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

NCT05131022 | Recruiting Phase 1 DMC FDA Drug

• 3 other identifiers: NX-5948-3012023-510541-25-002021-003125-29
• Study Type: interventional
• Target: 572
• Locations: 8 countries
• Sites: 62

Brief Summary

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.

Conditions

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); Secondary Central Nervous System Lymphoma (SCNSL)

Keywords

BTK Degrader; BTK Inhibitor; B-Cell Malignancy; Lymphoma; C481; C481S; Bruton's Tyrosine Kinase; NX-5948; Targeted Protein Degradation; Chimeric Targeting Molecule (CTM)

Outcome Measures

Primary Outcomes (5)

• 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(s)

  Phase 1a

  Up to 24 months

• To evaluate the anti-tumor activity of NX-5948 in the dose levels selected for Phase 1b safety expansion based on overall response rate (ORR) as assessed by Investigator

  Phase 1b Part 1

  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 / Phase 1b Part 1

  Up to 6 years

• To further evaluate the anti-tumor activity of NX-5948 in patients with CLL/SLL at the dose identified in Phase 1b Part 1 based on overall response rate (ORR) as assessed by Investigator

  Phase 1b Part 2

  Up to 3 years

Secondary Outcomes (7)

• Pharmacokinetic (PK) profile of NX-5948: Maximum Serum Concentration

  Up to 6 years

• Pharmacodynamic (PD) profile of NX-5948: Changes from baseline of BTK levels in B-cells

  Up to 6 years

• Complete response (CR) rate / CR with incomplete marrow recovery as assessed by the Investigator

  Up to 6 years

• Duration of response (DOR) as assessed by the Investigator

  Up to 6 years

• Progression-free survival (PFS) as assessed by the Investigator

  Up to 6 years

Study Arms (19)

Phase 1a Dose Escalation

EXPERIMENTAL

Multiple dose levels of NX-5948 to be evaluated; determination of Maximum Tolerated Dose/Phase 1b recommended dose(s)

Drug: NX-5948

Phase 1b Part 1 Cohort 1 in CLL or SLL with prior BTKi and BCL2i

EXPERIMENTAL

CLL or SLL with prior exposure to both a Bruton's tyrosine kinase inhibitor (BTKi) and BCL-2 inhibitor, unless previously deemed ineligible for a BCL-2i. Patients enrolled in CLL/SLL arm will be randomized to one of two dose levels.

Drug: NX-5948

Phase 1b Part 1 Cohort 2 in CLL/SLL with non-C481S BTK mutations

EXPERIMENTAL

Prior exposure to both BTKi and BCL-2i (unless deemed ineligible for BCL-2i by Investigator at the time of study enrollment) and documented BTK mutation other than C481S within 6 months prior to study entry

Drug: NX-5948

Phase 1b Part 1 Cohort 3 in CLL/SLL with prior non-covalent BTKi

EXPERIMENTAL

CLL/SLL with prior exposure to ncBTKi and are BCL-2i naïve.

Drug: NX-5948

Phase 1b Part 1 Cohort 4 in CLL/SLL with TP53 or 17p deletion, 2L, prior BTKi

EXPERIMENTAL

Patients with documented TP53 mutation or 17p deletion and 1 prior line of therapy that included a BTKi and are BCL-2i naïve.

Drug: NX-5948

Phase 1b Part 1 Cohort 5 in CLL/SLL with 2L+, prior BTKi

EXPERIMENTAL

Patients with at least 1 prior line of therapy that included a BTKi and are BCL-2i naïve.

Drug: NX-5948

Phase 1b Part 1 Cohort 6 in MCL

EXPERIMENTAL

Non-blastoid MCL with prior exposure to a BTKi and an anti-CD20 monoclonal antibody (mAb)-based chemoimmunotherapy regimen

Drug: NX-5948

Phase 1b Part 1 Cohort 7 in MZL

EXPERIMENTAL

MZL (EMZL, MALT, NMZL, SMZL) with prior exposure to an anti-CD20 mAb-based chemo-immunotherapy regimen and an additional line of therapy

Drug: NX-5948

Phase 1b Part 1 Cohort 8 in WM (3L+)

EXPERIMENTAL

WM with prior exposure to a BTKi and at least an additional line of therapy

Drug: NX-5948

Phase 1b Part 1 Cohort 9 in WM (2L)

EXPERIMENTAL

WM following upfront therapy with a BTKi

Drug: NX-5948

Phase 1b Part 1 Cohort 10 in DLBCL

EXPERIMENTAL

DLBCL which transformed from indolent lymphoma or Richters transformation with prior exposure to an anthracycline (unless previously deemed ineligible to receive), an anti-CD20 mAb-based chemoimmunotherapy regimen, and an additional line of therapy

Drug: NX-5948

Phase 1b Part 1 Cohort 11 in FL

EXPERIMENTAL

FL (grade 1-3a) with prior exposure to an anti-CD20 mAb-based chemoimmunotherapy regimen and an additional line of therapy

Drug: NX-5948

Phase 1b Part 1 Cohort 12 in PCNSL/SCNSL

EXPERIMENTAL

PCNSL following at least 1 prior line of therapy that included a BTKi (2L+) or following 2 or more prior lines of therapy (3L+), or SCNSL patients meeting criteria for a non-CLL/SLL cohort enrolling that disease with secondary CNS involvement of lymphoma

Drug: NX-5948

Phase 1b Part 1 Cohort 13 in PCNSL

EXPERIMENTAL

PCNSL following upfront therapy and with no prior exposure to a BTKi (2L).

Drug: NX-5948

Phase 1b Part 2 in CLL or SLL with prior BTKi and BCL-2i

EXPERIMENTAL

CLL or SLL with prior exposure to both a Bruton's tyrosine kinase inhibitor (BTKi) and BCL-2 inhibitor

Drug: NX-5948

Phase 1b Part 1 Cohort 14 in first-line WM

EXPERIMENTAL

Treatment-naïve WM deemed unfit for chemoimmunotherapy

Drug: NX-5948

Phase 1b Part 1 Cohort 15 in BTKi-naive CLL/SLL

EXPERIMENTAL

First-line (1L) or second-line+ (2L)+ CLL/SLL with no prior exposure to a BTKi

Drug: NX-5948

Phase 1b Part 1 Cohort 16 in CLL/SLL with secondary warm autoimmune hemolytic anemia (wAIHA)

EXPERIMENTAL

BTKi-exposed R/R CLL or SLL with secondary wAIHA

Drug: NX-5948

Phase 1b Part 1 Cohort 17 in CLL/SLL with CNS involvement

EXPERIMENTAL

BTKi-exposed R/R CLL or SLL with CNS involvement

Drug: NX-5948

Interventions

NX-5948 DRUG

Oral NX-5948

Phase 1a Dose Escalation; Phase 1b Part 1 Cohort 1 in CLL or SLL with prior BTKi and BCL2i; Phase 1b Part 1 Cohort 10 in DLBCL; Phase 1b Part 1 Cohort 11 in FL; Phase 1b Part 1 Cohort 12 in PCNSL/SCNSL; Phase 1b Part 1 Cohort 13 in PCNSL; Phase 1b Part 1 Cohort 14 in first-line WM; Phase 1b Part 1 Cohort 15 in BTKi-naive CLL/SLL; Phase 1b Part 1 Cohort 16 in CLL/SLL with secondary warm autoimmune hemolytic anemia (wAIHA); Phase 1b Part 1 Cohort 17 in CLL/SLL with CNS involvement; Phase 1b Part 1 Cohort 2 in CLL/SLL with non-C481S BTK mutations; Phase 1b Part 1 Cohort 3 in CLL/SLL with prior non-covalent BTKi; Phase 1b Part 1 Cohort 4 in CLL/SLL with TP53 or 17p deletion, 2L, prior BTKi; Phase 1b Part 1 Cohort 5 in CLL/SLL with 2L+, prior BTKi; Phase 1b Part 1 Cohort 6 in MCL; Phase 1b Part 1 Cohort 7 in MZL; Phase 1b Part 1 Cohort 8 in WM (3L+); Phase 1b Part 1 Cohort 9 in WM (2L); Phase 1b Part 2 in CLL or SLL with prior BTKi and BCL-2i

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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:
• Radiotherapy within 2 weeks of planned start of study drug (excluding limited palliative radiation).
• Prior systemic chemotherapy within 2 weeks of planned start of study drug.
• 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.
• Prior small molecule therapy within 2 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 60 days prior to start of study drug for Phase 1b).
• 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.
• Use of systemic immunosuppressive drugs other than systemic corticosteroids for any medical condition within 60 days prior to first dose of study drug
• 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:
• 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

Sponsors & Collaborators

• Nurix Therapeutics, Inc.: lead

Study Sites (62)

City of Hope

Duarte, California, 91010, United States

RECRUITING

University of California, San Francisco

San Francisco, California, 94143, United States

RECRUITING

Colorado Blood Cancer Institute

Denver, Colorado, 80218, United States

RECRUITING

Yale Cancer Center

New Haven, Connecticut, 06510, United States

RECRUITING

University of Miami

Miami, Florida, 33136, United States

RECRUITING

Florida Cancer Specialists

Sarasota, Florida, 34232, United States

RECRUITING

Winship Cancer Institute of Emory University

Atlanta, Georgia, 30322, United States

RECRUITING

Northwestern University

Chicago, Illinois, 60611, United States

RECRUITING

National Institute of Health

Bethesda, Maryland, 20814, United States

RECRUITING

Cayuga Medical Center

Ithaca, New York, 14850, United States

WITHDRAWN

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

ACTIVE NOT RECRUITING

Duke University Medical Center

Durham, North Carolina, 27705, United States

RECRUITING

University of Cincinnati Medical Center

Cincinnati, Ohio, 45219, United States

RECRUITING

Cleveland Clinic

Cleveland, Ohio, 44195, United States

RECRUITING

University of Pennsylvania, Abramson Cancer Center

Philadelphia, Pennsylvania, 19104, United States

RECRUITING

MD Anderson Cancer Center

Houston, Texas, 77030, United States

RECRUITING

Huntsman Cancer Institute

Salt Lake City, Utah, 84112, United States

WITHDRAWN

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

RECRUITING

CHU Angers

Angers, 49933, France

RECRUITING

Hôpital Avicenne

Bobigny, 93009, France

RECRUITING

CHU de Nantes

Nantes, 44093, France

RECRUITING

CHU Bordeaux

Pessac, 33604, France

RECRUITING

CHU de Poitiers

Poitiers, 86021, France

RECRUITING

Institut Curie-Site Saint-Cloud

Saint-Cloud, 92210, France

RECRUITING

CHRU de Nancy

Vandœuvre-lès-Nancy, 54500, France

RECRUITING

IRCCS - AOU di Bologna

Bologna, 40138, Italy

WITHDRAWN

ASST Spedali Civili Brescia

Brescia, 25123, Italy

WITHDRAWN

IRCCS Ospedale San Raffaele - Università Vita-Salute San Raffaele di Milano

Milan, 20132, Italy

RECRUITING

IRCCS Ospedale San Raffaele

Milan, 20132, Italy

RECRUITING

Fondazione Policlinico Universitario A. Gemelli IRCCS

Rome, 00168, Italy

RECRUITING

University Medical Center Groningen

Groningen, 9713 GZ, Netherlands

WITHDRAWN

Radboud University Medical Center

Nijmegen, 6525 GA, Netherlands

RECRUITING

Erasmus MC

Rotterdam, 3015 GD, Netherlands

RECRUITING

University Medical Center Utrecht

Utrecht, 3584 CX, Netherlands

RECRUITING

AidPort sp. Zo.o

Skórzewo, Greater Poland Voivodeship, 60-185, Poland

RECRUITING

Pratia MCM

Krakow, Lesser Poland Voivodeship, 30-272, Poland

RECRUITING

University Clinical Hostpital in Wroclaw

Wroclaw, Lower Silesian Voivodeship, 50-367, Poland

RECRUITING

Pratia MTZ

Warsaw, Masovian Voivodeship, 02-172, Poland

RECRUITING

National Institute of Oncology Warszawa

Warsaw, Masovian Voivodeship, 02-781, Poland

RECRUITING

Pratia Onkologia Katowice

Katowice, Silesian Voivodeship, 40-519, Poland

RECRUITING

Medical University of Lublin

Lublin, 20-090, Poland

RECRUITING

Hospital Universitari Vall d'Hebron

Barcelona, 08035, Spain

RECRUITING

Hospital Clínic de Barcelona

Barcelona, 08036, Spain

RECRUITING

Hospital Universitario de Cabuenes

Gijón, 33203, Spain

RECRUITING

Hospital Ramón y Cajal

Madrid, 28034, Spain

RECRUITING

Hospital Fundación Jimenez Díaz - START Madrid

Madrid, 28040, Spain

RECRUITING

Universitätsspital Basel

Basel, 4031, Switzerland

RECRUITING

Istituto Oncologico della Svizzera Italiana

Bellinzona, Switzerland

RECRUITING

Inselspital - Universitatsklinik Bern

Bern, 3010, Switzerland

RECRUITING

Hôpitaux Universitaires de Genève

Geneva, 1205, Switzerland

RECRUITING

Kantonsspital St.Gallen

Sankt Gallen, 9007, Switzerland

RECRUITING

University Hospital Zurich

Zurich, 8091, Switzerland

RECRUITING

The Beatson WOS Cancer Center

Glasgow, Scotland, G12 0YN, United Kingdom

RECRUITING

St. James Hospital

Leeds, LS9 7TF, United Kingdom

RECRUITING

Clatterbridge Cancer Center NHS Foundation Trust

Liverpool, L7 8YA, United Kingdom

RECRUITING

St. Bartholomew's Hospital, Barts NHS Trust

London, EC1A 7BE, United Kingdom

RECRUITING

Sarah Cannon Research Institute UK

London, W1G 6AD, United Kingdom

RECRUITING

The Christie NHS Foundation Trust

Manchester, M20 4BX, United Kingdom

RECRUITING

Oxford University Hospitals NHS Foundation Trust

Oxford, OX3 7LE, United Kingdom

RECRUITING

University Hospitals Plymouth NHS Trust

Plymouth, PL6 8DH, United Kingdom

RECRUITING

University Hospital Southampton NHS Foundation Trust

Southampton, SO16 6YD, United Kingdom

RECRUITING

Royal Marsden NHS Foundation Trust

Sutton, SM2 5PT, United Kingdom

RECRUITING

Related Publications (1)

• Zhang D, Harris HM, Chen J, Judy J, James G, Kelly A, McIntosh J, Tenn-McClellan A, Ambing E, Tan YS, Lu H, Gajewski S, Clifton MC, Yung S, Robbins DW, Pirooznia M, Skanland SS, Gaglione E, Mhibik M, Underbayev C, Ahn IE, Sun C, Herman SEM, Noviski M, Wiestner A. NRX-0492 degrades wild-type and C481 mutant BTK and demonstrates in vivo activity in CLL patient-derived xenografts. Blood. 2023 Mar 30;141(13):1584-1596. doi: 10.1182/blood.2022016934.

  PMID: 36375120 DERIVED

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Follicular; Lymphoma, Mantle-Cell; Lymphoma, B-Cell, Marginal Zone; Waldenstrom Macroglobulinemia; Lymphoma

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Neoplasms, Plasma Cell; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders

Study Officials

• Study Director

  Nurix Therapeutics, Inc.

  STUDY DIRECTOR

Central Study Contacts

Additional Site Contact Information

CONTACT

+1 (415) 417-3418; clinicaltrials@nurixtx.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 12, 2021
• First Posted: November 23, 2021
• Study Start: April 13, 2022
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2028
• Last Updated: April 14, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

ES (5); NL (4); GB (10); FR (7); IT (5); CH (6); PL (7); US (18)