Brief Title
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
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.
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), non-germinal center B-cell
subtype (non-GCB) diffuse large B-cell lymphoma (DLBCL) as determined by the Hans algorithm,
Richter-transformed DLBCL, high-grade B-cell lymphoma with MYC and B-cell lymphoma 2 [BCL-2]
and/or BCL-6 rearrangements, high-grade B-cell lymphomas not otherwise specified, FL (grade
1-3a; eligibility for systemic treatment as determined by the Groupe d'Etude des Lymphomes
Folliculaires [GELF] criteria), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL;
eligible subtypes include: extranodal MZL [EMZL], mucosa-associated lymphoid tissue [MALT],
nodal MZL [NMZL], and splenic MZL [SMZL]), or Waldenströms macroglobulinemia (WM), including
any of the diagnoses with central nervous system (CNS) involvement of their disease, as well
as primary central nervous system lymphoma (PCNSL) patients. Patients are required to have
received at least 2 prior lines of therapy and have no other therapeutic options that 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 patients with histologically confirmed R/R B-cell malignancy
indications who have received at least 2 prior lines of therapy in up to the following 4
cohorts:
- Cohort A: CLL or SLL with prior exposure to both a Bruton's tyrosine kinase inhibitor
(BTKi) and BCL-2 inhibitor, unless previously deemed ineligible for those therapies,
including those with secondary CNS involvement of their disease
- Cohort B: Non-GCB DLBCL with prior exposure to an anthracycline and an anti-CD20
monoclonal antibody (mAb)-based chemo-immunotherapy regimen, including transformed
indolent lymphoma (eg, grade 3b/transformed FL), Richter-transformed DLBCL, high-grade
B-cell lymphoma with MYC and BCL-2 and/or BCL-6 rearrangements, high-grade B-cell
lymphomas NOS, and patients with secondary CNS involvement of their disease; or MCL with
prior exposure to a BTKi and an anti-CD20 mAb-based chemo-immunotherapy regimen
including those with secondary CNS involvement of their disease.
- Cohort C: FL (grade 1-3a) with prior exposure to an anti-CD20 mAb-based
chemo-immunotherapy regimen and 1 additional line of therapy; or MZL (EMZL, MALT, NMZL,
SMZL) with prior exposure to an anti-CD20 mAb-based chemo-immunotherapy regimen and 1
additional line of therapy; or WM with prior exposure to a BTKi and 1 additional line of
therapy; or FL (grade 1-3a), MZL (EMZL, MALT, NMZL, SMZL), and WM patients meeting the
above criteria with secondary CNS involvement of their disease.
- Cohort D: PCNSL patients who have progressed or had no response to at least 2 prior
lines of therapy.
Study Phase
Phase 1
Study Type
Interventional
Primary Outcome
Number of participants with protocol specified dose-limiting toxicities
Secondary Outcome
Pharmacokinetic (PK) profile of NX-5948: Maximum Serum Concentration
Condition
Chronic Lymphocytic Leukemia (CLL)
Intervention
NX-5948
Study Arms / Comparison Groups
Phase 1a Dose Escalation
Description: Multiple dose levels of NX-5948 to be evaluated; determination of Maximum Tolerated Dose/Phase 1b recommended dose
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
130
Start Date
April 13, 2022
Completion Date
May 2024
Primary Completion Date
January 2024
Eligibility Criteria
Inclusion Criteria:
- Patients must be ≥18 years of age.
- Patients in Phase 1a (Dose Escalation) must have histologically confirmed R/R CLL,
SLL, non-GCB DLBCL, Richter-transformed DLBCL, high-grade B-cell lymphoma with MYC and
BCL-2 and/or BCL-6 rearrangements, high-grade B-cell lymphomas NOS, FL, MCL, MZL
(EMZL, MALT, NMZL, SMZL), or WM, including those with secondary CNS involvement in any
disease indication listed or PCNSL.
- Patients in Phase 1a must meet the following:
o Received at least 2 prior lines of therapy and have no other therapies known to
provide clinical benefit.
- 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 failed 2 prior lines of therapy: CLL or SLL, Non-GCB DLBCL, MCL, FL, MZL,
WM, including those with secondary CNS involvement of their disease for all above
indications, or PCNSL.
- Patients must have radiographically measurable disease per response criteria specific
to the malignancy. Target lymph nodes must be > 1.5 cm and extranodal lesions must be
≥ 1.0 cm in longest diameter.
- 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:
Key Exclusion Criteria:
- 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 4 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 4 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 30 days prior to start of study drug for Phase 1b). Must have
evidence of B-cell recovery if patient received prior CAR T-cell therapy.
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) 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 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:
1. 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.
2. 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.
3. 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.
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) 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.
Gender
All
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Paula O'Connor, MD, (415) 230-7860, [email protected]
Location Countries
United Kingdom
Location Countries
United Kingdom
Administrative Informations
NCT ID
NCT05131022
Organization ID
NX-5948-301
Responsible Party
Sponsor
Study Sponsor
Nurix Therapeutics, Inc.
Study Sponsor
Paula O'Connor, MD, Study Director, Nurix Therapeutics, Inc.
Verification Date
February 2023