DAYBreak CLL-306

Adults ≥18 with R/R CLL/SLL, ECOG 0–2, prior cBTKi with confirmed progression on cBTKi (not toxicity only), adequate organ function, willing to use contraception.

1. Must be ≥18 years of age. 2. Confirmed diagnosis of CLL/SLL that meets International Workshop on CLL (iwCLL) 2018 criteria for diagnosis and systemic treatment (Hallek 2018). 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. 4. Must have received at least one prior line of therapy for CLL/SLL that included a cBTKi and must have documented disease progression during treatment with, or after discontinuation of, the cBTKi. Patients who discontinued cBTKi due solely to toxicity/intolerance are not eligible. Note: A line of therapy is considered 2 or more consecutive cycles of a systemic anti-CLL/SLL treatment regimen. 5. Patients with SLL must have measurable disease by computed tomography (CT) per iwCLL. Measurable disease is defined as at least 1 lymph node >1.5 cm in longest diameter and measurable in 2 perpendicular dimensions. 6. Adequate organ and bone marrow function as follows: Hemoglobin: ≥75 g/L (≥7.5 g/dL; ≥4.66 mmol/L) or <75 g/L permitted if anemia is due to bone marrow involvement per investigator assessment. Note: transfusion support is allowed. ANC: ≥1,000 cells/μL (≥1.0 × 10^9/L) or ≥750 cells/μL (≥0.75 × 10^9/L) for patients with bone marrow involvement. G-CSF is allowed but ANC value must be without G-CSF support 7 days before assessment. Platelets: ≥75,000 cells/μL (75 × 10^9/L), or ≥50,000 cells/μL (50 × 10^9/L) in patients with documented bone marrow involvement, and without transfusion/thrombopoietin support 7 days before assessment. Coagulation (INR and PTT or aPTT): ≤1.5 × ULN Serum amylase: ≤1.5 × ULN Serum lipase: ≤1.5 × ULN AST and ALT: ≤3.0 × ULN Total bilirubin: ≤1.5 × ULN (unless documented Gilbert's syndrome, then total bilirubin must be <3 × ULN with conjugated bilirubin ≤1.5 × ULN) Creatinine clearance: ≥30 mL/minute using Cockcroft/Gault formula: {[(140 - age) × (weight in kg)] / (72 × serum creatinine in mg/dL)} × 0.85 (if female) QT interval: Triplicate ECG mean QTcF <470 msec, and QTcF <470 msec on at least 2/3 consecutive ECGs, measured by Fridericia's formula: [QTcF = QT/(RR^0.33)]. Note: For patients with pacemaker or bundle branch block, the QTcF should be <475 msec. 7. Women of childbearing potential (WOCBP) must agree to use highly effective contraception (failure rate of <1% per year) during the study from Screening through 6 months after the last dose of NX-5948 or 5 weeks after the last dose of pirtobrutinib (Appendix 6). WOCBP must agree to not donate eggs (ova, oocytes) during the same timeframe. 8. Male patients with WOCBP partners must agree to use highly effective contraception and barrier contraception during the study from Screening through 3 months after the last dose of NX-5948 or pirtobrutinib (Appendix 6). Men must agree to not donate sperm during the same timeframe. 9. Must be willing and able to adhere to the prohibitions and restrictions specified in this protocol. 10. Must sign an informed consent form indicating that he or she understands the purpose of the procedures required for the study and is willing to participate in the study. Consent must be obtained prior to the initiation of any study-related tests or procedures that are not part of standard-of-care for the patient's disease.

Excludes prior BTK degrader/ncBTKi, Richter's transformation, active CNS involvement, recent SCT/CAR-T (<90 days), active major infection, significant cardiac disease, or concurrent investigational therapy.

1. Known or suspected prolymphocytic leukemia, Richter's transformation at any time preceding enrollment. Note: In cases of clinical suspicion of a more aggressive phenotype, including Richter's transformation, positron emission tomography (PET) should be performed and the treating physician may determine if histopathological evaluation should be performed and results reviewed by the treating physician to rule out transformation prior to enrollment. 2. Investigational agent or anticancer therapy (eg, small molecules) within 5 half-lives or 14 days (whichever is shorter) prior to planned start of study treatment. Antineoplastic and immunosuppressant monoclonal antibody treatment (including bispecifics) must be discontinued a minimum of 4 weeks prior to the first dose of study treatment. In addition, no concurrent systemic anticancer therapy is permitted. Note: continuation of certain anticancer therapies, including hormonal therapy for breast and prostate cancer, is allowed, provided they are not on the list of prohibited concomitant medications (Section 6.10.1). 3. Palliative limited-field radiotherapy within 7 days of the first dose of study treatment or broad field radiotherapy (≥30% of bone marrow or whole brain radiotherapy) within 28 days of the first dose of study treatment. 4. Ongoing systemic corticosteroids ≥10 mg/day prednisone or equivalent. Note: Corticosteroids ≥10 mg/day prednisone or equivalent in select setting may be allowed (refer to Section 6.10.1). 5. Use of systemic immunosuppressive drugs other than systemic corticosteroids for any medical condition within 60 days prior to first dose of study treatment. 6. Previously treated with a BTK degrader or an ncBTKi. 7. History of allogeneic or autologous stem cell transplant (SCT) or chimeric antigen receptor (CAR) T-cell therapy within the past 90 days prior to enrollment. 8. Toxicities from previous anticancer therapies must have resolved to baseline levels or to Grade 1 (EXCEPT for alopecia, hypothyroidism with adequate replacement therapy, hypopituitarism with adequate replacement therapy, peripheral neuropathy, and in cases where hematologic parameters still meet inclusion criteria). 9. Active second primary malignancy unless in remission and with life expectancy >2 years; and with documented medical monitor approval. Exceptions include: a. Adequately treated nonmelanomatous skin cancer or lentigo maligna melanoma without current evidence of disease. b. Adequately treated cervical carcinoma in situ without current evidence of disease. c. Localized (eg, lymph node negative) breast cancer treated with curative intent with no evidence of active disease present for more than 3 years and receiving adjuvant hormonal therapy. d. Localized prostate cancer undergoing active surveillance. 10. Current or history of central nervous system lymphoma or leukemia, including the brain, spinal cord, leptomeninges, and cerebrospinal fluid (as documented by imaging cytology or biopsy). 11. Active uncontrolled autoimmune cytopenia (eg, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura) where new therapy introduced or concomitant therapy escalated within the 4 weeks prior to study enrollment is required to maintain adequate blood counts. 12. Unable to swallow capsules or malabsorption syndrome, disease or procedure significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, inflammatory bowel disease, or partial or complete bowel obstruction likely to interfere with the delivery, absorption, or metabolism of study treatment. 13. Has any of the following: a. Myocardial infarction, unstable angina, unstable symptomatic ischemic heart disease, or placement of a coronary arterial stent within 6 months of planned start of study treatment. b. Previously documented left ventricular ejection fraction (LVEF) by any method of ≤45% in the 12 months prior to planned start of study. Assessment of LVEF should be done at Screening if echocardiogram or multigated acquisition (MUGA) scan has not been done within the last 3 months prior to first dose of study treatment. c. Uncontrolled or symptomatic arrhythmias. d. Any Class 3 or 4 cardiac failure as defined by the New York Heart Association (Appendix 10). e. A history of congenital long QT syndrome or Torsades de Pointes. f. Any other significant cardiac condition (eg, pericardial effusion, restrictive cardiomyopathy, severe untreated valvular stenosis, severe congenital heart disease) within 6 months of planned start of study. g. Persistent, poorly controlled hypertension (defined as systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg despite optimal medical management). 14. Thromboembolic events (eg, deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events), stroke, or intracranial hemorrhage within 6 months of planned start of study treatment. 15. History of bleeding diathesis (eg, hemophilia, von Willebrand disease). 16. Patients who experienced a potential life-threatening bleeding related to a BTKi with signs or symptoms of hemodynamic compromise, or bleeding in a critical area or organ (eg, retroperitoneal, intra-articular, pericardial, epidural, or intracranial bleeding or intramuscular bleeding with compartment syndrome), or bleeding associated with a decrease in the hemoglobin level of at least 2 g/dL. 17. Requiring ongoing treatment with warfarin or an equivalent vitamin K antagonist within 7 days prior to first dose of study treatment. Note: direct oral anticoagulants (DOACs) are allowed. 18. Has known allergies, hypersensitivity, or intolerance to components of the study treatment. 19. Pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within the timeframe per Inclusion Criterion 7. For WOCBP, negative pregnancy status must be confirmed by serum pregnancy test at Screening and serum or urine within 24 hours prior to the first dose of study treatment. 20. Has had major surgery within 4 weeks before the planned first dose of study treatment(s), or will not have fully recovered from surgery. Note: Patients with minor planned surgical procedures to be conducted under local anesthesia may participate. 21. Active, significant bacterial, fungal, parasitic, or viral infection including: a. Positive serologic status reflecting active hepatitis B or C infection as follows: − Presence of HBsAg. − Patients with presence of HBcAb, in the absence of HBsAg, with detectable HBV DNA. Note: The limit of detection for HBV DNA must have a sensitivity of <20 IU/mL. Exception: Patients with presence of HBcAb but undetectable HBV DNA and who are willing to undergo HBV DNA monitoring every 4 weeks for HBV reactivation are eligible. − Patients with presence of HCV antibody and detectable HCV RNA. Note: The limit of detection for HCV RNA must have a sensitivity of <15 IU/mL. Exception: Patients with presence of HCV antibody and undetectable HCV RNA and who are willing to undergo HCV RNA monitoring every 4 weeks for HCV reactivation are eligible. b. Infection with human immunodeficiency virus (HIV)-1 or HIV-2. Exception: Patients with well-controlled HIV (eg, CD4 >350/mm3 and undetectable viral load) are eligible. 22. Any other medical or psychiatric condition or social situation that, in the opinion of the investigator, would compromise patient safety, or interfere with the study objectives or completion of treatment per protocol. 23. History of or ongoing drug-induced pneumonitis. 24. Presence of a gastrointestinal ulcer diagnosed by endoscopy or intestinal perforation within 3 months before Screening. 25. Vaccinated with a live vaccine within 28 days prior to the first dose of study treatment (refer to Section 6.10.1). 26. Administration of any strong cytochrome P450 3A (CYP3A) inhibitors or inducers within 14 days or 5 half-lives, whichever is longer, and any moderate CYP3A inhibitors or inducers within 7 days, or 5 half-lives, whichever is shorter, prior to first dose of study treatment (see Section 6.10.1.2). 27. Administration of any inhibitors of P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) transporters within 48 hours, or 5 half-lives, whichever is shorter, prior to first dose of study treatment (see Section 6.10.1.3). 28. Administration of a proton pump inhibitor (prescription or over-the-counter) within 7 days prior to first dose of study treatment (see Section 6.10.1.4). 29. Concurrent participation in another investigational or interventional clinical study. Note: Concurrent participation in observational or noninterventional studies is allowed. In addition, patients who have completed active treatment in a clinical study and are in the follow-up period can be enrolled in this study.