Nasopharyngeal Cancinoma (NPC)
Conditions
Keywords
anlotinib hydrochloride, PD-L1 antibody, Risk-Adapted therapy, chemoradiotherapy
Brief summary
The purpose of this study is to evaluate the efficacy and safety of a risk-adapted treatment strategy incorporating induction therapy (Gemcitabine + Cisplatin) with Anlotinib plus Benmelstobart, followed by treatment allocation based on post-induction plasma cell-free Epstein-Barr virus DNA (cfEBV DNA) status and radiographic response in patients with locoregionally advanced nasopharyngeal carcinoma. All participants will receive three cycles of induction therapy (Gemcitabine + Cisplatin) with Anlotinib plus Benmelstobart. After induction therapy, participants with cfEBV DNA clearance and a complete or partial response will be classified as low risk and receive intensity-modulated radiotherapy alone, followed by adjuvant Benmelstobart. Participants without cfEBV DNA clearance or with stable or progressive disease will be classified as high risk and receive intensity-modulated radiotherapy with concurrent cisplatin, followed by adjuvant Benmelstobart and capecitabine. The primary objectives are to evaluate the post-induction therapy complete response rate in the overall study population and event-free survival in the high-risk group.
Detailed description
This is a multicenter, prospective study evaluating a biomarker- and response-guided risk-adapted treatment strategy for locoregionally advanced nasopharyngeal carcinoma. All participants will receive three cycles of induction therapy (Gemcitabine + Cisplatin) with Anlotinib, a multi-targeting tyrosine kinase inhibitor, plus the PD-L1 inhibitor Benmelstobart. Risk assignment will be performed after completion of induction therapy using both plasma cell-free Epstein-Barr virus DNA (cfEBV DNA) status and radiographic tumor response. Participants with undetectable cfEBV DNA and a complete or partial response after induction therapy will be assigned to the low-risk group. These participants will then receive intensity-modulated radiotherapy without concurrent cisplatin, followed by adjuvant Benmelstobart. Participants with detectable cfEBV DNA after induction therapy, or whose best radiographic response is stable or progressive disease, will be assigned to the high-risk group. These participants will receive intensity-modulated radiotherapy with concurrent cisplatin, followed by adjuvant Benmelstobart and capecitabine. The study has two primary objectives: to evaluate the complete response rate after induction therapy in the overall study population and to evaluate event-free survival in the higher-risk group. Secondary evaluations include overall survival, distant metastasis-free survival, locoregional recurrence-free survival, cfEBV DNA clearance after induction therapy, safety, tolerability, and patient-reported quality of life.Exploratory analyses will investigate potential prognostic and treatment-response biomarkers in tumor tissue, blood, and stool samples. Clinical outcomes will also be explored across subgroups defined by age, sex, baseline cfEBV DNA level, percentage reduction or clearance of cfEBV DNA, clinical stage, and other relevant prognostic factors.
Interventions
Induction Therapy: Anlotinib hydrochloride 10mg, oral administration, Day1-14, (3 cycles, Q3W)
DRUGBenmelstobart
Induction Therapy: Benmelstobart 1200 mg, intravenous infusion, Day 1 (3 cycles, Q3W); Adjuvant Therapy: Benmelstobart 1200 mg, intravenous infusion, Day 1 (5 cycles, Q3W)
Induction Therapy: Gemcitabine 1g/m2, intravenous infusion, Day 1\&8 (3 cycles, Q3W)
Concurrent Chemoradiotherapy: Cisplatin 100 mg/m², intravenous infusion, Day 1 (2 cycles, Q3W)
RADIATIONIntensity-Modulated Radiotherapy
70 Gy in 33 fractions, once daily, 5 days per week
DRUGCapecitabine
Adjuvant Therapy: Capecitabine 650 mg/m², orally twice daily, Days 1-21 (17 cycles, Q3W)
Induction Therapy: Cisplatin 80 mg/m², intravenous infusion, Day 1 (2 cycles, Q3W);
Sponsors
Sun Yat-sen University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
All participants receive the same induction therapy and are subsequently stratified into low- and high-risk groups according to post-induction cfEBV DNA status and radiographic response, with each group receiving its protocol-defined treatment.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Age ≥18 and ≤65 years at diagnosis, regardless of sex. 2. Previously untreated nasopharyngeal carcinoma histologically confirmed as non-keratinizing carcinoma according to the World Health Organization (WHO) classification. 3. Locoregionally advanced nasopharyngeal carcinoma classified as stage II or III, excluding T3N0-1 disease, according to the 9th edition of the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) clinical staging system. 4. Eastern Cooperative Oncology Group performance score of 0-1. 5. Adequate marrow function: white blood cell count \> 4 × 10⁹/L hemoglobin \>90g/L and platelet count \>100×10⁹/L 6. Adequate hepatic and renal function： * Total bilirubin ≤ 1.5 × upper limit of normal (ULN) * Alanine Aminotransferase (ALT)/Aspartate Aminotransferase (AST) ≤2.5×ULN * Alkaline phosphatase ≤ 2.5 × ULN * clearance rate ≥ 60 ml/min 7. Other laboratory and clinical criteria * Normal thyroid function, serum amylase and lipase, pituitary hormone levels, inflammatory markers, cardiac enzyme tests and electrocardiogram (ECG) * For patients aged \>50 years with a history of smoking, normal pulmonary function test (PFT) results are required * For patients with abnormal ECG findings or a prior history of cardiovascular disease (not meeting any
Exclusion criteria
listed in Item 8), additional assessments including myocardial function evaluation and cardiac ultrasound (echocardiography) must be performed, with results within normal limits 8. Patients must be informed of the investigational nature of this study and give written informed consent, and be willing and able to comply with the study schedule, including follow-up visits, treatment procedures, laboratory testing, and other protocol-related requirements. 9. Women of childbearing potential (WOCBP) must be willing to adhere to effective contraception during treatment and for 1 year after the last dose of study drug (e.g., condoms, physician-guided regular use of oral contraceptives). 10. Positive plasma Epstein-Barr virus (EBV) DNA before initiation of treatment (\> 0 copies/mL).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Post-induction Therapy Complete Response Rate (post-IT CRR) | 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) in the High-Risk Group | 3 years & 5 years | The time from the date of enrollment to the first occurrence of locoregional recurrence, distant metastasis, or death from any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall survival (OS) | 3 years & 5 years | From date of enrollment to date of death from any cause |
| Distant Metastasis-Free Survival (DMFS) | 3 years & 5 years | From the date of enrollment to the date of first documented distant metastasis or death from any cause, whichever occurs first. |
| Locoregional Recurrence-Free Survival (LRRFS) | 3 years & 5 years | From the date of enrollment to the date of first documented locoregional recurrence or death from any cause, whichever occurs first. |
| Adverse Events (AEs) | 3 years & 5 years | Graded according to CTCAE V5.0 |
| 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 5 of adjuvant therapy | Patient-reported adverse events will be assessed using selected items from the National Cancer Institute Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (NCI PRO-CTCAE™), Chinese version, administered at each treatment cycle. Patients will self-report and rate the severity of relevant adverse events throughout the study treatment period. |
| 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), at the end of IMRT (Week 16), at the last adjuvant cycle (Week 31; each cycle is 21 days), and at 1, 3, 12, 24, 36, 48, and 60 months post-radiotherapy | Assesses general quality of life in cancer patients. Items are scored and linearly transformed to a 0-100 scale. For functional scales, higher scores indicate better functioning; for symptom scales, higher scores indicate greater symptom burden. |
| EORTC Quality of Life Questionnaire Head and Neck 35 (EORTC QLQ-H&N35, version 1) | At baseline, after completion of induction therapy (Week 10), at the end of IMRT (Week 16), at the last adjuvant cycle (Week 31; each cycle is 21 days), and at 1, 3, 12, 24, 36, 48, and 60 months post-radiotherapy | Assesses head and neck cancer-specific symptoms. Items are scored and linearly transformed to a 0-100 scale. Higher scores indicate more severe symptoms. |
| Functional Assessment of Cancer Therapy - Head and Neck (FACT-H&N, Chinese version 4) | At baseline, after completion of induction therapy (Week 10), at the end of IMRT (Week 16), at the last adjuvant cycle (Week 31; each cycle is 21 days), and at 1, 3, 12, 24, 36, 48, and 60 months post-radiotherapy | Assesses quality of life specific to head and neck cancer patients. Items are rated on a 0-4 scale and summed to a total score of 0-156. Higher scores indicate better quality of life. |
Contacts
CONTACTJun Ma, M.D.
CONTACTYa-Qin Wang, Ph.D.
Outcome results
None listed