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
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 572
- 试验地点
- 74
- 主要终点
- Number of participants with protocol specified dose-limiting toxicities
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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).
研究组 & 干预措施
Phase 1b Part 1 Cohort 11 in FL
FL (grade 1-3a) with prior exposure to an anti-CD20 mAb-based chemoimmunotherapy regimen and an additional line of therapy
干预措施: NX-5948 (Drug)
Phase 1b Part 1 Cohort 9 in WM (2L)
WM following upfront therapy with a BTKi
干预措施: NX-5948 (Drug)
Phase 1b Part 1 Cohort 7 in MZL
MZL (EMZL, MALT, NMZL, SMZL) with prior exposure to an anti-CD20 mAb-based chemo-immunotherapy regimen and an additional line of therapy
干预措施: NX-5948 (Drug)
Phase 1b Part 1 Cohort 6 in MCL
Non-blastoid MCL with prior exposure to a BTKi and an anti-CD20 monoclonal antibody (mAb)-based chemoimmunotherapy regimen
干预措施: NX-5948 (Drug)
Phase 1b Part 1 Cohort 3 in CLL/SLL with prior non-covalent BTKi
CLL/SLL with prior exposure to ncBTKi and are BCL-2i naïve.
干预措施: NX-5948 (Drug)
Phase 1b Part 1 Cohort 5 in CLL/SLL with 2L+, prior BTKi
Patients with at least 1 prior line of therapy that included a BTKi and are BCL-2i naïve.
干预措施: NX-5948 (Drug)
Phase 1b Part 1 Cohort 14 in first-line WM
Treatment-naïve WM deemed unfit for chemoimmunotherapy
干预措施: NX-5948 (Drug)
Phase 1b Part 1 Cohort 15 in BTKi-naive CLL/SLL
First-line (1L) or second-line+ (2L)+ CLL/SLL with no prior exposure to a BTKi
干预措施: NX-5948 (Drug)
Phase 1b Part 1 Cohort 10 in DLBCL
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
干预措施: NX-5948 (Drug)
Phase 1b Part 2 in CLL or SLL with prior BTKi and BCL-2i
CLL or SLL with prior exposure to both a Bruton's tyrosine kinase inhibitor (BTKi) and BCL-2 inhibitor
干预措施: NX-5948 (Drug)
Phase 1b Part 1 Cohort 13 in PCNSL
PCNSL following upfront therapy and with no prior exposure to a BTKi (2L).
干预措施: NX-5948 (Drug)
Phase 1b Part 1 Cohort 1 in CLL or SLL with prior BTKi and BCL2i
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.
干预措施: NX-5948 (Drug)
Phase 1a Dose Escalation
Multiple dose levels of NX-5948 to be evaluated; determination of Maximum Tolerated Dose/Phase 1b recommended dose(s)
干预措施: NX-5948 (Drug)
Phase 1b Part 1 Cohort 2 in CLL/SLL with non-C481S BTK mutations
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
干预措施: NX-5948 (Drug)
Phase 1b Part 1 Cohort 8 in WM (3L+)
WM with prior exposure to a BTKi and at least an additional line of therapy
干预措施: NX-5948 (Drug)
Phase 1b Part 1 Cohort 4 in CLL/SLL with TP53 or 17p deletion, 2L, prior BTKi
Patients with documented TP53 mutation or 17p deletion and 1 prior line of therapy that included a BTKi and are BCL-2i naïve.
干预措施: NX-5948 (Drug)
Phase 1b Part 1 Cohort 16 in CLL/SLL with secondary warm autoimmune hemolytic anemia (wAIHA)
BTKi-exposed R/R CLL or SLL with secondary wAIHA
干预措施: NX-5948 (Drug)
Phase 1b Part 1 Cohort 17 in CLL/SLL with CNS involvement
BTKi-exposed R/R CLL or SLL with CNS involvement
干预措施: NX-5948 (Drug)
Phase 1b Part 1 Cohort 12 in PCNSL/SCNSL
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
干预措施: NX-5948 (Drug)
结局指标
主要结局
Number of participants with protocol specified dose-limiting toxicities
时间窗: Up to 24 months
Phase 1a
To establish the maximum tolerated dose and/or recommended Phase 1b dose(s)
时间窗: 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
时间窗: Up to 3 years
Phase 1b Part 1
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
时间窗: Up to 6 years
Phase 1a / 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
时间窗: Up to 3 years
Phase 1b Part 2
次要结局
- Pharmacokinetic (PK) profile of NX-5948: Maximum Serum Concentration(Up to 6 years)
- Pharmacodynamic (PD) profile of NX-5948: Changes from baseline of BTK levels in B-cells(Up to 6 years)
- Complete response (CR) rate / CR with incomplete marrow recovery as assessed by the Investigator(Up to 6 years)
- Duration of response (DOR) as assessed by the Investigator(Up to 6 years)
- Progression-free survival (PFS) as assessed by the Investigator(Up to 6 years)
- Time to next therapy(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(Up to 3 years)
研究者
研究点 (74)
相似试验
相关资讯
10 articles