A Phase 1, Dose Escalation, Safety and Tolerability Study of NX-2127, 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
- 248
- 试验地点
- 16
- 主要终点
- To establish the MTD and/or recommended Phase 1b dosage(s) of NX-2127
研究概览
简要总结
This is a first-in-human Phase 1a/1b multicenter, open-label oncology study designed to evaluate the safety and anti-cancer activity of NX-2127 in patients with advanced B-cell malignancies.
详细描述
Phase 1a (Dose Escalation) will evaluate the safety and tolerability of NX-2127 in adult patients with relapsed/refractory (R/R) B-cell malignancies, who have required and received at least 2 prior systemic therapies (or at least 1 prior therapy for patients with WM or PCNSL) and for which no other therapies are known to provide clinical benefit.
Phase 1b (Dose Optimization) will use a 2-stage design to further investigate the safety, tolerability, and preliminary efficacy of NX-2127 in R/R B-cell malignancies based on the dosage(s) selected in Phase 1a.
Stage 1 will enroll approximately 10 participants per group based on B-cell lymphoma/leukemia indication at a specific dose selected from the first part of the study. The Sponsor may decide to open Stage 2 for any given group after review of safety and anti-tumor activity data from Stage 1.
In Stage 2, an additional 10 participants will be enrolled at the dose from Stage 1 as well as 20 additional participants at a second alternative dose. Participants will be randomly assigned to one of the 2 dose levels in Stage 2.
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
- •Patients must be ≥ 18 years of age
- •Patients must have measurable disease per disease-specific response criteria
- •Patients with indolent forms of NHL must meet the criteria requiring systemic treatment (i.e., iwCLL, IWG, Lugano Classification of Lymphoma response criteria, or International PCNSL Collaborative Group response criteria)
- •Patients with transformed lymphoma are eligible for the study with the exception of those detailed in
排除标准
- •#1: Prolymphocytic leukemia, MCL with blastoid histology, MCL with pleomorphic morphology, or MCL with known TP53 mutation
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (non-PCNSL indications) or 0 - 2 (PCNSL patients)
- •Adequate organ and bone marrow function
- •Patients of child-bearing potential must use adequate contraceptive measures to avoid pregnancy for the duration of the study as defined in the protocol
- •Inclusion Criteria for Patients in Phase 1a:
- •Have histologically confirmed R/R CLL, SLL, WM, MCL, and MZL, FL, DLBCL, or PCNSL
- •Received at least 2 prior systemic therapies (or at least 1 prior therapy for patients with WM or PCNSL) and have no other therapies known to provide clinical benefit
- •Must require systemic therapy
- •Inclusion Criteria for Patients in Phase 1b:
- •Must have one of the following histologically documented R/R B-cell malignancies:
- •CLL/SLL whose disease has failed treatment with a BTKi;
- •MCL whose disease has failed treatment with BTKi and an anti-CD20 mAb-based regimen
- •FL or MZL whose disease has failed treatment with an anti-CD20 mAb-based regimen; or WM whose disease has failed treatment with a BTKi
- •PCNSL whose disease failed at least 1 prior line of treatment
- •DLBCL whose disease has failed treatment with an anti-CD20 mAb-based regimen and either: an anthracycline-based regimen; or an anti-CD19-based regimen, or another/ palliative regimen (either progressed post stem cell transplant or transplant-ineligible)
- •Exclusion Criteria:
- •Active, uncontrolled autoimmune hemolytic anemia or autoimmune thrombocytopenia
- •History of known/suspected other autoimmune disease (exception(s): patients with alopecia, vitiligo, resolved childhood atopic dermatitis, hypothyroidism, or hyperthyroidism that is clinically euthyroid at screening are allowed.)
- •Unable to swallow capsules or have a condition that may interfere in the delivery, absorption, or metabolism of the study drug
- •Bleeding diathesis, or other known risk for acute blood loss
- •Patients requiring ongoing treatment with warfarin or an equivalent vitamin K antagonist and within 7 days prior to the first dose of study drug
- •Prior radiotherapy within 2 weeks of planned start of study drug (excluding limited palliative radiation)
- •Toxicities from previous anticancer therapies must have resolved to baseline levels or to Grade 1 (except for alopecia, hypothyroidism with adequate replacement therapy, hypopituitarism with adequate replacement therapy, peripheral neuropathy or hematologic parameters meeting inclusion criteria).
- •Active known second malignancy. Exception: patients with non-metastatic, non-melanoma skin cancer are eligible
- •Patient has had major surgery (e.g. requiring general anesthesia) within 4 weeks before the planned first dose of study drug
- •Infection with human immunodeficiency virus (HIV)-1 or HIV-
- •Exception: patients with well-controlled HIV (e.g., CD4 > 350/mm3 and undetectable viral load) are eligible.
- •Current active liver disease from any cause
- •Active viral reactivation (e.g., CMV or EBV)
- •Use of systemic corticosteroids exceeding 20 mg/day prednisone (or equivalent) for non-PCNSL indications within 15 days prior to the planned start of study drug. PCNSL patients may not exceed corticosteroid doses of 40 mg/day prednisone (or equivalent) and should be on a stable or decreasing dose for 7 days prior to planned study start.
- •Use of non-steroidal immunosuppressive drugs within 30 days prior to start of the study
- •Clinically significant, uncontrolled cardiac, cardiovascular disease, or history of myocardial infarction within 6 months of planned start of study drug
- •Administration of any strong cytochrome P450 3A (CYP3A) inducers or inhibitors for 14 days prior to the first dose of study drug, and any P-glycoprotein inhibitors (for 2 days) or moderate inducers of CYP3A for 7 days
研究组 & 干预措施
Phase 1b Dose Optimization Stage 2 in MCL (Randomized to Dose A or Dose B)
MCL patients whose disease has failed treatment with a BTK inhibitor and an anti-CD20 monoclonal antibody (mAb) based regimen
干预措施: NX-2127 (Drug)
Phase 1a Dose Escalation
Multiple dose levels of NX-2127 to be evaluated; determination of MTD/Phase 1b recommended dose
干预措施: NX-2127 (Drug)
Phase 1b Dose Optimization Stage 1 in CLL or SLL (Dose A)
CLL/SLL patients whose disease has failed treatment with a BTK inhibitor
干预措施: NX-2127 (Drug)
Phase 1b Dose Optimization Stage 1 in MCL (Dose A)
MCL patients whose disease has failed treatment with a BTK inhibitor and an anti-CD20 monoclonal antibody (mAb) based regimen
干预措施: NX-2127 (Drug)
Phase 1b Dose Optimization Stage 1 in FL, MZL or WM (Dose A)
FL or MZL patients whose disease has failed treatment with an anti-CD20 mAb-based regimen; or WM whose disease has failed treatment with a BTK inhibitor
干预措施: NX-2127 (Drug)
Phase 1b Dose Optimization Stage 1 in DLBCL (Dose A)
DLBCL patients whose disease has failed treatment with an anti-CD20 mAb-based regimen and either: an anthracycline-based regimen; or an anti-CD19-based regimen; or another/palliative regimen
干预措施: NX-2127 (Drug)
Phase 1b Dose Optimization Stage 2 in PCNSL (Randomized to Dose A or Dose B)
PCNSL patients whose disease has failed at least 1 prior line of treatment
干预措施: NX-2127 (Drug)
Phase 1b Dose Optimization Stage 1 in PCNSL (Dose A)
PCNSL patients whose disease has failed at least 1 prior line of treatment
干预措施: NX-2127 (Drug)
Phase 1b Dose Optimization Stage 2 in CLL or SLL (Randomized to Dose A or Dose B)
CLL/SLL patients whose disease has failed treatment with a BTK inhibitor
干预措施: NX-2127 (Drug)
Phase 1b Dose Optimization Stage 2 in FL, MZL or WM (Randomized to Dose A or Dose B)
FL or MZL patients whose disease has failed treatment with an anti-CD20 mAb-based regimen; or WM whose disease has failed treatment with a BTK inhibitor
干预措施: NX-2127 (Drug)
Phase 1b Dose Optimization Stage 2 in DLBCL (Randomized to Dose A or Dose B)
DLBCL patients whose disease has failed treatment with an anti-CD20 mAb-based regimen and either: an anthracycline-based regimen; or an anti-CD19-based regimen; or another/palliative regimen
干预措施: NX-2127 (Drug)
结局指标
主要结局
To establish the MTD and/or recommended Phase 1b dosage(s) of NX-2127
时间窗: Up to 24 months
Phase 1a
Number of Participants with Protocol Specified Dose-Limiting Toxicities
时间窗: Up to 24 months
Phase 1a
To evaluate the clinical activity of NX-2127 at the recommended Phase 1b dosage(s) based on overall response rate (ORR) as assessed by the Investigator
时间窗: Up to 4 years
Phase 1b
Number of Participants with Adverse Events and Clinical Laboratory Abnormalities
时间窗: Up to 5 years
Phase 1a/1b
次要结局
- Overall survival (OS) as assessed by the Investigator(Up to 4 years)
- Progression-free survival (PFS) as assessed by the Investigator(Up to 5 years)
- Pharmacokinetic (PK) Profile of NX-2127: Maximum Serum Concentration(Up to 5 years)
- Duration of response (DOR) as assessed by the Investigator(Up to 5 years)
- To further evaluate the safety and tolerability of NX-2127 by collecting adverse events, treatment emergent adverse events, and incidence of all deaths(Up to 4 years)
- Complete response (CR) rate / CR with incomplete marrow recovery as assessed by the Investigator(Up to 5 years)