Clinical trial NCT05131022: A Study of NX-5948 in Adults With Relapsed/Refractory B-cell Malignancies
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
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)
Keywords: BTK Degrader
BTK Inhibitor
B-Cell Malignancy
Lymphoma
C481
C481S
Bruton's Tyrosine Kinase
NX-5948
Targeted Protein Degradation
Chimeric Targeting Molecule (CTM)
Lead sponsor: Nurix Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2021-11-23
Enrollment: 572
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility 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).

Primary outcomes:
measure: Number of participants with protocol specified dose-limiting toxicities
timeFrame: Up to 24 months
measure: To establish the maximum tolerated dose and/or recommended Phase 1b dose(s)
timeFrame: Up to 24 months
measure: 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
timeFrame: Up to 3 years
measure: 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
timeFrame: Up to 6 years
measure: 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
timeFrame: Up to 3 years
Secondary outcomes:
measure: Pharmacokinetic (PK) profile of NX-5948: Maximum Serum Concentration
timeFrame: Up to 6 years
measure: Pharmacodynamic (PD) profile of NX-5948: Changes from baseline of BTK levels in B-cells
timeFrame: Up to 6 years
measure: Complete response (CR) rate / CR with incomplete marrow recovery as assessed by the Investigator
timeFrame: Up to 6 years
measure: Duration of response (DOR) as assessed by the Investigator
timeFrame: Up to 6 years
measure: Progression-free survival (PFS) as assessed by the Investigator
timeFrame: Up to 6 years
measure: Time to next therapy
timeFrame: Up to 6 years
measure: 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
timeFrame: Up to 3 years
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Denver
country: United States
facility: Colorado Blood Cancer Institute
state: Colorado
city: New Haven
country: United States
facility: Yale Cancer Center
state: Connecticut
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Sarasota
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Atlanta
country: United States
facility: Winship Cancer Institute of Emory University
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Bethesda
country: United States
facility: National Institute of Health
state: Maryland
city: Ithaca
country: United States
facility: Cayuga Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania, Abramson Cancer Center
state: Pennsylvania
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Angers
country: France
facility: CHU Angers
city: Bobigny
country: France
facility: Hôpital Avicenne
city: Nantes
country: France
facility: CHU de Nantes
city: Pessac
country: France
facility: CHU Bordeaux
city: Poitiers
country: France
facility: CHU de Poitiers
city: Saint-Cloud
country: France
facility: Institut Curie-Site Saint-Cloud
city: Vandœuvre-lès-Nancy
country: France
facility: CHRU de Nancy
city: Bologna
country: Italy
facility: IRCCS - AOU di Bologna
city: Brescia
country: Italy
facility: ASST Spedali Civili Brescia
city: Milano
country: Italy
facility: IRCCS Ospedale San Raffaele - Università Vita-Salute San Raffaele di Milano
city: Milano
country: Italy
facility: IRCCS Ospedale San Raffaele
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Center
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht
city: Wrocław
country: Poland
facility: University Clinical Hostpital in Wroclaw
state: Dolnośląskie
city: Warsaw
country: Poland
facility: Pratia MTZ
state: Mazowieckie
city: Warsaw
country: Poland
facility: National Institute of Oncology Warszawa
state: Mazowieckie
city: Kraków
country: Poland
facility: Pratia MCM
state: Małopolskie
city: Skorzewo
country: Poland
facility: AidPort sp. Zo.o
state: Wielkopolskie
city: Lublin
country: Poland
facility: Medical University of Lublin
city: Katowice
country: Poland
facility: Pratia Onkologia Katowice
state: Śląskie
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clínic de Barcelona
city: Gijón
country: Spain
facility: Hospital Universitario de Cabuenes
city: Madrid
country: Spain
facility: Hospital Ramón y Cajal
city: Madrid
country: Spain
facility: Hospital Fundación Jimenez Díaz - START Madrid
city: Basel
country: Switzerland
facility: Universitätsspital Basel
city: Bellinzona
country: Switzerland
facility: Istituto Oncologico della Svizzera Italiana
city: Bern
country: Switzerland
facility: Inselspital - Universitatsklinik Bern
city: Geneva
country: Switzerland
facility: Hôpitaux Universitaires de Genève
city: Saint Gallen
country: Switzerland
facility: Kantonsspital St.Gallen
city: Zürich
country: Switzerland
facility: University Hospital Zurich
city: Glasgow
country: United Kingdom
facility: The Beatson WOS Cancer Center
state: Scotland
city: Leeds
country: United Kingdom
facility: St. James Hospital
city: Liverpool
country: United Kingdom
facility: Clatterbridge Cancer Center NHS Foundation Trust
city: London
country: United Kingdom
facility: St. Bartholomew's Hospital, Barts NHS Trust
city: London
country: United Kingdom
facility: Sarah Cannon Research Institute UK
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals NHS Foundation Trust
city: Plymouth
country: United Kingdom
facility: University Hospitals Plymouth NHS Trust
city: Southampton
country: United Kingdom
facility: University Hospital Southampton NHS Foundation Trust
city: Sutton
country: United Kingdom
facility: Royal Marsden NHS Foundation Trust
Study officials:
affiliation: Nurix Therapeutics, Inc.
name: Paula O'Connor, MD
role: STUDY_DIRECTOR
References:
citation: Zhang D, Harris HM, Chen J, Judy J, James G, Kelly A, McIntosh J, Tenn-McClellan A, Ambing E, Tan YS, Lu H, Gajewski S, Clifton MC, Yung S, Robbins DW, Pirooznia M, Skanland SS, Gaglione E, Mhibik M, Underbayev C, Ahn IE, Sun C, Herman SEM, Noviski M, Wiestner A. NRX-0492 degrades wild-type and C481 mutant BTK and demonstrates in vivo activity in CLL patient-derived xenografts. Blood. 2023 Mar 30;141(13):1584-1596. doi: 10.1182/blood.2022016934.