This is a first-in-human Phase 1a/1b multicenter, open-label study designed to evaluate the safety and anti-cancer activity of NX-5948 in patients with advanced B-cell malignancies.

Phase 1a is a dose escalation to evaluate the safety and tolerability of NX-5948 in adult patients with relapsed/refractory (R/R) B cell malignancies who have received at least 2 prior lines of therapy, or at least 1 prior line of therapy for Primary Central Nervous System Lymphoma (PCNSL), and for whom no other therapies are known to provide clinical benefit. Indications include: Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), Diffuse Large B-cell Lymphoma (DLBCL), Mantle Cell Lymphoma (MCL), Waldenstrom Macroglobulinemia (WM), Marginal Zone Lymphoma (MZL), Follicular Lymphoma (FL), Primary Central Nervous System Lymphoma (PCNSL) or any of the above indications with disease in the central nervous system or Secondary Central Nervous System Lymphoma (SCNSL).

Phase 1b Part 1, called safety expansion, investigates the safety and anti-tumor activity of NX-5948 at the dose(s) selected in Phase 1a in up to 17 expansion cohorts of patients with histologically confirmed B-cell malignancy indications who have received specified prior therapies based on indication:

• CLL or SLL (patients may be randomized to one of two dose levels investigated for CLL/SLL until an optimal dose is selected)
• MCL
• MZL
• WM
• DLBCL
• FL
• PCNSL/SCNSL

Phase 1b Part 2, called cohort expansion, will further investigate the anti-tumor activity of NX-5948 at the dose(s) selected in Phase 1b par 1 in one additional expansion arm of CLL/SLL patients.

Key Inclusion Criteria:

• Age ≥18 years

• Patients in Phase 1a (Dose Escalation) must have histologically confirmed R/R CLL, SLL, DLBCL (subgroups include Richter-transformed DLBCL, germinal center B-cell type, activated B-cell type, high-grade B-cell lymphoma with MYC and BCL-2 and/or BCL-6 rearrangements, high-grade B-cell lymphomas NOS), FL, MCL, MZL (subtypes include EMZL, MALT, NMZL, SMZL), WM, or PCNSL.

• Patients in Phase 1a must meet the following:

  o For non-PCNSL indications, received at least 2 prior lines of therapy and have no other available therapies known to provide clinical benefit. For PCNSL, received at least 1 prior line of therapy

• Patients in Phase 1b (Safety and Cohort Expansion) must have 1 of the following histologically documented B-cell malignancies, must meet criteria for systemic treatment, and must have received prior therapies and/or molecular features based on details described for each cohort: CLL or SLL, DLBCL, MCL, FL, MZL, WM, or PCNSL/SCNSL.

• Measurable disease per response criteria specific to the malignancy.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (0-2 for patients with PCNSL and secondary CNS involvement).

• Adequate organ and bone marrow function

Key Exclusion Criteria:

• Known or suspected active prolymphocytic leukemia or Richter's transformation to Hodgkin's lymphoma prior to study enrollment

• Prior treatment for the indication under study for anti-cancer intent that includes:

  1. Radiotherapy within 2 weeks of planned start of study drug (excluding limited palliative radiation).
  2. Prior systemic chemotherapy within 2 weeks of planned start of study drug.
  3. Prior monoclonal antibody therapy within 4 weeks of planned start of study drug, except for patients enrolling in Cohort 16 (CLL with secondary wAIHA) where a 16-week washout period is required.
  4. Prior small molecule therapy within 2 weeks or 5 half-lives (whichever is shorter) of planned start of study drug.
  5. Autologous or allogeneic stem cell transplant within 100 days prior to planned start of study drug.
  6. Chimeric antigen receptor (CAR) T-cell therapy within 100 days prior to start of study drug (within 60 days prior to start of study drug for Phase 1b).
  7. Use of systemic corticosteroids outside of dosing limits described below and within 7 days prior to initiation of study treatment excepting those used as prophylaxis for radio diagnostic contrast. Patients with PCNSL/SCNSL: no greater than 40 mg/day prednisone, or equivalent. Patients with PCNSL/SCNSL using greater than 20 mg/day prednisone, or equivalent, must be clinically stable at that dose for 7 days. All other diagnoses: no greater than 20 mg/day prednisone or equivalent.
  8. Use of systemic immunosuppressive drugs other than systemic corticosteroids for any medical condition within 60 days prior to first dose of study drug
  9. Previously treated with a BTK degrader

• Active, uncontrolled autoimmune hemolytic anemia (except for patients enrolling in Cohort 16) or active, uncontrolled autoimmune thrombocytopenia.

• Patient has any of the following within 6 months of planned start of study drug:

  1. Myocardial infarction, unstable angina, unstable symptomatic ischemic heart disease, or placement of a coronary arterial stent
  2. Uncontrolled atrial fibrillation or other clinically significant arrhythmias, conduction abnormalities, or New York Heart Association (NYHA) class III or IV heart failure
  3. Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events), stroke, or intracranial hemorrhage
  4. Any other significant cardiac condition (e.g., pericardial effusion, restrictive cardiomyopathy, severe untreated valvular stenosis, severe congenital heart disease, or persistent uncontrolled hypertension defined as systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg despite optimal medical management)

• Bleeding diathesis, or other known risk for acute blood loss.

• History of Grade ≥ 2 hemorrhage within 28 days of planned start of study drug.

• Active known concurrent malignancy or malignancy other than the one under study within the past 3 years. (Exceptions include, but are not limited to, patients with more recent history of basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast may enroll if they have undergone curative therapy and have no evidence of disease).