A Phase I/II, Open-label, Multicenter Study to Evaluate the Safety, Tolerability and Preliminary Efficacy of EMB-07 (a Bispecific Antibody Targeting CD3 and Receptor-tyrosine-kinase-like Orphan Receptor 1 [ROR1]) Combination Therapy in Patients With Aggressive B-cell Non-Hodgkin Lymphoma
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 115
- 试验地点
- 1
- 主要终点
- Maximum tolerated dose (MTD) of EMB-07（Phase I only）
研究概览
简要总结
This is an open-label, multicenter, Phase I/II study designed to evaluate the safety, tolerability, pharmacokinetic characteristics, and preliminary efficacy of EMB-07 combination therapy in adult patients with aggressive B-cell non-Hodgkin lymphoma (B-NHL). The study consists two phases: Phase I of dose escalation and Phase II of dose expansion. Approximately 115 patients will be enrolled in this study (i.e., 5 cohorts of approximately 23 patients per cohort). Multiple EMB-07-based combination regimens will be evaluated in patients with relapsed/refractory (R/R) aggressive B-NHL (Cohort A) and patients with newly diagnosed aggressive B-NHL (Cohort B).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 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
- •Ability to understand and voluntarily sign the Informed Consent Form (ICF);
- •Patients aged ≥18 years;
- •Life expectancy > 12 weeks;
- •ECOG performance status score: ≤1 point during the dose escalation phase, ≤2 points during the dose expansion phase.
- •Cohort A: Pathologically confirmed aggressive R/R B-NHL, including DLBCL, not otherwise specified (NOS), or DLBCL transformed from indolent lymphoma (e.g., follicular lymphoma) (t-DLBCL), or other aggressive B-NHL judged to potentially benefit from study treatment by the investigator and sponsor (e.g., high-grade B-cell lymphoma [HGBL], Richter transformation, other large B-cell lymphoma subtypes).
- •Cohort B: Newly diagnosed, treatment-naïve DLBCL NOS confirmed by pathology, or t-DLBCL not previously treated with adequate (at least 2 cycles) R-CHOP therapy (excluding Richter transformation or HGBL with BCL2/MYC±BCL6 rearrangements). Patients with newly diagnosed DLBCL NOS should have an International Prognostic Index (IPI) score ≥2 and Ann Arbor stage ≥
- •The sponsor will reserve the right to limit the number of t-DLBCL patients enrolled in the study. Other aggressive B-NHLs patients who may benefit from the study treatment can be enrolled after careful risk/benefit assessment by the sponsor and investigator.
排除标准
- •Current or prior central nervous system (CNS) or meningeal involvement related to the underlying disease.
- •Cohort A: Prior exposure to any ROR1-targeted agent (e.g., biologic or CAR-T); or Cohort A1: Prior exposure to Gemcitabine-based chemotherapy (≥ 2 consecutive cycles); or Cohort A2: Prior exposure to Polatuzumab Vedotin; or Cohorts A3 and A4: Refractory to prior Lenalidomide/Zanubrutinib or Chidamide therapy, respectively.
- •Contraindications to any agent included in the combination therapy regimen.
- •Cohort A: Candidates suitable for ASCT or CAR-T cell therapy.
- •Cohort A: Use of any standard or investigational therapy for the underlying disease within 28 days before C1D1 or 5 half-lives (whichever is shorter), including chemotherapy, immunotherapy, radioimmunotherapy, non-palliative radiotherapy, or any other anti-tumor therapy. Only palliative radiotherapy to non-target lesions will be permitted.
- •Cohort B: B-NHL with prior receipt of at least 2 consecutive cycles of R-CHOP (prior lymph node biopsy or local radiotherapy will not be an exclusion criterion).
- •Major surgery or live vaccine administration within 28 days prior to C1D
- •History of allogeneic hematopoietic stem cell transplantation or solid organ transplantation (except corneal transplantation). In addition, patients who received ASCT within 3 months before C1D1, CAR-T within 6 months before C1D1, or diagnosed with graft-versus-host disease (GVHD) will be excluded.
- •Any AE related to prior therapy (excluding alopecia) that has not resolved to Grade ≤ 1 (per the Common Terminology Criteria for Adverse Events [CTCAE], Version 5.0) or baseline at C1D
- •Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening. Patients with positive HBsAg and/or positive HBcAb but negative HBV DNA will be eligible for enrollment. Patients with positive HCV antibody but negative HCV RNA are also eligible for enrollment.
- •Known positive HIV serology or history of active viral infection
- •Active infection requiring parenteral antibiotics, antivirals, or antifungals within 14 days before C1D1; prophylactic use of these agents (including parenteral administration) will be permitted.
- •Prior malignancy requiring treatment or with evidence of recurrence within 5 years before C1D1 (except non-melanoma skin cancer or adequately treated carcinoma in situ of the cervix). Patients with a history of cancer treated with curative intent > 5 years before C1D1 and no evidence of recurrence will be eligible.
- •Ischemic or hemorrhagic stroke of Grade ≥ 3, or gastrointestinal bleeding of Grade ≥ 3, within 6 months before C1D
- •Active, unstable cardiovascular function:
- •Myocardial infarction within 6 months before C1D1;
- •Unstable angina within 3 months before C1D1;
- •Clinically significant uncontrolled arrhythmias (e.g., sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes);
- •Mobitz type II second-degree or third-degree atrioventricular block;
- •Congestive heart failure at class ≥ 3 per New York Heart Association (NYHA)
- •Known left ventricular ejection fraction (LVEF) < 50%.
- •Known or suspected history of hemophagocytic lymphohistiocytosis (HLH);
- •Known history of progressive multifocal leukoencephalopathy;
- •Active autoimmune disease requiring treatment
- •Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid hormone replacement will be eligible.
- •Type 1 diabetes mellitus well-controlled with insulin therapy will be permitted.
- •Patients with a history of autoimmune hepatitis, systemic lupus erythematosus, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, granulomatosis with polyangiitis, Sjögren's syndrome, multiple sclerosis, or glomerulonephritis will be excluded.
- •Patients with a history of immune thrombocytopenic purpura, autoimmune hemolytic anemia, Guillain-Barré syndrome, myasthenia gravis, myositis, rheumatoid arthritis, vasculitis, or other autoimmune diseases are excluded unless no systemic therapy has been required in the past 12 months.
- •Prior systemic immunosuppressive medication (including but not limited to cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) within 28 days before C1D
- •Systemic corticosteroid use within 2 weeks before study treatment at a dose equivalent to > 10 mg/day Prednisone. Inhaled, topical, or ophthalmic steroids will be permitted. Short-term corticosteroid use (e.g., prophylaxis for intravenous contrast) will be permitted.
- •Any other severe underlying medical condition (e.g., active gastric ulcer, uncontrolled seizures, cerebrovascular event, gastrointestinal bleeding, coagulation/thrombotic disorders with severe signs/symptoms, cardiac disease), or psychiatric, psychological, familial, or geographic factors that, in the investigator's judgment, possibly interfere with scheduled disease assessments, treatment, and follow-up, compromise patient compliance, or place the patient at high risk of treatment-related complications.
- •Female patients who are pregnant or breastfeeding. Abuse of alcohol, cannabis-derived products, or other controlled substances.
研究组 & 干预措施
Phase I: Dose Escalation, Phase II: Dose Expansion
Phase I: Dose Escalation During the dose escalation, the planned starting dose of EMB-07 is 6 mg. A dose escalation scheme of "3+3" will be followed to determine DLT, MTD, and RP2CD.
Phase II: Dose Expansion For each cohort: During the dose-expansion, approximately 10 to 15 patients will be enrolled and administrated in each cohort to further characterize the safety profile and anti-tumor activity of the combination therapies.
Approximately 20 patients per cohort receiving RP2CD will be pooled from the dose escalation and dose expansion phases to evaluate preliminary efficacy signals.
干预措施: Rituximab/Gemcitabine/Oxaliplatin (Drug)
Phase I: Dose Escalation, Phase II: Dose Expansion
Phase I: Dose Escalation During the dose escalation, the planned starting dose of EMB-07 is 6 mg. A dose escalation scheme of "3+3" will be followed to determine DLT, MTD, and RP2CD.
Phase II: Dose Expansion For each cohort: During the dose-expansion, approximately 10 to 15 patients will be enrolled and administrated in each cohort to further characterize the safety profile and anti-tumor activity of the combination therapies.
Approximately 20 patients per cohort receiving RP2CD will be pooled from the dose escalation and dose expansion phases to evaluate preliminary efficacy signals.
干预措施: EMB07 (Drug)
结局指标
主要结局
Maximum tolerated dose (MTD) of EMB-07（Phase I only）
时间窗: Up to 28 days
Rate of Adverse Events (AE) and Serious Adverse Events (SAE)
时间窗: From enrollment up to 30 days after the last dose
Adverse events and serious adverse events as assessed by CTCAE v5.0
Recommended phase II dose (RP2D) of EMB-07
时间窗: Up to 28 days
Objective Response Rate (ORR)
时间窗: From first dose until the date of first documented progression or date of death from any cause, whichever comes first, up to 2 years
Objective response rate, measured by Lugano 2014
次要结局
- Duration of Response (DOR)(From first dose until the date of first documented progression or date of death from any cause, whichever comes first; up to 2 years)
- Duration of Complete Response（DOCR）(From first dose until the date of first documented progression or date of death from any cause, whichever comes first; up to 2 years)
- Time to Treatment Response（TTR）(From first dose until the date of first documented progression or date of death from any cause, whichever comes first; up to 2 years)
- Time to Complete Response（TTCR）(From first dose until the date of first documented progression or date of death from any cause, whichever comes first; up to 2 years)
- Event-Free Survival（EFS）(From first dose until the date of first documented progression or date of death from any cause, whichever comes first; up to 2 years)
- Progression Free Survival (PFS)(From first dose until the date of first documented progression or date of death from any cause, whichever comes first; up to 2 years)
- Overall Survival（OS）(From first dose until the date of first documented progression or date of death from any cause, whichever comes first; up to 2 years)
- Maximum Plasma Concentration (Cmax) of EMB-07(From predose up to 3 months after first dose)
- Time to Maximum Plasma Concentration (Tmax) of EMB-07(From predose up to 30 days after the last dose)
- Trough Serum Concentration (Ctrough) of EMB-07(From predose up to 30 days after the last dose)
- Anti-Drug Antibody (ADA) Positive Rate of EMB-07(From predose up to 30 days after the last dose)