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A Phase 1 Study of NX-5948 in Adults With Relapsed/Refractory B-cell Malignancies

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ClinicalTrials.gov Identifier: NCT05131022
Recruitment Status : Not yet recruiting
First Posted : November 23, 2021
Last Update Posted : November 23, 2021
Sponsor:
Information provided by (Responsible Party):
Nurix Therapeutics, Inc.

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

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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
Estimated Study Start Date : November 2021
Estimated Primary Completion Date : January 2024
Estimated Study Completion Date : May 2024


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




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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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 (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 within 14 days prior to first dose of study drug of >20 mg/day prednisone or > 4 mg/day of dexamethasone or equivalent for patients without CNS lymphoma (CNSL), or >40 mg/day prednisone or >8 mg/day dexamethasone or equivalent for patients with CNSL, except for prophylaxis for radio diagnostic contrast reactions. Patients with CNSL using >20 mg/day prednisone or >4 mg/day dexamethasone or equivalent must be clinically stable at that dose for 14 days.
    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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05131022


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

Sponsors and Collaborators
Nurix Therapeutics, Inc.
Investigators
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Study Director: Su Young Kim, MD, PhD Nurix Therapeutics, Inc.
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Responsible Party: Nurix Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT05131022    
Other Study ID Numbers: NX-5948-301
First Posted: November 23, 2021    Key Record Dates
Last Update Posted: November 23, 2021
Last Verified: November 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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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
Leukemia, B-Cell
Lymphoma, B-Cell
Neoplasms, Plasma Cell
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders