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

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

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	18 Years and Over
Gender	All

More Inclusion & Exclusion 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 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.

Key

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: 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. 3. 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. 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 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. 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 (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: 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, 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).

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT05131022
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 1
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	Nurix Therapeutics, Inc.
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Paula O'Connor, MD
Principal Investigator Affiliation	Nurix Therapeutics, Inc.
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Industry
Overall Status	Recruiting
Countries	France, Italy, Netherlands, Poland, Spain, Switzerland, United Kingdom, United States
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	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), Secondary Central Nervous System Lymphoma (SCNSL)

Additional Details

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), Primary Central Nervous System Lymphoma (PCNSL) or any of the above indications with disease in the central nervous system or Secondary Central Nervous System Lymphoma (SCNSL). Phase 1b Part 1, called safety expansion, investigates the safety and anti-tumor activity of NX-5948 at the dose(s) selected in Phase 1a in up to 17 expansion cohorts of patients with histologically confirmed B-cell malignancy indications who have received specified prior therapies based on indication:

- CLL or SLL (patients may be randomized to one of two dose levels investigated for CLL/SLL until an optimal dose is selected) - MCL.

- MZL.

- WM.

- DLBCL.

- FL.

- PCNSL/SCNSL.

Phase 1b Part 2, called cohort expansion, will further investigate the anti-tumor activity of NX-5948 at the dose(s) selected in Phase 1b par 1 in one additional expansion arm of CLL/SLL patients.

Arms & Interventions

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)

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 naïve.

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 naïve.

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 naïve.

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-naïve 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

Interventions

Drug: - NX-5948

Oral NX-5948

Contact a Trial Team

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City of Hope, Duarte, California

Status

Recruiting

Address

City of Hope

Duarte, California, 91010

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