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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Chronic Lymphocytic Leukemia (CLL); Small Lymphocytic Lymphoma (SLL); Mantle Cell Lymphoma (MCL); Follicular Lymphoma (FL); Primary Central Nervous System Lymphoma (PCNSL); Marginal Zone Lymphoma (MZL); Waldenstrom Macroglobulinemia (WM); Diffuse Large B Cell Lymphoma (DLBCL)
• Intervention / Treatment: Drug: NX-5948

Detailed Description

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), 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 7 expansion arms of patients with histologically confirmed R/R B-cell malignancy indications who have received the specified prior therapies based on indication:

• CLL or SLL (two dose levels will be investigated for CLL/SLL)
• MCL
• MZL
• WM
• DLBCL
• FL
• PCNSL/SCNSL

• Study Type: Interventional
• Enrollment (Estimated): 292
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Patient Outreach; Phone Number: 7821 +1 (415) 417-3441; Email: NX5948301@nurixtx.com

Study Locations

• Netherlands
  • Nijmegen, Netherlands, 6525 GA
    • Recruiting
    • Radboud University Medical Center
  • Rotterdam, Netherlands, 3015 GD
    • Recruiting
    • Erasmus MC
  • Utrecht, Netherlands, 3584 CX
    • Recruiting
    • University Medical Center Utrecht
• United Kingdom
  • Leeds, United Kingdom, LS9 7TF
    • Recruiting
    • St. James Hospital
  • Liverpool, United Kingdom, L7 8YA
    • Recruiting
    • Clatterbridge Cancer Center NHS Foundation Trust
  • London, United Kingdom, W1G 6AD
    • Recruiting
    • Sarah Cannon Research Institute UK
  • London, United Kingdom, EC1A 7BE
    • Recruiting
    • St. Bartholomew's Hospital, Barts NHS Trust
  • Manchester, United Kingdom, M20 4BX
    • Recruiting
    • The Christie NHS Foundation Trust
  • Oxford, United Kingdom, OX3 7LE
    • Recruiting
    • Oxford University Hospitals NHS Foundation Trust
  • Plymouth, United Kingdom, PL6 8DH
    • Recruiting
    • University Hospitals Plymouth NHS Trust
  • Southampton, United Kingdom, SO16 6YD
    • Recruiting
    • University Hospital Southampton NHS Foundation Trust
  • Sutton, United Kingdom, SM2 5PT
    • Recruiting
    • Royal Marsden NHS Foundation Trust
  • Scotland
    • Glasgow, Scotland, United Kingdom, G12 0YN
      • Recruiting
      • The Beatson WOS Cancer Center
      • Contact: Pam McKay
• United States
  • California
    • Duarte, California, United States, 91010
      • Recruiting
      • City of Hope
    • San Francisco, California, United States, 94143
      • Recruiting
      • University of California, San Francisco
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Recruiting
      • Yale Cancer Center
  • Florida
    • Miami, Florida, United States, 33136
      • Recruiting
      • University of Miami
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Recruiting
      • Winship Cancer Institute of Emory University
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Recruiting
      • Northwestern University
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Recruiting
      • Duke University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • Recruiting
      • University of Cincinnati Medical Center
    • Cleveland, Ohio, United States, 44195
      • Recruiting
      • Cleveland Clinic
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Recruiting
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 therapies known to provide clinical benefit. For PCNSL, received at least 1 prior line of therapy

• 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 received prior therapies based on indication: 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 prolymphocytic leukemia or Richter's transformation to Hodgkin's lymphoma at any time preceding 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. Note: Use of intrathecal chemotherapy is allowed per Institutional guidelines.
  3. Prior monoclonal antibody therapy within 4 weeks of planned start of study drug.
  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 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, including both primary and secondary 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.
  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 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 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 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).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1b in MCL; MCL with prior exposure to a BTKi and an anti-CD20 monoclonal antibody (mAb)-based chemo-immunotherapy regimen	Drug: NX-5948; Oral NX-5948
Experimental: Phase 1b in MZL; 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; Oral NX-5948
Experimental: Phase 1b in PCNSL/SCNSL; PCNSL patients who have progressed or had no response to at least 2 prior lines of therapy, or SCNSL patients meeting criteria for non-CLL/SLL arms above with secondary CNS involvement of lymphoma	Drug: NX-5948; Oral NX-5948
Experimental: Phase 1b in WM; WM with prior exposure to a BTKi and an additional line of therapy	Drug: NX-5948; Oral NX-5948
Experimental: Phase 1b in DLBCL; DLBCL 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; Oral NX-5948
Experimental: Phase 1b in FL; FL (grade 1-3a) with prior exposure to an anti-CD20 mAb-based chemoimmunotherapy regimen and an additional line of therapy	Drug: NX-5948; Oral NX-5948
Experimental: Phase 1a Dose Escalation; Multiple dose levels of NX-5948 to be evaluated; determination of Maximum Tolerated Dose/Phase 1b recommended dose(s)	Drug: NX-5948; Oral NX-5948
Experimental: Phase 1b in CLL or SLL; 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. Patients enrolled in CLL/SLL arm will be randomized to one of two dose levels. This is the only randomization component in the trial.	Drug: NX-5948; Oral NX-5948

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with protocol specified dose-limiting toxicities	Phase 1a	Up to 24 months
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
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)	Phase 1b	Up to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Complete response (CR) rate / CR with incomplete marrow recovery as assessed by the Investigator	Phase 1a/1b	Up to 5 years
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
Time to next therapy	Phase 1a/1b	Up to 5 years

Collaborators and Investigators

• Sponsor: Nurix Therapeutics, Inc.
• Investigators: Study Director: Paula O'Connor, MD, Nurix Therapeutics, Inc.

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): April 13, 2022
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): January 1, 2027

Study Registration Dates

• First Submitted: November 12, 2021
• First Submitted That Met QC Criteria: November 12, 2021
• First Posted (Actual): November 23, 2021

Study Record Updates

• Last Update Posted (Actual): April 2, 2024
• Last Update Submitted That Met QC Criteria: April 1, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Lymphoma; BTK Inhibitor; C481S; Bruton's Tyrosine Kinase; C481; BTK Degrader; B-Cell Malignancy; NX-5948; Targeted Protein Degradation; Chimeric Targeting Molecule (CTM)
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Disease Attributes; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Neoplasms, Plasma Cell; Leukemia, Lymphoid; Leukemia; Leukemia, B-Cell; Lymphoma, B-Cell; Chronic Disease; Neoplasms; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Waldenstrom Macroglobulinemia; Leukemia, Lymphocytic, Chronic, B-Cell
• Other Study ID Numbers: NX-5948-301

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes