A Study of NX-5948 in Adults With Relapsed/Refractory B-cell Malignancies

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-celltype, activated B-cell type, high-grade B-cell lymphoma with MYC and BCL-2 and/orBCL-6 rearrangements, high-grade B-cell lymphomas NOS), FL, MCL, MZL (subtypesinclude 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 noother available therapies known to provide clinical benefit. For PCNSL, received atleast 1 prior line of therapy

• Patients in Phase 1b (Safety and Cohort Expansion) must have 1 of the followinghistologically documented R/R B-cell malignancies, must meet criteria for systemictreatment, and must have received prior therapies and/or molecular features based ondetails described for each cohort: CLL or SLL, DLBCL, MCL, FL, MZL, WM, orPCNSL/SCNSL.

• Measurable disease per response criteria specific to the malignancy.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (0-2 forpatients 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 toHodgkin'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 limitedpalliative radiation).

2. Prior systemic chemotherapy within 2 weeks of planned start of study drug.Note: Use of intrathecal chemotherapy is allowed per Institutional guidelines.

3. Prior monoclonal antibody therapy within 4 weeks of planned start of studydrug.

4. Prior small molecule therapy within 2 weeks or 5 half-lives (whichever isshorter) of planned start of study drug.

5. Autologous or allogeneic stem cell transplant within 100 days prior to plannedstart of study drug.

6. Chimeric antigen receptor (CAR) T-cell therapy within 100 days prior to startof 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 andwithin 7 days prior to initiation of study treatment excepting those used asprophylaxis for radio diagnostic contrast. Patients with PCNSL/SCNSL: nogreater than 40 mg/day prednisone, or equivalent. Patients with PCNSL/SCNSLusing greater than 20 mg/day prednisone, or equivalent, must be clinicallystable at that dose for 7 days. All other diagnoses: no greater than 20 mg/dayprednisone or equivalent.

8. Use of systemic immunosuppressive drugs other than systemic corticosteroids forany medical condition within 60 days prior to first dose of study drug

9. Previously treated with a BTK degrader

• Active, uncontrolled autoimmune hemolytic anemia or 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 heartdisease, 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 IVheart failure

3. Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, orsymptomatic cerebrovascular events), stroke, or intracranial hemorrhage

4. Any other significant cardiac condition (e.g., pericardial effusion,restrictive cardiomyopathy, severe untreated valvular stenosis, severecongenital heart disease, or persistent uncontrolled hypertension defined assystolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHgdespite 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 studywithin the past 3 years. (Exceptions include, but are not limited to, patients withmore recent history of basal or squamous cell skin cancer, superficial bladdercancer, or carcinoma in situ of the cervix or breast may enroll if they haveundergone curative therapy and have no evidence of disease).