A Randomized, Controlled, Multicenter, Phase III Trial of Becotatug Vedotin in Combination With PD-1 Blockade Plus Chemoradiotherapy Versus PD-1 Blockade Plus Chemoradiotherapy in Patients With High-Risk Locoregionally Advanced Nasopharyngeal Carcinoma
Overview
- Phase
- Phase 3
- Status
- Not yet recruiting
- Sponsor
- Sun Yat-sen University
- Enrollment
- 514
- Primary Endpoint
- Post-induction Therapy Complete Response Rate (post-IT CRR)
Overview
Brief Summary
This randomized controlled trial aims to evaluate the efficacy and safety of Becotatug Vedotin (MRG003), an antibody-drug conjugate (ADC), combined with the PD-1 inhibitor Pucotenlimab as induction therapy for high-risk locoregionally advanced nasopharyngeal carcinoma (NPC), compared to the standard gemcitabine and cisplatin (GP) regimen combined with Pucotenlimab, followed by concurrent chemoradiotherapy (CCRT) and adjuvant immunotherapy.
Detailed Description
Patients in the experimental arm will receive MRG003 (2.0 mg/kg, Day 1, Q3W × 3 cycles) plus Pucotenlimab (200 mg, Day 1, Q3W × 3 cycles) as induction therapy, followed by CCRT [intensity-modulated radiotherapy (IMRT): 70 Gy in 33 fractions, 5 days/week, once daily; cisplatin 100 mg/m², Day 1, Q3W × 2 cycles], and adjuvant Pucotenlimab (200 mg, Day 1, Q3W × 6 cycles). Patients in the control arm will receive gemcitabine (1000 mg/m², Days 1 and 8, Q3W × 3 cycles) plus cisplatin (80 mg/m², Day 1, Q3W × 3 cycles) and Pucotenlimab (200 mg, Day 1, Q3W × 3 cycles) as induction therapy, followed by the same CCRT regimen and adjuvant Pucotenlimab.
The primary objectives are to assess whether ADC-based induction therapy improves the post-induction therapy complete response rate (post-IT CRR) and event-free survival (EFS) compared to the GP-based standard of care. Secondary objectives include comparisons of overall survival (OS), distant metastasis-free survival (DMFS), and locoregional recurrence-free survival (LRRFS), as well as evaluation of the safety, tolerability, and quality of life associated with the MRG003-containing regimen.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •1\. Age ≥ 18 years at the time of diagnosis, regardless of sex
- •2\. Histologically confirmed newly diagnosed nasopharyngeal carcinoma (NPC) of non-keratinizing carcinoma histology (WHO classification)
- •3\. Locoregionally advanced NPC staged as T4N2 or T1-4N3 according to the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) 9th edition staging system. All patients must undergo the following evaluations prior to initiation of any treatment to confirm clinical staging: complete medical history and physical examination, complete blood count (CBC) and biochemistry panel, plasma Epstein-Barr virus (EBV) DNA titer and serology, nasopharyngoscopy, magnetic resonance imaging (MRI) of the head and neck, chest X-ray or computed tomography (CT) of the chest, abdominal ultrasound, and bone scintigraphy. 18F-fluorodeoxyglucose positron emission tomography/CT (¹⁸F-FDG PET/CT) may be used as a substitute for the latter three imaging modalities.
- •4\. At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1)
- •5\. Willing to provide archived tumor tissue (primary or metastatic lesion, obtained within 2 years prior to enrollment) or fresh biopsy specimen. Patients unable to provide tumor tissue may still be enrolled at the investigator's discretion, provided all other eligibility criteria are met.
- •6\. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days prior to first dose
- •7\. Adequate organ function, as defined by the following laboratory parameters, obtained within 4 weeks prior to screening, with no blood transfusions, hematopoietic growth factors, or thrombopoietic agents administered during this period: a) Hematology: Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L; white blood cell count \> 4 × 10⁹/L; hemoglobin \> 90 g/L; platelet count \> 100 × 10⁹/L; b) Hepatic and renal function: Serum total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN); aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 2.5 × ULN; alkaline phosphatase (ALP) ≤ 2.5 × ULN; creatinine clearance ≥ 60 mL/min; urinary protein ≤ 2+ or ≤ 1000 mg/24 hours; c) Coagulation: International normalized ratio (INR) ≤ 1.5 × ULN and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN (patients receiving stable low-dose anticoagulation therapy, such as aspirin 100 mg/day, are permitted)
- •8\. Normal findings on thyroid function tests, serum amylase and lipase, pituitary function tests, inflammatory and infectious markers, cardiac enzyme panel, and electrocardiogram (ECG): a) Patients aged \> 50 years with a smoking history must have normal pulmonary function test results; b) Patients with ECG abnormalities or a prior cardiovascular history (not meeting
Exclusion Criteria
- •) must additionally undergo myocardial function testing and echocardiography, with normal results required for enrollment
- •9\. Willing and able to provide written informed consent and to comply with all protocol-specified requirements, including scheduled visits, treatment administration, laboratory assessments, and other study procedures
- •10\. Patients of reproductive potential must agree to use effective contraception from the time of informed consent through 6 months after the last dose of study treatment. Women of childbearing potential (WOCBP), defined as premenopausal women and women within 2 years of menopause, must have a negative serum pregnancy test within 7 days prior to the first dose of study treatment.
- •Exclusion Criteria:
- •1\. History of any other malignancy within the past 5 years, with the exception of curatively treated cervical carcinoma in situ, papillary thyroid carcinoma, or basal cell carcinoma of the skin
- •2\. Prior receipt of any anti-tumor therapy for nasopharyngeal carcinoma, or any of the following: a) Any ADC drug with a monomethyl auristatin E (MMAE) payload within 3 months prior to first dose; b) Any investigational drug from another clinical trial within 28 days prior to first dose; c) Major surgery within 28 days prior to first dose without full recovery, or planned major surgery within the first 12 weeks after initiation of study treatment
- •3\. Positive human immunodeficiency virus antibody (HIV-Ab); active tuberculosis; active hepatitis B virus infection (HBV-DNA \> 1 × 10³ copies/mL); or active hepatitis C virus infection (HCV antibody positive and HCV-RNA above the lower limit of detection)
- •4\. History of primary immunodeficiency, or active autoimmune disease requiring immunosuppressive therapy or systemic corticosteroids (≥ 10 mg/day prednisone or equivalent) within 2 weeks prior to enrollment. The following conditions are exempt: type 1 diabetes mellitus; hypothyroidism (including autoimmune thyroid disease) stable on hormone replacement therapy; psoriasis, vitiligo, or alopecia not requiring systemic treatment; and use of topical or inhaled corticosteroids, or short-term (≤ 7 days) systemic corticosteroids for prophylaxis or treatment of non-autoimmune, non-recurrent allergic conditions
- •5\. Uncontrolled cardiac disease, including any of the following: (1) heart failure of New York Heart Association (NYHA) Class ≥ 2; (2) unstable angina; (3) myocardial infarction within the past 1 year; (4) prolonged QT interval (QTc \> 450 ms in males or QTc \> 470 ms in females), complete left bundle branch block, third-degree atrioventricular block, or supraventricular or ventricular arrhythmia requiring treatment or intervention
- •6\. Hypertension inadequately controlled with two antihypertensive agents (systolic blood pressure \> 150 mmHg or diastolic blood pressure \> 100 mmHg)
Arms & Interventions
ADC + PD-1Inhibitor Induction Therapy
Induction Therapy (3 cycles, Q3W):
Becotatug Vedotin (MRG003) 2.0 mg/kg, intravenous infusion, Day 1 + Pucotenlimab 200 mg, intravenous infusion, Day 1;
Concurrent Chemoradiotherapy (CCRT):
Intensity-modulated radiotherapy (IMRT): 70 Gy in 33 fractions, once daily, 5 days per week + Cisplatin 100 mg/m², intravenous infusion, Day 1 (2 cycles, Q3W);
Adjuvant Immunotherapy (6 cycles, Q3W):
Pucotenlimab 200 mg, intravenous infusion, Day 1
Intervention: Becotatug Vedotin (Drug)
ADC + PD-1Inhibitor Induction Therapy
Induction Therapy (3 cycles, Q3W):
Becotatug Vedotin (MRG003) 2.0 mg/kg, intravenous infusion, Day 1 + Pucotenlimab 200 mg, intravenous infusion, Day 1;
Concurrent Chemoradiotherapy (CCRT):
Intensity-modulated radiotherapy (IMRT): 70 Gy in 33 fractions, once daily, 5 days per week + Cisplatin 100 mg/m², intravenous infusion, Day 1 (2 cycles, Q3W);
Adjuvant Immunotherapy (6 cycles, Q3W):
Pucotenlimab 200 mg, intravenous infusion, Day 1
Intervention: intensity-modulated radiotherapy (Radiation)
GP + PD-1 Inhibitor Induction Therapy
Induction Therapy (3 cycles, Q3W):
Gemcitabine 1000 mg/m², intravenous infusion, Days 1 and 8 + Cisplatin 80 mg/m², intravenous infusion, Day 1 + Pucotenlimab 200 mg, intravenous infusion, Day 1;
Concurrent Chemoradiotherapy (CCRT):
Intensity-modulated radiotherapy (IMRT): 70 Gy in 33 fractions, once daily, 5 days per week + Cisplatin 100 mg/m², intravenous infusion, Day 1 (2 cycles, Q3W);
Adjuvant Immunotherapy (6 cycles, Q3W):
Pucotenlimab 200 mg, intravenous infusion, Day 1
Intervention: Gemcitabine + cisplatin (GP) (Drug)
GP + PD-1 Inhibitor Induction Therapy
Induction Therapy (3 cycles, Q3W):
Gemcitabine 1000 mg/m², intravenous infusion, Days 1 and 8 + Cisplatin 80 mg/m², intravenous infusion, Day 1 + Pucotenlimab 200 mg, intravenous infusion, Day 1;
Concurrent Chemoradiotherapy (CCRT):
Intensity-modulated radiotherapy (IMRT): 70 Gy in 33 fractions, once daily, 5 days per week + Cisplatin 100 mg/m², intravenous infusion, Day 1 (2 cycles, Q3W);
Adjuvant Immunotherapy (6 cycles, Q3W):
Pucotenlimab 200 mg, intravenous infusion, Day 1
Intervention: intensity-modulated radiotherapy (Radiation)
GP + PD-1 Inhibitor Induction Therapy
Induction Therapy (3 cycles, Q3W):
Gemcitabine 1000 mg/m², intravenous infusion, Days 1 and 8 + Cisplatin 80 mg/m², intravenous infusion, Day 1 + Pucotenlimab 200 mg, intravenous infusion, Day 1;
Concurrent Chemoradiotherapy (CCRT):
Intensity-modulated radiotherapy (IMRT): 70 Gy in 33 fractions, once daily, 5 days per week + Cisplatin 100 mg/m², intravenous infusion, Day 1 (2 cycles, Q3W);
Adjuvant Immunotherapy (6 cycles, Q3W):
Pucotenlimab 200 mg, intravenous infusion, Day 1
Intervention: Pucotenlimab (Drug)
GP + PD-1 Inhibitor Induction Therapy
Induction Therapy (3 cycles, Q3W):
Gemcitabine 1000 mg/m², intravenous infusion, Days 1 and 8 + Cisplatin 80 mg/m², intravenous infusion, Day 1 + Pucotenlimab 200 mg, intravenous infusion, Day 1;
Concurrent Chemoradiotherapy (CCRT):
Intensity-modulated radiotherapy (IMRT): 70 Gy in 33 fractions, once daily, 5 days per week + Cisplatin 100 mg/m², intravenous infusion, Day 1 (2 cycles, Q3W);
Adjuvant Immunotherapy (6 cycles, Q3W):
Pucotenlimab 200 mg, intravenous infusion, Day 1
Intervention: Cisplatin (Drug)
ADC + PD-1Inhibitor Induction Therapy
Induction Therapy (3 cycles, Q3W):
Becotatug Vedotin (MRG003) 2.0 mg/kg, intravenous infusion, Day 1 + Pucotenlimab 200 mg, intravenous infusion, Day 1;
Concurrent Chemoradiotherapy (CCRT):
Intensity-modulated radiotherapy (IMRT): 70 Gy in 33 fractions, once daily, 5 days per week + Cisplatin 100 mg/m², intravenous infusion, Day 1 (2 cycles, Q3W);
Adjuvant Immunotherapy (6 cycles, Q3W):
Pucotenlimab 200 mg, intravenous infusion, Day 1
Intervention: Pucotenlimab (Drug)
ADC + PD-1Inhibitor Induction Therapy
Induction Therapy (3 cycles, Q3W):
Becotatug Vedotin (MRG003) 2.0 mg/kg, intravenous infusion, Day 1 + Pucotenlimab 200 mg, intravenous infusion, Day 1;
Concurrent Chemoradiotherapy (CCRT):
Intensity-modulated radiotherapy (IMRT): 70 Gy in 33 fractions, once daily, 5 days per week + Cisplatin 100 mg/m², intravenous infusion, Day 1 (2 cycles, Q3W);
Adjuvant Immunotherapy (6 cycles, Q3W):
Pucotenlimab 200 mg, intravenous infusion, Day 1
Intervention: Cisplatin (Drug)
Outcomes
Primary Outcomes
Post-induction Therapy Complete Response Rate (post-IT CRR)
Time Frame: Within 9 to 21 days after the last dose of induction therapy
The proportion of patients achieving complete response following induction therapy
Event-Free Survival (EFS)
Time Frame: 3 years & 5 years
From date of randomization until the date of first documented locoregional recurrence, distant metastasis, or death from any cause, whichever occurred first.
Secondary Outcomes
- Overall survival (OS)(3 years & 5 years)
- Distant Metastasis-Free Survival (DMFS)(3 years & 5 years)
- Locoregional Recurrence-Free Survival (LRRFS)(3 years & 5 years)
- Adverse Events (AEs)(3 years & 5 years)
- Patient-Reported Adverse Events (PRO-CTCAE)(At the end of each treatment cycle (each cycle is 21 days), from Cycle 1 of induction therapy through Cycle 6 of adjuvant therapy)
- European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Score(At baseline, after completion of induction therapy (Week 10), mid-IMRT(Week 16), after completion of IMRT (Week 19), at the last adjuvant cycle (Week 34; each cycle is 21 days), and at 3, 12, 24, 36, 48, and 60 months post-radiotherapy)
- EORTC Quality of Life Questionnaire Head and Neck 35 (EORTC QLQ-H&N35, version 1)(At baseline, after completion of induction therapy (Week 10), mid-IMRT(Week 16), after completion of IMRT (Week 19), at the last adjuvant cycle (Week 34; each cycle is 21 days), and at 3, 12, 24, 36, 48, and 60 months post-radiotherapy)
- Functional Assessment of Cancer Therapy - Head and Neck (FACT-H&N, Chinese version 4)(At baseline, after completion of induction therapy (Week 10), mid-IMRT(Week 16), after completion of IMRT (Week 19), at the last adjuvant cycle (Week 34; each cycle is 21 days), and at 3, 12, 24, 36, 48, and 60 months post-radiotherapy)
Investigators
Jun Ma, MD
Professor
Sun Yat-sen University