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

Chronic Lymphocytic Leukemia (CLL) Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05131022
• Other study ID #: NX-5948-301
• Status: Recruiting
• Phase: Phase 1
• Start date: April 13, 2022
• Est. completion date: January 2027

Study information

• Verified date: April 2024
• Source: Nurix Therapeutics, Inc.
• Contact: Patient Outreach
• Phone: +1 (415) 417-3441
• Email: NX5948301[@]nurixtx.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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), or Primary Central Nervous System Lymphoma (PCNSL). Phase 1b will investigate the efficacy of NX-5948 at the dose(s) selected in Phase 1a in up to 7 expansion arms of patients with histologically confirmed R/R B-cell malignancy indications who have received the specified prior therapies based on indication: - CLL or SLL (two dose levels will be investigated for CLL/SLL) - MCL - MZL - WM - DLBCL - FL - PCNSL/SCNSL

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 292
• Est. completion date: January 2027
• Est. primary completion date: December 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 therapies known to provide clinical benefit. For PCNSL, received at least 1 prior line of therapy

• Patients in Phase 1b (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 based on indication: 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 prolymphocytic leukemia or Richter's transformation to Hodgkin's lymphoma at any time preceding 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 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, central nervous system lymphoma (CNSL, including both primary and secondary 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.

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 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).

Related Conditions & MeSH terms

• Chronic Lymphocytic Leukemia (CLL)
• Diffuse Large B Cell Lymphoma (DLBCL)
• Follicular Lymphoma (FL)
• Leukemia, Lymphocytic, Chronic, B-Cell
• Lymphoma
• Lymphoma, Large B-Cell, Diffuse
• Lymphoma, Mantle-Cell
• Mantle Cell Lymphoma (MCL)
• Marginal Zone Lymphoma (MZL)
• Neoplasms
• Primary Central Nervous System Lymphoma (PCNSL)
• Small Lymphocytic Lymphoma (SLL)
• Waldenstrom Macroglobulinemia
• Waldenstrom Macroglobulinemia (WM)

Intervention

Drug:
• NX-5948
Oral NX-5948

Locations

Country	Name	City	State
Netherlands	Radboud University Medical Center	Nijmegen
Netherlands	Erasmus MC	Rotterdam
Netherlands	University Medical Center Utrecht	Utrecht
United Kingdom	The Beatson WOS Cancer Center	Glasgow	Scotland
United Kingdom	St. James Hospital	Leeds
United Kingdom	Clatterbridge Cancer Center NHS Foundation Trust	Liverpool
United Kingdom	Sarah Cannon Research Institute UK	London
United Kingdom	St. Bartholomew's Hospital, Barts NHS Trust	London
United Kingdom	The Christie NHS Foundation Trust	Manchester
United Kingdom	Oxford University Hospitals NHS Foundation Trust	Oxford
United Kingdom	University Hospitals Plymouth NHS Trust	Plymouth
United Kingdom	University Hospital Southampton NHS Foundation Trust	Southampton
United Kingdom	Royal Marsden NHS Foundation Trust	Sutton
United States	Winship Cancer Institute of Emory University	Atlanta	Georgia
United States	Northwestern University	Chicago	Illinois
United States	University of Cincinnati Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic	Cleveland	Ohio
United States	City of Hope	Duarte	California
United States	Duke University Medical Center	Durham	North Carolina
United States	University of Miami	Miami	Florida
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Yale Cancer Center	New Haven	Connecticut
United States	University of California, San Francisco	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Nurix Therapeutics, Inc.

Countries where clinical trial is conducted

United States,  Netherlands,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of participants with protocol specified dose-limiting toxicities	Phase 1a	Up to 24 months
Primary	To establish the maximum tolerated dose and/or recommended Phase 1b dose(s)	Phase 1a	Up to 24 months
Primary	To evaluate the anti-tumor activity of NX-5948 in the dose levels selected for Phase 1b safety expansion based on overall response rate (ORR)	Phase 1b	Up to 3 years
Primary	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	Phase 1a/1b	Up to 5 years
Secondary	Pharmacokinetic (PK) profile of NX-5948: Maximum Serum Concentration	Phase 1a/1b - Sampling following the first dose, pre- and post-dose at selected cycles and at the end of treatment	Up to 5 years
Secondary	Pharmacodynamic (PD) profile of NX-5948: Changes from baseline of BTK levels in B-cells	Phase 1a/1b - Sampling at screening, following the first dose, pre and post-dose at selected cycles and at the end of treatment	Up to 5 years
Secondary	Complete response (CR) rate / CR with incomplete marrow recovery as assessed by the Investigator	Phase 1a/1b	Up to 5 years
Secondary	Duration of response (DOR) as assessed by the Investigator	Phase 1a/1b	Up to 5 years
Secondary	Progression-free survival (PFS) as assessed by the Investigator	Phase 1a/1b	Up to 5 years
Secondary	Time to next therapy	Phase 1a/1b	Up to 5 years