A Phase I/II Study to Evaluate the Safety, Tolerability, and Preliminary Efficacy of the EMB-07 Combination Therapy in Patients With Aggressive B-Cell Non-Hodgkin Lymphoma

Официальное название

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

Обзор

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).

Вмешательства

• Препарат EMB07
  EMB-07 is a bispecific antibody targeting CD3 and receptor-tyrosine-kinase-like orphan receptor 1 \[ROR1\]
• Препарат Rituximab/Gemcitabine/Oxaliplatin
  Rituximab is a monoclonal antibody drug specifically targeting the CD20 antigen. Gemcitabine is a chemotherapy drug classified as an antimetabolite. Oxaliplatin is a platinum-based chemotherapy drug.

Первичные конечные точки

• Maximum tolerated dose (MTD) of EMB-07（Phase I only） [Срок оценки: Up to 28 days]
• Rate of Adverse Events (AE) and Serious Adverse Events (SAE) [Срок оценки: From enrollment up to 30 days after the last dose]
• Recommended phase II dose (RP2D) of EMB-07 [Срок оценки: Up to 28 days]
• Objective Response Rate (ORR) [Срок оценки: From first dose until the date of first documented progression or date of death from any cause, whichever comes first, up to 2 years]

Вторичные конечные точки (11)

• Duration of Response (DOR) [Срок оценки: 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） [Срок оценки: 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） [Срок оценки: 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） [Срок оценки: 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） [Срок оценки: 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) [Срок оценки: 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） [Срок оценки: 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 [Срок оценки: From predose up to 3 months after first dose]
• Time to Maximum Plasma Concentration (Tmax) of EMB-07 [Срок оценки: From predose up to 30 days after the last dose]
• Trough Serum Concentration (Ctrough) of EMB-07 [Срок оценки: From predose up to 30 days after the last dose]
• Anti-Drug Antibody (ADA) Positive Rate of EMB-07 [Срок оценки: From predose up to 30 days after the last dose]

Критерии участия

Критерии включения

• 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 ≥2. 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.

Критерии исключения

• 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 C1D1.
• 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 C1D1.
• 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 C1D1.
• 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 C1D1.
• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Идентификаторы

NCT: NCT07432022 · EMB07X102

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗