A Study of NX-5948 in Adults With Relapsed/Refractory B-cell Malignancies
- Conditions
- 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)
- Interventions
- Registration Number
- NCT05131022
- Lead Sponsor
- Nurix Therapeutics, Inc.
- Brief 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.
- Detailed 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, 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 572
-
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.
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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
-
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)
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Bleeding diathesis, or other known risk for acute blood loss.
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History of Grade ≥ 2 hemorrhage within 28 days of planned start of study drug.
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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).
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Phase 1a Dose Escalation NX-5948 Multiple dose levels of NX-5948 to be evaluated; determination of Maximum Tolerated Dose/Phase 1b recommended dose(s) Phase 1b Part 1 Cohort 1 in CLL or SLL with prior BTKi and BCL2i NX-5948 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. Phase 1b Part 1 Cohort 2 in CLL/SLL with non-C481S BTK mutations NX-5948 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 Phase 1b Part 1 Cohort 3 in CLL/SLL with prior non-covalent BTKi NX-5948 CLL/SLL with prior exposure to ncBTKi and are BCL-2i naïve. Phase 1b Part 1 Cohort 4 in CLL/SLL with TP53 or 17p deletion, 2L, prior BTKi NX-5948 Patients with documented TP53 mutation or 17p deletion and 1 prior line of therapy that included a BTKi and are BCL-2i naïve. Phase 1b Part 1 Cohort 5 in CLL/SLL with 2L+, prior BTKi NX-5948 Patients with at least 1 prior line of therapy that included a BTKi and are BCL-2i naïve. Phase 1b Part 1 Cohort 6 in MCL NX-5948 Non-blastoid MCL with prior exposure to a BTKi and an anti-CD20 monoclonal antibody (mAb)-based chemoimmunotherapy regimen Phase 1b Part 1 Cohort 7 in MZL NX-5948 MZL (EMZL, MALT, NMZL, SMZL) with prior exposure to an anti-CD20 mAb-based chemo-immunotherapy regimen and an additional line of therapy Phase 1b Part 1 Cohort 8 in WM (3L+) NX-5948 WM with prior exposure to a BTKi and at least an additional line of therapy Phase 1b Part 1 Cohort 9 in WM (2L) NX-5948 WM following upfront therapy with a BTKi Phase 1b Part 1 Cohort 10 in DLBCL NX-5948 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 Phase 1b Part 1 Cohort 11 in FL NX-5948 FL (grade 1-3a) with prior exposure to an anti-CD20 mAb-based chemoimmunotherapy regimen and an additional line of therapy Phase 1b Part 1 Cohort 12 in PCNSL/SCNSL NX-5948 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 Phase 1b Part 1 Cohort 13 in PCNSL NX-5948 PCNSL following upfront therapy and with no prior exposure to a BTKi (2L). Phase 1b Part 2 in CLL or SLL with prior BTKi and BCL-2i NX-5948 CLL or SLL with prior exposure to both a Bruton's tyrosine kinase inhibitor (BTKi) and BCL-2 inhibitor Phase 1b Part 1 Cohort 14 in first-line WM NX-5948 Treatment-naïve WM deemed unfit for chemoimmunotherapy Phase 1b Part 1 Cohort 15 in BTKi-naive CLL/SLL NX-5948 First-line (1L) or second-line+ (2L)+ CLL/SLL with no prior exposure to a BTKi Phase 1b Part 1 Cohort 16 in CLL/SLL with secondary warm autoimmune hemolytic anemia (wAIHA) NX-5948 BTKi-exposed R/R CLL or SLL with secondary wAIHA Phase 1b Part 1 Cohort 17 in CLL/SLL with CNS involvement NX-5948 BTKi-exposed R/R CLL or SLL with CNS involvement
- Primary Outcome Measures
Name Time Method 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 6 years Phase 1a / Phase 1b Part 1
Number of participants with protocol specified dose-limiting toxicities Up to 24 months Phase 1a
To establish the maximum tolerated dose and/or recommended Phase 1b dose(s) Up to 24 months Phase 1a
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) as assessed by Investigator Up to 3 years Phase 1b Part 1
To further evaluate the anti-tumor activity of NX-5948 in patients with CLL/SLL at the dose identified in Phase 1b Part 1 based on overall response rate (ORR) as assessed by Investigator Up to 3 years Phase 1b Part 2
- Secondary Outcome Measures
Name Time Method Pharmacokinetic (PK) profile of NX-5948: Maximum Serum Concentration Up to 6 years Phase 1a / Phase 1b Part 1 and Part 2 - 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 6 years Phase 1a / Phase 1b Part 1 and Part 2 - 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 6 years Phase 1a / Phase 1b Part 1 and Part 2
Duration of response (DOR) as assessed by the Investigator Up to 6 years Phase 1a / Phase 1b Part 1 and Part 2
Progression-free survival (PFS) as assessed by the Investigator Up to 6 years Phase 1a / Phase 1b Part 1 and Part 2
Time to next therapy Up to 6 years Phase 1a / Phase 1b Part 1 and Part 2
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 1b Part 2
Trial Locations
- Locations (57)
IRCCS Ospedale San Raffaele
🇮🇹Milano, Italy
University Hospital Zurich
🇨🇭Zürich, Switzerland
The Beatson WOS Cancer Center
🇬🇧Glasgow, Scotland, United Kingdom
CHU Angers
🇫🇷Angers, France
Hôpital Avicenne
🇫🇷Bobigny, France
CHU de Nantes
🇫🇷Nantes, France
CHU de Poitiers
🇫🇷Poitiers, France
Institut Curie-Site Saint-Cloud
🇫🇷Saint-Cloud, France
CHRU de Nancy
🇫🇷Vandœuvre-lès-Nancy, France
IRCCS Ospedale San Raffaele - Università Vita-Salute San Raffaele di Milano
🇮🇹Milano, Italy
University Clinical Hostpital in Wroclaw
🇵🇱Wrocław, Dolnośląskie, Poland
Pratia MTZ
🇵🇱Warsaw, Mazowieckie, Poland
National Institute of Oncology Warszawa
🇵🇱Warsaw, Mazowieckie, Poland
Medical University of Lublin
🇵🇱Lublin, Poland
City of Hope
🇺🇸Duarte, California, United States
University of California, San Francisco
🇺🇸San Francisco, California, United States
Yale Cancer Center
🇺🇸New Haven, Connecticut, United States
University of Miami
🇺🇸Miami, Florida, United States
Florida Cancer Specialists
🇺🇸Sarasota, Florida, United States
Colorado Blood Cancer Institute
🇺🇸Denver, Colorado, United States
Winship Cancer Institute of Emory University
🇺🇸Atlanta, Georgia, United States
Cayuga Medical Center
🇺🇸Ithaca, New York, United States
University of Cincinnati Medical Center
🇺🇸Cincinnati, Ohio, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
Northwestern University
🇺🇸Chicago, Illinois, United States
National Institute of Health
🇺🇸Bethesda, Maryland, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
University of Pennsylvania, Abramson Cancer Center
🇺🇸Philadelphia, Pennsylvania, United States
MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
Huntsman Cancer Institute
🇺🇸Salt Lake City, Utah, United States
Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
University Medical Center Groningen
🇳🇱Groningen, Netherlands
Radboud University Medical Center
🇳🇱Nijmegen, Netherlands
Erasmus MC
🇳🇱Rotterdam, Netherlands
University Medical Center Utrecht
🇳🇱Utrecht, Netherlands
Pratia MCM
🇵🇱Kraków, Małopolskie, Poland
AidPort sp. Zo.o
🇵🇱Skorzewo, Wielkopolskie, Poland
Pratia Onkologia Katowice
🇵🇱Katowice, Śląskie, Poland
Hospital Universitari Vall d'Hebron
🇪🇸Barcelona, Spain
Hospital Clínic de Barcelona
🇪🇸Barcelona, Spain
Hospital Universitario de Cabuenes
🇪🇸Gijón, Spain
Hospital Ramón y Cajal
🇪🇸Madrid, Spain
Hospital Fundación Jimenez Díaz - START Madrid
🇪🇸Madrid, Spain
Universitätsspital Basel
🇨🇭Basel, Switzerland
Istituto Oncologico della Svizzera Italiana
🇨🇭Bellinzona, Switzerland
Hôpitaux Universitaires de Genève
🇨🇭Geneva, Switzerland
Kantonsspital St.Gallen
🇨🇭Saint Gallen, Switzerland
St. James Hospital
🇬🇧Leeds, United Kingdom
Clatterbridge Cancer Center NHS Foundation Trust
🇬🇧Liverpool, United Kingdom
St. Bartholomew's Hospital, Barts NHS Trust
🇬🇧London, United Kingdom
Sarah Cannon Research Institute UK
🇬🇧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 Kingdom