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

Sponsor

Nurix Therapeutics, Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT05131022

Collaborator

(none)

130

Enrollment

Locations

Arms

24.6

Anticipated Duration (Months)

43.3

Patients Per Site

1.8

Patients Per Site Per Month

Study Details

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 (or at least 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 at least 1 prior therapy for patients with WM, primary central nervous system lymphoma (PCNSL), or secondary central nervous system involvement.

Cohort A: CLL or SLL with disease progression after at least 2 prior systemic therapies
Cohort B: CLL or SLL with disease progression after both a BTK inhibitor (BTKi) and BCL-2 inhibitor (may have been individually or in combination)
Cohort C: MCL with disease progression on a BTKi and an anti-CD20 monoclonal antibody (mAb)-based regimen
Cohort D: DLBCL with disease progression on an anthracycline and an anti-CD20 mAb-based regimen, or FL with disease progression on an anti-CD20 mAb-based regimen, or MZL with disease progression on an anti-CD20 mAb-based regimen, or WM with disease progression on a BTKi, or any of the indications listed in Cohorts A-D with CNS involvement, with disease progression on at least 1 prior therapy
Cohort E: PCNSL with disease progression on at least 1 prior therapy

Study Design

Study Type:

Interventional

Anticipated 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 :

Apr 13, 2022

Anticipated Primary Completion Date :

Jan 1, 2024

Anticipated Study Completion Date :

May 1, 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 A - CLL or SLL CLL or SLL with disease progression after at least 2 prior systemic therapies	Drug: NX-5948 Oral NX-5948
Experimental: Phase 1b Cohort B - CLL or SLL CLL or SLL with disease progression after both a BTK inhibitor (BTKi) and BCL-2 inhibitor (may have been individually or in combination)	Drug: NX-5948 Oral NX-5948
Experimental: Phase 1b Cohort C - MCL MCL with disease progression on a BTKi and an anti-CD20 monoclonal antibody (mAb)-based regimen	Drug: NX-5948 Oral NX-5948
Experimental: Phase 1b Cohort D - DLBCL, FL, MZL, WM, or secondary CNS DLBCL with disease progression on an anthracycline and an anti-CD20 mAb-based regimen, or FL with disease progression on an anti-CD20 mAb-based regimen, or MZL with disease progression on an anti-CD20 mAb-based regimen, or WM with disease progression on a BTKi, or any of the study indications with CNS involvement, with disease progression on at least 1 prior therapy	Drug: NX-5948 Oral NX-5948
Experimental: Phase 1b Cohort E in PCNSL PCNSL with disease progression on at least 1 prior therapy	Drug: NX-5948 Oral NX-5948

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

Pharmacokinetic (PK) profile of NX-5948: Maximum Serum Concentration [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
Pharmacodynamic (PD) profile of NX-5948: Changes from baseline of BTK levels in B-cells [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
Complete response (CR) rate / CR with incomplete marrow recovery as assessed by the Investigator [Up to 3 years]
Phase 1a/1b
Duration of response (DOR) as assessed by the Investigator [Up to 3 years]
Phase 1a/1b
Progression-free survival (PFS) as assessed by the Investigator [Up to 3 years]
Phase 1a/1b
Time to next therapy [Up to 3 years]
Phase 1a/1b

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 at least 1 prior therapy for WM) and have no other therapies known to provide clinical benefit.

Patients in Phase 1b (Cohort Expansion) must have histologically documented R/R CLL, SLL, DLBCL, FL, MCL, MZL, WM, PCNSL or any of these 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 at least 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. Target lymph nodes must be > 1.5 cm and extranodal lesions must be ≥ 1.0 cm in longest diameter. Other quantifiable disease (such as bone marrow infiltration, minimal residual disease, splenic enlargement) 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 for anti-cancer intent that includes:

Radiotherapy within 2 weeks of planned start of study drug (excluding limited palliative radiation).
Prior systemic chemotherapy within 4 weeks of planned start of study drug. Note: Use of intrathecal chemotherapy is allowed per Institutional guidelines.
Prior monoclonal antibody therapy within 4 weeks of planned start of study drug.
Prior small molecule therapy within 4 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 T-cell (CAR-T) therapy within 100 days prior to start of study drug (within 30 days prior to start of study drug for Phase 1b). Must have evidence of B-cell recovery if patient received prior CAR-T therapy.
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.
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:

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.
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.
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.
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 of planned start of study drug.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	The Christie NHS Foundation Trust	Manchester	United Kingdom	M20 4BX
2	Churchill Hospital	Oxford	United Kingdom	OX3 7LE
3	University Hospital Southampton NHS Foundation Trust	Southampton	United Kingdom	SO16 6YD