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 17, 2022
• Sponsor: Nurix Therapeutics, Inc.
• Information provided by (Responsible Party): Nurix Therapeutics, Inc.

Study Description

Brief Summary:

This is a first-in-human dose escalation and cohort expansion multicenter, open-label study designed to evaluate the safety and preliminary efficacy of NX-5948 in patients with advanced B-cell malignancies.

Condition or disease	Intervention/treatment	Phase
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)	Drug: NX-5948	Phase 1

Detailed Description:

There are 2 parts to this study. The phase 1a portion (dose escalation) evaluates the safety and tolerability of NX-5948 in adult patients with relapsed/refractory (R/R) 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), or Waldenströms macroglobulinemia (WM), who have received at least 2 prior systemic therapies (1 prior therapy for WM), and for whom no other therapies are known to provide clinical benefit.

The phase 1b portion (cohort expansion) investigates the efficacy of NX-5948 at the dose selected in Phase 1a in up to 5 cohorts of patients with R/R B-cell malignancies, who have received at least 2 prior systemic therapies (or 1 prior therapy for patients with WM, primary central nervous system lymphoma (PCNSL), or secondary central nervous system involvement.

• Cohort A: CLL or (SLL) without a BTK C481 mutation
• Cohort B: CLL or SLL with a BTK C481 mutation
• Cohort C: DLBCL or MCL
• Cohort D: FL, MZL, or WM
• Cohort E: PCNSL, or any of the indications listed above with Central Nervous System involvement

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 130 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: April 13, 2022
• Estimated Primary Completion Date: January 2024
• Estimated Study Completion Date: May 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Phase 1a Dose Escalation; Multiple dose levels of NX-5948 to be evaluated; determination of Maximum Tolerated Dose/Phase 1b recommended dose	Drug: NX-5948; Oral NX-5948
Experimental: Phase 1b Cohort Expansion in CLL or SLL without a BTK C481 mutation; CLL or SLL without a BTK C481 mutation with disease progression on a BTK inhibitor (BTKi)	Drug: NX-5948; Oral NX-5948
Experimental: Phase 1b Cohort Expansion in CLL or SLL with a BTK C481 mutation; CLL or SLL with a BTK C481 mutation with disease progression on a BTKi	Drug: NX-5948; Oral NX-5948
Experimental: Phase 1b Cohort Expansion in DLBCL or MCL; DLBCL with disease progression on an anthracycline and an anti-CD20 monoclonal antibody (mAb)-based regimen, or MCL with disease progression on a BTKi and an anti-CD20 mAb-based regimen	Drug: NX-5948; Oral NX-5948
Experimental: Phase 1b Cohort Expansion in FL, MZL, or WM; FL with disease progression on an anti-CD20 mAb-based regimen, MZL with disease progression on an anti-CD20 mAb-based regimen, or WM with disease progression on a BTKi	Drug: NX-5948; Oral NX-5948
Experimental: Phase 1b Cohort Expansion in PCNSL or secondary CNS involvement; PCNSL with disease progression on 1 prior therapy, or any of the indications listed above with CNS involvement, with disease progression on 1 prior therapy	Drug: NX-5948; Oral NX-5948

Outcome Measures

Primary Outcome Measures :

1. Number of participants with protocol specified dose-limiting toxicities [ Time Frame: Up to 10 months ]
   Phase 1a
2. To establish the maximum tolerated dose and/or recommended Phase 1b dose [ Time Frame: Up to 10 months ]
   Phase 1a
3. 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
4. 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

Secondary Outcome Measures :

1. 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
2. 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
3. Complete response (CR) rate / CR with incomplete marrow recovery as assessed by the Investigator [ Time Frame: Up to 3 years ]
   Phase 1a/1b
4. Duration of response (DOR) as assessed by the Investigator [ Time Frame: Up to 3 years ]
   Phase 1a/1b
5. Progression-free survival (PFS) as assessed by the Investigator [ Time Frame: Up to 3 years ]
   Phase 1a/1b
6. Time to next therapy [ Time Frame: Up to 3 years ]
   Phase 1a/1b

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Patients must be ≥18 years of age.
• Patients in Phase 1a (Dose Escalation) must have histologically confirmed R/R CLL, SLL, DLBCL, FL, MCL, MZL, or WM.

• Patients in Phase 1a must meet the following:

  o Received at least 2 prior systemic therapies (or 1 prior therapy for WM) and have no other therapies known to provide clinical benefit.

• Patients in Phase 1b (Cohort Expansion) must have histologically confirmed R/R CLL, SLL, DLBCL, FL, MCL, MZL, WM, PCNSL or any of the above indications with CNS involvement
• Patients in Phase 1b (Cohort Expansion) must meet criteria for systemic treatment and must have failed 2 prior lines of therapy (or 1 prior line of therapy for patients with WM, PCNSL, or secondary CNS involvement).
• Patients must have radiographically measurable disease per response criteria specific to the malignancy, evaluable disease in bone marrow or other compartments is also allowed.
• ECOG performance status of 0 or 1.
• Adequate organ and bone marrow function, in the absence of growth factors and without platelet transfusions as defined by lab parameters

Exclusion Criteria:

Key Exclusion Criteria:

• Prior treatment for the indication under study including:

  1. Radiotherapy within 2 weeks of planned start of study drug (excluding limited palliative radiation).
  2. Prior chemotherapy within 4 weeks of planned start of study drug.
  3. Prior monoclonal antibody therapy within 4 weeks of planned start of study drug.
  4. Prior small molecule therapy within 4 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 T-cell (CAR-T) therapy within 100 days prior to start of study drug (30 days for Phase 1b). Must have evidence of B-cell recovery if patient received prior CAR-T therapy.
  7. Use of systemic corticosteroids outside of dosing limits described below and within the 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, 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 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:

  1. Myocardial infarction, unstable angina, unstable symptomatic ischemic heart disease, or placement of a coronary arterial stent within 6 months of planned start of study drug.
  2. Uncontrolled atrial fibrillation or other clinically significant arrhythmias, conduction abnormalities, or New York Heart Association (NYHA) class III or IV heart failure within 6 months of planned start of study drug.
  3. Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events), stroke, or intracranial hemorrhage within 6 months of planned start of study drug.
  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) within 6 months of planned start of study drug.
• Bleeding diathesis, or other known risk for acute blood loss.
• History of Grade ≥ 2 hemorrhage within 28 days.

Contacts and Locations

Contacts

Contact: Patient Outreach; (415) 230-7860; NX5948301@nurixtx.com

Locations

United Kingdom

The Christie NHS Foundation Trust; Recruiting

Manchester, United Kingdom, M20 4BX

Churchill Hospital; Recruiting

Oxford, United Kingdom, OX3 7LE

Sponsors and Collaborators

Nurix Therapeutics, Inc.

Investigators

• Study Director: Su Young Kim, MD, PhD; Nurix Therapeutics, Inc.

More Information

• Responsible Party: Nurix Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT05131022
• Other Study ID Numbers: NX-5948-301
• First Posted: November 23, 2021
• Last Update Posted: May 17, 2022
• Last Verified: May 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Keywords provided by Nurix Therapeutics, Inc.:

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

Additional relevant MeSH terms:

Lymphoma; Neoplasms; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Lymphoma, Large B-Cell, Diffuse; Waldenstrom Macroglobulinemia; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma, Non-Hodgkin; Leukemia, Lymphoid; Leukemia; Lymphoma, B-Cell; Leukemia, B-Cell; Neoplasms, Plasma Cell; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders