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

Study Overview
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Brief Summary
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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.

Detailed Description
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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 and for whom no other therapies are known to provide clinical benefit. Indications include: Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), non-germinal center B-cell subtype (non-GCB) Diffuse Large B-cell Lymphoma (DLBCL), Mantle Cell Lymphoma (MCL), Waldenstrom Macroglobulinemia (WM), Marginal Zone Lymphoma (MZL), Follicular Lymphoma (FL) including those with secondary CNS involvement in any disease indication listed, or Primary Central Nervous System Lymphoma (PCNSL). Phase 1b will investigate the efficacy of NX-5948 at the dose(s) selected in Phase 1a in up to 4 cohorts of patients with histologically confirmed R/R B-cell malignancy indications who have received at least 2 prior lines of therapy (or at least 1 prior line for patients with WM or PCNSL): CLL or SLL including those with secondary CNS involvement of their disease Non-GCB DLBCL or MCL including those with secondary CNS involvement of their disease MZL, WM, or FL including those with secondary CNS involvement of their disease PCNSL

Official Title
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A Phase 1, Dose Escalation, and Cohort Expansion Study Evaluating NX-5948, a Bruton's Tyrosine Kinase (BTK) Degrader, in Adults With Relapsed/Refractory B-cell Malignancies

Conditions
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Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), Diffuse Large B Cell Lymphoma (DLBCL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL), Marginal Zone Lymphoma (MZL), Waldenstrom Macroglobulinemia (WM), Primary Central Nervous System Lymphoma (PCNSL)

Intervention / Treatment
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* Drug: NX-5948


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Age ≥18 years Patients in Phase 1a (Dose Escalation) must have histologically confirmed R/R CLL, SLL, non-GCB DLBCL, Richter-transformed DLBCL, high-grade B-cell lymphoma with MYC and BCL-2 and/or BCL-6 rearrangements, high-grade B-cell lymphomas NOS, FL, MCL, MZL (EMZL, MALT, NMZL, SMZL), or WM, including those with secondary CNS involvement in any disease indication listed or PCNSL. Patients in Phase 1a must meet the following: o Received at least 2 prior lines of therapy and have no other therapies known to provide clinical benefit. Patients in Phase 1b (Cohort Expansion) must have 1 of the following histologically documented R/R B-cell malignancies, must meet criteria for systemic treatment, and must have failed 2 prior lines of therapy: CLL or SLL, Non-GCB DLBCL, MCL, FL, MZL, WM, including those with secondary CNS involvement of their disease for all above indications, or PCNSL. Radiographically measurable disease per response criteria specific to the malignancy. Target lymph nodes must be > 1.5 cm and extranodal lesions must be ≥ 1.0 cm in longest diameter. 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: Prior treatment for the indication under study for anti-cancer intent that includes: Radiotherapy within 2 weeks of planned start of study drug (excluding limited palliative radiation). Prior systemic chemotherapy within 4 weeks of planned start of study drug. Note: Use of intrathecal chemotherapy is allowed per Institutional guidelines. Prior monoclonal antibody therapy within 4 weeks of planned start of study drug. Prior small molecule therapy within 4 weeks or 5 half-lives (whichever is shorter) of planned start of study drug. Autologous or allogeneic stem cell transplant within 100 days prior to planned start of study drug. Chimeric antigen receptor (CAR) T-cell therapy within 100 days prior to start of study drug (within 30 days prior to start of study drug for Phase 1b). Must have evidence of B-cell recovery if patient received prior CAR T-cell therapy. Use of systemic corticosteroids outside of dosing limits described below and within 14 days prior to initiation of study treatment excepting those used as prophylaxis for radio diagnostic contrast. Patients with CNSL: no greater than 40 mg/day prednisone, or equivalent, central nervous system lymphoma (CNSL) patients using greater than 20 mg/day prednisone, or equivalent must be clinically stable at that dose for 14 days. All other diagnoses: no greater than 20 mg/day prednisone or equivalent. Use of immunosuppressive drugs other than systemic corticosteroids within 30 days prior to first dose of study drug Active, uncontrolled autoimmune hemolytic anemia or autoimmune thrombocytopenia. Patient has any of the following within 6 months of planned start of study drug: Myocardial infarction, unstable angina, unstable symptomatic ischemic heart disease, or placement of a coronary arterial stent Uncontrolled atrial fibrillation or other clinically significant arrhythmias, conduction abnormalities, or New York Heart Association (NYHA) class III or IV heart failure Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events), stroke, or intracranial hemorrhage 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1a Dose Escalation<br>Multiple dose levels of NX-5948 to be evaluated; determination of Maximum Tolerated Dose/Phase 1b recommended dose | Drug: NX-5948<br>* Oral NX-5948<br>|
| Experimental: Phase 1b in CLL or SLL<br>CLL or SLL with prior exposure to both a Bruton's tyrosine kinase inhibitor (BTKi) and BCL-2 inhibitor, unless previously deemed ineligible for those therapies, including those with secondary CNS involvement of their disease. | Drug: NX-5948<br>* Oral NX-5948<br>|
| Experimental: Phase 1b in Non-GCB DLBCL or MCL<br>Non-GCB DLBCL with prior exposure to an anthracycline and an anti-CD20 monoclonal antibody (mAb)-based chemo-immunotherapy regimen, including transformed indolent lymphoma, Richter-transformed DLBCL, high-grade B-cell lymphoma with MYC and BCL-2 and/or BCL-6 rearrangements, high-grade B-cell lymphomas NOS, and patients with secondary CNS involvement of their disease; or MCL with prior exposure to a BTKi and an anti-CD20 mAb-based chemo-immunotherapy regimen including those with secondary CNS involvement of their disease. | Drug: NX-5948<br>* Oral NX-5948<br>|
| Experimental: Phase 1b in FL, MZL, or WM<br>FL with prior exposure to an anti-CD20 mAb-based chemo-immunotherapy regimen and 1 additional line of therapy; or MZL (EMZL, MALT, NMZL, SMZL) with prior exposure to an anti-CD20 mAb-based chemo-immunotherapy regimen and 1 additional line of therapy; or WM with prior exposure to a BTKi and 1 additional line of therapy; or FL, MZL (EMZL, MALT, NMZL, SMZL), and WM patients meeting the above criteria with secondary CNS involvement of their disease. | Drug: NX-5948<br>* Oral NX-5948<br>|
| Experimental: Phase 1b in PCNSL<br>PCNSL patients who have progressed or had no response to at least 2 prior lines of therapy. | Drug: NX-5948<br>* Oral NX-5948<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with protocol specified dose-limiting toxicities | Phase 1a | Up to 24 months | 
| To establish the maximum tolerated dose and/or recommended Phase 1b dose | Phase 1a | Up to 24 months | 
| To evaluate the anti-tumor activity of NX-5948 at the recommended Phase 1b dose based on overall response rate (ORR) as assessed by the Investigator | Phase 1b | Up to 3 years | 
| Number of participants with treatment-emergent adverse events (TEAEs); Grade 3, 4, 5 TEAEs, serious adverse events (SAEs), TEAEs leading to study drug discontinuation, deaths due to TEAEs, and all deaths | Phase 1a/1b | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK) profile of NX-5948: Maximum Serum Concentration | Phase 1a/1b - Sampling following the first dose, pre- and post-dose at selected cycles and at the end of treatment | Up to 5 years | 
| Pharmacodynamic (PD) profile of NX-5948: Changes from baseline of BTK levels in B-cells | Phase 1a/1b - Sampling at screening, following the first dose, pre and post-dose at selected cycles and at the end of treatment | Up to 5 years | 
| Complete response (CR) rate / CR with incomplete marrow recovery as assessed by the Investigator | Phase 1a/1b | Up to 5 years | 
| Duration of response (DOR) as assessed by the Investigator | Phase 1a/1b | Up to 5 years | 
| Progression-free survival (PFS) as assessed by the Investigator | Phase 1a/1b | Up to 5 years | 
| Time to next therapy | Phase 1a/1b | Up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BTK Inhibitor, C481, BTK Degrader, B-Cell Malignancy, Lymphoma, C481S, Bruton's Tyrosine Kinase, NX-5948, Targeted Protein Degradation, Chimeric Targeting Molecule (CTM)