepatitis B virus (HBV) DNA is undetectable (\< 20 IU), and if they are willing to undergo monitoring for HBV reactivation.
  • Presence of hepatitis C virus (HCV) antibody. Patients with presence of HCV antibody are eligible if HCV RNA is undetectable.
  • 11\. Major surgery within 4 weeks of the first dose of study drug. 12. Any uncontrolled or clinically significant cardiovascular disease including the following:
  • New York Heart Association class III or IV congestive heart failure
  • History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricu-lar fibrillation, torsades de pointes) 13. History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand dis-ease, or history of spontaneous bleeding requiring blood transfusion or other medical inter-vention.
  • 14\. History of stroke or intracranial hemorrhage within 6 months before first dose of study drug.
  • 15\. Severe or debilitating pulmonary disease. 16. Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery proce-dures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.
  • 17\. Use of investigational agents, e.g. monoclonal antibodies or other experimental drugs within clinical trials, which might interfere with the study drug within 28 days (or 5 times half-life \[t1/2\] of the compound, whichever is longer) prior to registration.
  • 18\. Known hypersensitivity to zZanubrutinib or sonrotoclax or any of the excipients.
  • 19\. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment).
  • 20\. Fertile men or women of childbearing potential unless:
  • surgically sterile or ≥ 2 years after the onset of menopause, or
  • willing to use two methods of reliable contraception including one highly effective contra-ceptive method (Pearl Index \<1) and one additional effective (barrier) method during study treatment and for 90 days after sonrotoclax and 30 days after zanubrutinib respec-tively. Vaccination with a live vaccine \<28 days prior to randomizationregistration.
  • 21\. Vaccination with a live vaccine \<28 days prior to randomizationregistration.
  • 22\. Legal incapacity. 23. Prisoners or subjects who are institutionalized by regulatory or court order.
  • 24\. Persons who are in dependence to the sponsor or an investigator.

• Age ≥80 years OR considered frail defined by a frailty score of \>2 on the FRAIL s-Scale via the patient´s assessment
• Hasve documented treatment-naïve CLL or small lymphocytic lymphoma (SLL) according to iwCLL 2018 criteria4
• CLL/SLL requiring treatment according to the iwCLL 2018 criteria4
• Adequate marrow function independent of growth factor or transfusion support within 2 weeks of screening as follows, unless cytopenia is due to marrow involvement of CLL:
  • Absolute neutrophil count ≥ 1.0 × 10\^9/L
  • Platelet counts ≥ 30 × 10\^9/L; in cases of thrombocytopenia clearly due to marrow in-volvement of CLL (per the discretion of the investigator); platelet count should be ≥ 10 × 10\^9/L if there is bone marrow involvement
  • Total haemoglobin ≥ 9 g/dL (without transfusion support, unless anaemia is due to mar-row involvement of CLL)
• Adequate liver function as indicated by a total bilirubin, AST, and ALT ≤2 times the institutional upper limit of normal (ULN) value unless directly attributable to the patient's CLL or Gilbert's syndrome
• Negative serological testing for hepatitis B (HBsAg negative and anti-HBc negative; patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed repeatedly until 6 months after last month of treatment), negative testing for hepa-titis C RNA within 6 weeks prior to registration.
• Life expectancy ≥ 3 months
• In case of a recent previous (i.e. debulking) treatment, patients must have recovered from acute toxicities and treatment regimen must be stopped within the following time periods be-fore start of the study treatment in the CLL-Frail2 trial • chemotherapy ≥ 28 days
  • antibody treatment ≥ 14 days
  • corticosteroids may be applied until the start of the study therapy, these have to be re-duced to an equivalent of ≤ 20mg prednisolone per day during treatment
• Signed informed consent and, in the investigator's judgment, able to comply with the study protocol
• Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements