A Phase I, Dose Escalation and Cohort Expansion Study Evaluating NX-5948, a Bruton's Tyrosine Kinase (BTK) Degrader, in Adults with Relapsed/Refractory B-cell Malignancies

Study Identifier:
NX-5948-301
CT.gov Identifier:
NCT05131022
EudraCT Identifier:
2021-003125-29
EU Trial (CTIS) Number:
2023-510541-25-00
Study Contact Information:
(210) 593-5651 or [email protected]
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Study Summary

To evaluate the safety, tolerability, and clinical activity of NX-5948 in adult pts with relapsed/refractory B cell malignancies Phase 1a will evaluate safety and tolerability of NX-5948 in pts with relapsed/refractory CLL, SLL, non-GCB DLBCL, FL, MCL, MZL, and WM, including those with secondary CNS involvement in any disease indication listed as well as PCNSL To investigate longer-term safety and anti-tumor activity of NX-5948 at the recommended dose(s) selected in phase 1a in patients with relapsed/refractory B cell malignancies across four cohorts The recommended phase 1b dose(s) will be determined following assessment of PK/PD, safety, and anti-tumor activity. Pharmacokinetic parameters are generated using non-compartmental analysis. Pharmacodynamic biomarkers are assessed in whole blood longitudinally using a 10-color flow cytometry assay designed to quantify BTK. Phase 1a (dose escalation) evaluates safety and tolerability of NX-5948 via a standard 3+3 dose escalation in patients with relapsed/refractory B cell malignancies. Endpoints include dose-limiting toxicities (DLTs); treatment-emergent adverse events (TEAEs); deaths; changes in safety parameters; objective response rate per disease-specific response criteria To report updated findings from a Phase 1a/b trial of NX-5948 in patients (pts) with R/R CLL. To study clinical outcomes from an ongoing Phase 1a/b trial of bexobrutideg in patients with WM who have progressed after multiple lines of therapy, including BTKi, illustrating the role of BTK degradation in relapsed, refractory WM. To evaluate safety/tolerability and activity of bexobrutideg in relapsed/refractory B-cell malignancies, including CLL/SLL and NHL/WM, in parallel 3+3 dose-escalation and dose-expansion cohorts. To report updated findings from a Phase 1a trial of bexobrutideg in patients with relapsed/refractory (R/R) CLL.

The Phase 1b study includes cohorts testing the safety and efficacy of the 600 mg dose of bexobrutideg in earlier lines of therapy in CLL patients.

Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
  • Leukemia
  • Lymphoma
  • Waldenstrom Macroglobulinemia
    • Phase
    The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
    I
    Sex
    Female & Male
    Age
    18 - 100 Years
    Study Drug
  • Drug: Participant Group/Arm: Experimental: Phase 1a Dose Escalation Multiple dose levels of NX-5948 to be evaluated; determination of Maximum Tolerated Dose/Phase 1b recommended dose(s) Experimental: Phase 1b Part 1 Cohort 1 in CLL or SLL with prior BTKi and BCL2i 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. Experimental: Phase 1b Part 1 Cohort 2 in CLL/SLL with non-C481S BTK mutations 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 Experimental: Phase 1b Part 1 Cohort 3 in CLL/SLL with prior non-covalent BTKi CLL/SLL with prior exposure to ncBTKi and are BCL-2i naive. Experimental: Phase 1b Part 1 Cohort 4 in CLL/SLL with TP53 or 17p deletion, 2L, prior BTKi Patients with documented TP53 mutation or 17p deletion and 1 prior line of therapy that included a BTKi and are BCL-2i naive. Experimental: Phase 1b Part 1 Cohort 5 in CLL/SLL with 2L+, prior BTKi Patients with at least 1 prior line of therapy that included a BTKi and are BCL-2i naive. Experimental: Phase 1b Part 1 Cohort 6 in MCL Non-blastoid MCL with prior exposure to a BTKi and an anti-CD20 monoclonal antibody (mAb)-based chemoimmunotherapy regimen Experimental: Phase 1b Part 1 Cohort 7 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 Experimental: Phase 1b Part 1 Cohort 8 in WM (3L+) WM with prior exposure to a BTKi and at least an additional line of therapy Experimental: Phase 1b Part 1 Cohort 9 in WM (2L) WM following upfront therapy with a BTKi Experimental: Phase 1b Part 1 Cohort 10 in DLBCL 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 Experimental: Phase 1b Part 1 Cohort 11 in FL FL (grade 1-3a) with prior exposure to an anti-CD20 mAb-based chemoimmunotherapy regimen and an additional line of therapy Experimental: Phase 1b Part 1 Cohort 12 in PCNSL/SCNSL 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 Experimental: Phase 1b Part 1 Cohort 13 in PCNSL PCNSL following upfront therapy and with no prior exposure to a BTKi (2L). Experimental: Phase 1b Part 2 in CLL or SLL with prior BTKi and BCL-2i CLL or SLL with prior exposure to both a Bruton's tyrosine kinase inhibitor (BTKi) and BCL-2 inhibitor Experimental: Phase 1b Part 1 Cohort 14 in first-line WM Treatment-naive WM deemed unfit for chemoimmunotherapy Experimental: Phase 1b Part 1 Cohort 15 in BTKi-naive CLL/SLL First-line (1L) or second-line+ (2L)+ CLL/SLL with no prior exposure to a BTKi Experimental: Phase 1b Part 1 Cohort 16 in CLL/SLL with secondary warm autoimmune hemolytic anemia (wAIHA) BTKi-exposed R/R CLL or SLL with secondary wAIHA Experimental: Phase 1b Part 1 Cohort 17 in CLL/SLL with CNS involvement BTKi-exposed R/R CLL or SLL with CNS involvement Intervention/Treatment: Drug: NX-5948 Oral NX-5948 Patients were treated with NX-5948 at doses ranging from 50 mg to 600 mg once daily by oral administration. As per Netherlands: Research product and/or intervention: Phase 1a: Subjects in this phase who meet all inclusion criteria and do not meet any of the exclusion criteria will be assigned to 1 dose of the dose escalation period. Subjects will receive one or more capsules once daily to achieve a daily dose of 50, 100, 200, 300, 450, 600, 800, or 1000 mg. Higher doses may be decided upon. Each dose escalation cohort will include 3-6 subjects and may include a maximum of 12 additional subjects per previously cleared dose level. The study drug is a capsule taken with water in the morning. The subjects must fast for 2 hours both before and after taking the capsules. Prior to the intensive PK visits (Cycle 1 Day 1 and Cycle 2 Day 1), the subjects must fast for at least 8 hours before and for 2 hours after taking the study drug. Phase 1b: In the second part of the study (the extension), different groups of participants will receive the selected dose from the dose escalation part with a maximum of 20 participants per arm. 18 patients with WM were enrolled and were treated at four daily dose levels: 200 mg (n=1), 300 mg (n=3), 450 mg (n=2), 600 mg (n=12).
    • Study Status
    Indicates the current recruitment status or the expanded access status
    Recruiting

    Requirements information
    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:
    • .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
    • 2 prior lines of treatment and ECOG PS 0-1.
    Exclusion criteria
    • 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
    • Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events), stroke, or intracranial hemorrhage
    • 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, but are not limited to, 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).

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    Study Locations

    Location
    Investigator
    Status
    Condition(s) Treated at Site
    Location
    START Madrid, Spain (FJD)
    Madrid, Spain, 28040
    Investigator
    Daniel Morillo Giles
    Status
    Recruiting
    Condition(s) Treated at Site
    Leukemia
    Lymphoma
    Waldenstrom Macroglobulinemia