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

Nurix Therapeutics

Status and phase: Enrolling; Phase 1

Conditions: Waldenstrom Macroglobulinemia (WM); Small Lymphocytic Lymphoma (SLL); Marginal Zone Lymphoma (MZL); Follicular Lymphoma (FL); Mantle Cell Lymphoma (MCL); Diffuse Large B Cell Lymphoma (DLBCL); Primary Central Nervous System Lymphoma (PCNSL); Chronic Lymphocytic Leukemia (CLL); Secondary Central Nervous System Lymphoma

Treatments: Drug: NX-5948

Study type: Interventional

Funder types: Industry

Identifiers

NCT05131022

NX-5948-301

2023-510541-25-00 (EU Trial (CTIS) Number)

2021-003125-29 (EudraCT Number)

Details and patient eligibility

About

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.

Full 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), 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, will investigate the safety and anti-tumor activity of NX-5948 at the dose(s) selected in Phase 1a in up to 13 expansion cohorts of patients with histologically confirmed R/R B-cell malignancy indications who have received the specified prior therapies based on indication:

• CLL or SLL (patients may be randomized to one of two dose levels investigated for CLL/SLL)
• 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.

Enrollment: 492 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and 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 R/R 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. 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 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 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, 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 design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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492 participants in 15 patient groups

Phase 1a Dose Escalation

Experimental group

Description:

Multiple dose levels of NX-5948 to be evaluated; determination of Maximum Tolerated Dose/Phase 1b recommended dose(s)

Treatment:

Drug: NX-5948

Phase 1b Part 1 Cohort 1 in CLL or SLL with prior BTKi and BCL2i

Experimental group

Description:

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.

Treatment:

Drug: NX-5948

Phase 1b Part 1 Cohort 2 in CLL/SLL with non-C481S BTK mutations

Experimental group

Description:

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

Treatment:

Drug: NX-5948

Phase 1b Part 1 Cohort 3 in CLL/SLL with prior non-covalent BTKi

Experimental group

Description:

CLL/SLL with prior exposure to ncBTKi and BCL-2i naïve.

Treatment:

Drug: NX-5948

Phase 1b Part 1 Cohort 4 in CLL/SLL with TP53 or 17p deletion, 2L, prior BTKi

Experimental group

Description:

Patients with documented TP53 mutation or 17p deletion and 1 prior line of therapy that included a BTKi and BCL-2i naïve.

Treatment:

Drug: NX-5948

Phase 1b Part 1 Cohort 5 in CLL/SLL with 2L+, prior BTKi

Experimental group

Description:

Patients with at least 1 prior line of therapy that included a BTKi and BCL-2i naïve.

Treatment:

Drug: NX-5948

Phase 1b Part 1 Cohort 6 in MCL

Experimental group

Description:

Non-blastoid MCL with prior exposure to a BTKi and an anti-CD20 monoclonal antibody (mAb)-based chemoimmunotherapy regimen

Treatment:

Drug: NX-5948

Phase 1b Part 1 Cohort 7 in MZL

Experimental group

Description:

MZL (EMZL, MALT, NMZL, SMZL) with prior exposure to an anti-CD20 mAb-based chemo-immunotherapy regimen and an additional line of therapy

Treatment:

Drug: NX-5948

Phase 1b Part 1 Cohort 8 in WM (3L+)

Experimental group

Description:

WM with prior exposure to a BTKi and at least an additional line of therapy

Treatment:

Drug: NX-5948

Phase 1b Part 1 Cohort 9 in WM (2L)

Experimental group

Description:

WM following upfront therapy with a BTKi

Treatment:

Drug: NX-5948

Phase 1b Part 1 Cohort 10 in DLBCL

Experimental group

Description:

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

Treatment:

Drug: NX-5948

Phase 1b Part 1 Cohort 11 in FL

Experimental group

Description:

FL (grade 1-3a) with prior exposure to an anti-CD20 mAb-based chemoimmunotherapy regimen and an additional line of therapy

Treatment:

Drug: NX-5948

Phase 1b Part 1 Cohort 12 in PCNSL/SCNSL

Experimental group

Description:

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 cohort enrolling that disease with secondary CNS involvement of lymphoma

Treatment:

Drug: NX-5948

Phase 1b Part 1 Cohort 13 in PCNSL

Experimental group

Description:

PCNSL following upfront therapy and with no prior exposure to a BTKi (2L).

Treatment:

Drug: NX-5948

Phase 1b Part 2 in CLL or SLL with prior BTKi and BCL-2i

Experimental group

Description:

CLL or SLL with prior exposure to both a Bruton's tyrosine kinase inhibitor (BTKi) and BCL-2 inhibitor

Treatment:

Drug: NX-5948