tReatment Individualisation By EBV stratificatiON in Nasopharyngeal Carcinoma: an Umbrella Platform Study (RIBBON-Umbrella)

Обзор

This is a prospective platform study that will investigate the outcomes of patients with locoregionally-advanced nasopharyngeal carcinoma (LA-NPC) or recurrent-metastatic nasopharyngeal carcinoma (RM-NPC) who are assigned to treatment arms of different chemotherapy sequencing and intensity based on their pre- and on-treatment plasma EBV DNA results.

Подробное описание

The primary objectives of this platform are: (1) to prospectively validate the prognostic potential of an EBV DNA-based risk-stratification strategy of patients with LA- and RM-NPC; and (2) to test if treatment individualization strategies based on pre- and on-treatment plasma EBV DNA will improve survival outcomes.

For LA-NPC, the study design consists of two components: (1) to allocate adult patients with UICC/AJCC 8th edition TNM-stage 2-4A LA-NPC to 3 treatment arms of different intensities by their plasma EBV DNA levels pre-treatment and post-induction chemotherapy (IC); and (2) to incorporate open-label, single-arm, phase 2 trials within the platform for patients who are deemed to be at high-risk of relapse, defined by a persistently detectable EBV DNA following 3 cycles of IC. Primary study end-point is 2-year disease-free survival (DFS).

Вмешательства

• Другое Arm 1
  Concurrent chemoradiotherapy (CCRT) using cisplatin (100 mg/m2 IV) or carboplatin (AUC 5 IV) with radiotherapy +/- adjuvant chemotherapy (AC). For AC, physicians can choose between cisplatin-5FU d1-4, q4w for 3 cycles, or capecitabine 650 mg/m2 bid for 12 months or 1000 mg/m2 bid oral, d1-21, q3w for 6 months
• Другое Arm 2
  IC using cisplatin (80 mg/m2 IV) or carboplatin (AUC 3-5 IV) in combination with gemcitabine (1000 mg/m2 d1,8) or 5-fluorouracil (1000 mg/m2 bolus IV d1-4) or docetaxel (75 mg/m2 IV), and CCRT +/- metronomic capecitabine (650 mg/m2 bid oral for 12 months)
• Другое Arm 3
  IC using cisplatin (80 mg/m2 IV) or carboplatin (AUC 3-5 IV) in combination with gemcitabine (1000 mg/m2 d1,8) or 5-fluorouracil (1000 mg/m2 bolus IV d1-4) or docetaxel (75 mg/m2 IV), followed by either of the following: 1. RIBBON-LA-01 (NCT06093061) 2. CCRT + metronomic capecitabine (650 mg/m2 bid oral for 12 months)
• Другое Group 1
  Combination chemotherapy (using cisplatin or carboplatin with gemcitabine, 5-fluorouracil or docetaxel) and consolidative RT to the nasopharynx and neck (if good response to chemotherapy) +/- metastasis-directed therapy (surgery, radiofrequency ablation or RT) +/- immune checkpoint blockade (ICB) or capecitabine
• Другое Group 2
  Combination chemotherapy (using cisplatin or carboplatin with gemcitabine, 5-fluorouracil or docetaxel) with or without ICB +/- maintenance ICB or capecitabine

Первичные конечные точки

• Disease-Free Survival [Срок оценки: 2 years from end of treatment]

Вторичные конечные точки (5)

• Overall survival [Срок оценки: 2 years after end of treatment]
• Distant metastasis-free survival [Срок оценки: 2 years after end of treatment]
• Loco-regional recurrence-free survival [Срок оценки: 2 years after end of treatment]
• Treatment-related adverse events [Срок оценки: From start of treatment to 30 days after last treatment and up to 5 years post - treatment]
• Genome sequencing of biological samples [Срок оценки: baseline, mid/post IC, mid CCRT, 1-2 weeks post-RT, 3 months post-RT/mid-adjuvant chemotherapy, at point of recurrence and post immune checkpoint blockade treatment (for recurrence, if any) up to 5 years]

Критерии участия

Критерии включения

Each patient eligible to participate in this study must meet all the following criteria:

• Able to provide written informed consent and can understand and agree to comply with the requirements of the study and the schedule of assessments.
• Age ≥21 years on the day of signing the ICF
• Fulfil one of the following three scenarios:

• Suspected NPC cases, diagnosed clinically based on symptoms (neck swelling, unilateral epistaxis, nasal obstruction etc.)
• Newly-diagnosed, histologically confirmed NPC patients with Stages 2-4A disease based on the AJCC/UICC 8th Edition TNM stage classification
• Newly-diagnosed patients with RM-NPC

All confirmed NPC patients must meet these additional criteria before they can continue participation in the study:

• NPC associated with EBV infection, determined as:

• The presence of EBV has been confirmed in the tumour by immunohistochemistry for EBV antigens or in situ hybridization for EBV early RNA (EBER), or
• NPC occurred in association with a raised serum titre of IgA to EBV viral capsid antigen (VCA) or early antigen (EA) in a patient living in endemic area of high incidence of EBV+ undifferentiated NPC, or
• NPC in the context of an elevated circulating EBV genome level
• AJCC 8th edition stage 2-4A or RM NPC based on the following diagnostic workup:

• Evaluation of tumour extent with magnetic resonance imaging (MRI) of the nasopharynx and neck. If MRI is medically contraindicated, computed tomography (CT) scan with ≤3 mm and intravenous contrast is acceptable.
• Distant metastasis staging:

• CT scan with contrast of the chest, abdomen, and pelvis or a total body 18F-Fluorodeoxygenase positron emission tomography CT (18F-FDG-PET-CT) scan;
• Bone scan, if a 18F-FDG-PET-CT scan is not performed.
• ECOG Performance Status ≤1
• Adequate organ function

Критерии исключения

Patients who meet any of the following criteria are not eligible to enrol:

• Age <21 years or >99 years old
• Has received any prior RT or systemic anti-cancer therapy including investigational agents that are not part of the intended treatment plan for NPC
• Any known central nervous system metastases and/or carcinomatous meningitis
• Any active malignancy ≤2 years before start of study except for the specific cancer under investigation in this study and any locally recurring cancer that has been treated curatively (e.g., resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast)
• Patients with severe chronic or active infections requiring systemic antibacterial, antifungal or antiviral therapy, including tuberculosis infection, etc.

a. Severe infections within 4 weeks before start of study, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia.

• Patients with untreated chronic hepatitis B or chronic hepatitis B virus (HBV) carriers whose HBV DNA is >500 IU/mL or patients with active hepatitis C virus (HCV) should be excluded.

Note: Inactive hepatitis B surface antigen (HBsAg) carriers, treated and stable hepatitis B (HBV DNA <500 IU/mL), and cured hepatitis C patients can be enrolled

• Prior allogeneic stem cell transplantation or organ transplantation
• Any of the following cardiovascular risk factors:

• Cardiac chest pain, defined as moderate pain or any cardiac condition e.g., arrhythmias, malignant hypertension, etc. that limits instrumental activities of daily living, ≤28 days before start of study
• Pulmonary embolism ≤28 days before start of study
• Any history of cerebrovascular accident or seizure ≤ 28 days before start of study
• A history of severe hypersensitivity reactions to gemcitabine, cisplatin, capecitabine and/or any of its excipients
• Has received any herbal medicine used to control cancer within 14 days of the start of study
• Patients with toxicities (as a result of prior anticancer therapy) which have not recovered to baseline or stabilized, except for adverse events (AEs) not considered a likely safety risk (eg, alopecia, neuropathy and specific laboratory abnormalities)
• Underlying medical conditions (including laboratory abnormalities) or alcohol or drug abuse or dependence that, will be unfavorable for the administration of treatment or affect the explanation of drug toxicity or AEs or result in insufficient or might impair compliance with study conduct
• Concurrent participation in another therapeutic clinical study

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

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

Сингапур · 1 центр

• National Cancer Centre Singapore — Singapore

Идентификаторы

NCT: NCT05517135 · 2022/2315

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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