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

Overview

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.

Interventions

• Drug NX-5948
  Oral NX-5948

Primary outcome measures

• Number of participants with protocol specified dose-limiting toxicities [Time frame: Up to 24 months]
• To establish the maximum tolerated dose and/or recommended Phase 1b dose(s) [Time frame: Up to 24 months]
• 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 [Time frame: Up to 3 years]
• 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 [Time frame: Up to 6 years]
• 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 [Time frame: Up to 3 years]

Secondary outcome measures (7)

• Pharmacokinetic (PK) profile of NX-5948: Maximum Serum Concentration [Time frame: Up to 6 years]
• Pharmacodynamic (PD) profile of NX-5948: Changes from baseline of BTK levels in B-cells [Time frame: Up to 6 years]
• Complete response (CR) rate / CR with incomplete marrow recovery as assessed by the Investigator [Time frame: Up to 6 years]
• Duration of response (DOR) as assessed by the Investigator [Time frame: Up to 6 years]
• Progression-free survival (PFS) as assessed by the Investigator [Time frame: Up to 6 years]
• Time to next therapy [Time frame: Up to 6 years]
• 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 [Time frame: Up to 3 years]

Eligibility criteria

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

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:

• 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)
• 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).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 18 centers

• City of Hope — Duarte
• University of California, San Francisco — San Francisco
• Colorado Blood Cancer Institute — Denver
• Yale Cancer Center — New Haven
• University of Miami — Miami
• Florida Cancer Specialists — Sarasota
• Winship Cancer Institute of Emory University — Atlanta
• Northwestern University — Chicago
• … and 10 more centers

United Kingdom · 10 centers

• The Christie NHS Foundation Trust — Manchester
• The Beatson WOS Cancer Center — Glasgow
• St. James Hospital — Leeds
• Clatterbridge Cancer Center NHS Foundation Trust — Liverpool
• St. Bartholomew's Hospital, Barts NHS Trust — London
• Sarah Cannon Research Institute UK — London
• Oxford University Hospitals NHS Foundation Trust — Oxford
• University Hospitals Plymouth NHS Trust — Plymouth
• … and 2 more centers

France · 7 centers

• CHU Angers — Angers
• Hôpital Avicenne — Bobigny
• CHU de Nantes — Nantes
• CHU Bordeaux — Pessac
• CHU de Poitiers — Poitiers
• Institut Curie-Site Saint-Cloud — Saint-Cloud
• CHRU de Nancy — Vandœuvre-lès-Nancy

Poland · 7 centers

• AidPort sp. Zo.o — Skórzewo
• Pratia MCM — Krakow
• University Clinical Hostpital in Wroclaw — Wroclaw
• Pratia MTZ — Warsaw
• National Institute of Oncology Warszawa — Warsaw
• Pratia Onkologia Katowice — Katowice
• Medical University of Lublin — Lublin

Switzerland · 6 centers

• Universitätsspital Basel — Basel
• Istituto Oncologico della Svizzera Italiana — Bellinzona
• Inselspital - Universitatsklinik Bern — Bern
• Hôpitaux Universitaires de Genève — Geneva
• Kantonsspital St.Gallen — Sankt Gallen
• University Hospital Zurich — Zurich

Italy · 5 centers

• IRCCS - AOU di Bologna — Bologna
• ASST Spedali Civili Brescia — Brescia
• IRCCS Ospedale San Raffaele - Università Vita-Salute San Raffaele di Milano — Milan
• IRCCS Ospedale San Raffaele — Milan
• Fondazione Policlinico Universitario A. Gemelli IRCCS — Rome

Spain · 5 centers

• Hospital Universitari Vall d'Hebron — Barcelona
• Hospital Clínic de Barcelona — Barcelona
• Hospital Universitario de Cabuenes — Gijón
• Hospital Ramón y Cajal — Madrid
• Hospital Fundación Jimenez Díaz - START Madrid — Madrid

Netherlands · 4 centers

• University Medical Center Groningen — Groningen
• Radboud University Medical Center — Nijmegen
• Erasmus MC — Rotterdam
• University Medical Center Utrecht — Utrecht

Publications

• 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; PMID 36375120

Identifiers

NCT: NCT05131022 · NX-5948-301 · 2023-510541-25-00 · 2021-003125-29

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗