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

• ClinicalTrials.gov Identifier: NCT05131022
• Recruitment Status: Recruiting
• First Posted: November 23, 2021
• Last Update Posted: May 16, 2024
• Sponsor: Nurix Therapeutics, Inc.
• Information provided by (Responsible Party): Nurix Therapeutics, Inc.

Tracking Information

• First Submitted Date: November 12, 2021
• First Posted Date: November 23, 2021
• Last Update Posted Date: May 16, 2024
• Actual Study Start Date: April 13, 2022
• Estimated Primary Completion Date: December 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 8, 2024)

• Number of participants with protocol specified dose-limiting toxicities [ Time Frame: Up to 24 months ]
  Phase 1a
• To establish the maximum tolerated dose and/or recommended Phase 1b dose(s) [ Time Frame: Up to 24 months ]
  Phase 1a
• 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) [ Time Frame: Up to 3 years ]
  Phase 1b
• 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 [ Time Frame: Up to 5 years ]
  Phase 1a/1b

Original Primary Outcome Measures (submitted: November 12, 2021)

• Number of participants with protocol specified dose-limiting toxicities [ Time Frame: Up to 10 months ]
  Phase 1a
• To establish the maximum tolerated dose and/or recommended Phase 1b dose [ Time Frame: Up to 10 months ]
  Phase 1a
• 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 [ Time Frame: Up to 3 years ]
  Phase 1b
• 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 [ Time Frame: Up to 3 years ]
  Phase 1a/1b

Current Secondary Outcome Measures (submitted: October 9, 2023)

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

Original Secondary Outcome Measures (submitted: November 12, 2021)

• Pharmacokinetic (PK) profile of NX-5948: Maximum Serum Concentration [ Time Frame: Up to 3 years ]
  Phase 1a/1b - Sampling following the first dose, pre- and post-dose at selected cycles and at the end of treatment
• Pharmacodynamic (PD) profile of NX-5948: Changes from baseline of BTK levels in B-cells [ Time Frame: Up to 3 years ]
  Phase 1a/1b - Sampling at screening, following the first dose, pre and post-dose at selected cycles and at the end of treatment
• Complete response (CR) rate / CR with incomplete marrow recovery as assessed by the Investigator [ Time Frame: Up to 3 years ]
  Phase 1a/1b
• Duration of response (DOR) as assessed by the Investigator [ Time Frame: Up to 3 years ]
  Phase 1a/1b
• Progression-free survival (PFS) as assessed by the Investigator [ Time Frame: Up to 3 years ]
  Phase 1a/1b
• Time to next therapy [ Time Frame: Up to 3 years ]
  Phase 1a/1b

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of NX-5948 in Adults With Relapsed/Refractory B-cell Malignancies
• Official Title: 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
• 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.

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
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• 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

Drug: NX-5948

Oral NX-5948

Study Arms

• Experimental: Phase 1a Dose Escalation
  Multiple dose levels of NX-5948 to be evaluated; determination of Maximum Tolerated Dose/Phase 1b recommended dose(s)
  Intervention: Drug: 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.
  Intervention: Drug: NX-5948
• Experimental: Phase 1b in MCL
  MCL with prior exposure to a BTKi and an anti-CD20 monoclonal antibody (mAb)-based chemo-immunotherapy regimen
  Intervention: Drug: 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
  Intervention: Drug: 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
  Intervention: Drug: NX-5948
• Experimental: Phase 1b in WM
  WM with prior exposure to a BTKi and an additional line of therapy
  Intervention: Drug: 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
  Intervention: Drug: 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
  Intervention: Drug: NX-5948

• 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.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 1, 2024): 292
• Original Estimated Enrollment (submitted: November 12, 2021): 130
• Estimated Study Completion Date: January 2027
• Estimated Primary Completion Date: December 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

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).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Patient Outreach; +1 (415) 417-3441 ext 7821; NX5948301@nurixtx.com

• Listed Location Countries: Netherlands, United Kingdom, United States

Administrative Information

• NCT Number: NCT05131022
• Other Study ID Numbers: NX-5948-301
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Nurix Therapeutics, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Nurix Therapeutics, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: Nurix Therapeutics, Inc.
• Verification Date: May 2024