Tislelizumab Combined With Chemotherapy Versus Chemotherapy Alone in Recurrent or Metastatic Nasopharyngeal Cancer (NPC) (RATIONALE-309)

A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study to Compare the Efficacy and Safety of Tislelizumab (BGB-A317) Combined With Gemcitabine Plus Cisplatin Versus Placebo Combined With Gemcitabine Plus Cisplatin as First-Line Treatment for Recurrent or Metastatic Nasopharyngeal Cancer

This study was designed to compare the efficacy and safety of tislelizumab (BGB-A317) combined with gemcitabine plus cisplatin versus placebo combined with gemcitabine plus cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal cancer.

Study Overview

• Status: Completed
• Conditions: Recurrent or Metastatic Nasopharyngeal Cancer
• Intervention / Treatment: Drug: Tislelizumab; Drug: Gemcitabine; Drug: Cisplatin; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 263
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Anhui
    • Hefei, Anhui, China, 230000
      • Anhui Provincial Hospital
  • Beijing
    • Beijing, Beijing, China, 100142
      • Beijing Cancer Hospital
  • Chongqing
    • Chongqing, Chongqing, China, 404000
      • Chongqing Three Gorges Central Hospital
    • Chongqing, Chongqing, China, 400030
      • Chongqing Cancer Hospital
  • Fujian
    • Fuzhou, Fujian, China, 350014
      • Fujian Cancer Hospital
    • Xiamen, Fujian, China, 361003
      • The First Affiliated Hospital of Xiamen University
  • Guangdong
    • Guangzhou, Guangdong, China, 510080
      • Guangdong Provincial Peoples Hospital
    • Guangzhou, Guangdong, China, 510060
      • Sun Yat Sen University Cancer Center
    • Guangzhou, Guangdong, China, 510000
      • Sun Yat Sen Memorial Hospital, Sun Yat Sen University (North)
    • Guangzhou, Guangdong, China, 510030
      • Cancer Center of Guangzhou Medical University
    • Guangzhou, Guangdong, China, 510405
      • The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine
    • Shantou, Guangdong, China, 515031
      • Cancer Hospital of Shantou University Medical College
    • Zhanjiang, Guangdong, China, 524000
      • Affiliated Hospital of Guangdong Medical University
    • Zhongshan, Guangdong, China, 528403
      • The Peoples Hospital of Zhongshan City
    • Zhuhai, Guangdong, China, 519000
      • The Fifth Affiliated Hospital Sun Yat Sen University
  • Guangxi
    • Nanning, Guangxi, China, 530021
      • The Peoples Hospital of Guangxi Zhuang Autonomous Region
    • Nanning, Guangxi, China, 530021
      • The Tumor Hospital Affiliated to Guangxi Medical University
  • Hainan
    • Haikou, Hainan, China, 570206
      • Hainan General Hospital
  • Heilongjiang
    • Harbin, Heilongjiang, China, 150000
      • Harbin Medical University Cancer Hospital
  • Hubei
    • Wuhan, Hubei, China, 430079
      • Hubei Cancer Hospital
    • Wuhan, Hubei, China, 430022
      • Union Hospital of Tongji Medical College, Huazhong University of Science and Technology
  • Hunan
    • Changsha, Hunan, China, 410013
      • Hunan Cancer Hospital
    • Changsha, Hunan, China, 410004
      • Changsha Central Hospital
  • Jiangsu
    • Nantong, Jiangsu, China, 201203
      • Affiliated Hospital of Nantong University
  • Jiangxi
    • Nanchang, Jiangxi, China, 330006
      • The First Affiliated Hospital of Nanchang University Branch Donghu
  • Shanghai
    • Shanghai, Shanghai, China, 200120
      • Shanghai East Hospital
    • Shanghai, Shanghai, China, 200032
      • Affiliated Zhongshan Hospital of Fudan University
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • West China Hospital, Sichuan University
    • Chengdu, Sichuan, China, 610041
      • Sichuan Cancer Hospital and Institute
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310022
      • Zhejiang Cancer Hospital
• Taiwan
  • Changhua, Taiwan, 50006
    • Changhua Christian Hospital
  • Taichung, Taiwan, 40705
    • Veterans General Hospital Taichung
  • Tainan, Taiwan, 704
    • National Cheng Kung University Hospital
• Thailand
  • Bangkok, Thailand, 10400
    • Ramathibodi Hospital Mahidol University Hematology
  • Hat Yai, Thailand, 90110
    • Songklanagarind Hospital (Prince of Songkhla University)
  • Muang, Thailand, 50200
    • Maharaj Nakorn Chiang Mai Hospital (Chiang Mai University)
  • Muang, Thailand, 40002
    • Srinagarind Hospital (Khon Kaen University)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. Able to provide written informed consent and can understand and agree to comply with the requirements of the study and the schedule of assessments
2. Aged between 18 to 75 years on the day of signing the informed consent form (or the legal age of consent in the jurisdiction in which the study is taking place)
3. Histologically or cytologically confirmed, recurrent or metastatic NPC
4. Participants must be able to provide fresh or archival tumor tissues (formalin-fixed paraffin-embedded [FFPE] blocks or approximately 10 [≥ 6] freshly cut unstained FFPE slides) with an associated pathological report. The archival tumor tissues must be collected within 2 years before screening. In the absence of sufficient archival tumor tissues, a fresh biopsy of a tumor lesion at baseline is mandatory
5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
6. Must have ≥ 1 measurable lesions as defined per RECIST v1.1
7. Must be treatment-naive for recurrent or metastatic NPC.

Key Exclusion Criteria:

1. Participants with locally recurrence suitable for curative surgery or radiotherapy

2. Received any approved systemic anticancer therapy, including hormonal therapy, within 28 days prior to initiation of study treatment. The following exception is allowed:

   • Palliative radiotherapy for bone metastases or soft tissue lesions should be completed > 7 days prior to baseline imaging.
3. Has received any immunotherapy (including but not limited to interferons, interleukin 2, tumor necrosis factor interleukin, and thymoxin) or any investigational therapies within 14 days or 5 half-lives (whichever is longer) of randomization
4. Received prior therapies targeting programmed cell death protein-1 (PD-1) or programmed cell death protein ligand-1 (PD-L1)
5. Active leptomeningeal disease or uncontrolled, untreated brain metastasis
6. Active autoimmune diseases or history of autoimmune diseases that may relapse
7. Any active malignancy ≤ 2 years before randomization except for the specific cancer under investigation in this study and any locally recurring cancer that has been treated curatively (eg, resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast)

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: Tislelizumab + Gemcitabine + Cisplatin; Participants received tislelizumab 200 mg intravenously (IV) once every 3 weeks (Q3W), gemcitabine 1 g/m^2 IV on days 1 and 8 of each 21-day cycle and cisplatin 80 mg/m^2 IV on day 1 of each cycle for 4 to 6 treatment cycles. Participants may have received treatment for longer at the Investigator's discretion until disease progression. Participants with confirmed disease progression may have continued to receive tislelizumab monotherapy.	Drug: Tislelizumab; 200 mg intravenously (IV) once every 3 weeks (Q3W); Other Names: BGB-A317; Drug: Gemcitabine; 1 gram per square meter of body surface area (g/m^2) on Day 1 and day 8 of each cycle, administered as an IV infusion within 30 minutes, for 4 to 6 cycles; Drug: Cisplatin; 80 milligrams per square meter of body surface area (mg/m^2) on Day 1 of each cycle, administered as an IV infusion for over 4 hours if possible or with proper infusion time based on local clinical guidelines or clinical practice and according to the treating physician's clinical judgment, for 4 to 6 cycles.
Placebo Comparator: Arm B: Placebo + Gemcitabine + Cisplatin; Participants received placebo IV once every 3 weeks, gemcitabine 1 g/m^2 IV on days 1 and 8 of each 21-day cycle and cisplatin 80 mg/m^2 IV on day 1 of each cycle for 4 to 6 treatment cycles. Participants may have received treatment for longer at the Investigator's discretion until disease progression. Participants with confirmed disease progression may have crossed over to receive tislelizumab 200 mg IV Q3W monotherapy.	Drug: Gemcitabine; 1 gram per square meter of body surface area (g/m^2) on Day 1 and day 8 of each cycle, administered as an IV infusion within 30 minutes, for 4 to 6 cycles; Drug: Cisplatin; 80 milligrams per square meter of body surface area (mg/m^2) on Day 1 of each cycle, administered as an IV infusion for over 4 hours if possible or with proper infusion time based on local clinical guidelines or clinical practice and according to the treating physician's clinical judgment, for 4 to 6 cycles.; Drug: Placebo; Placebo to match tislelizumab (administered intravenously Q3W)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival as Assessed by the Independent Review Committee (IRC)	Defined as the time from randomization to the first objectively documented disease progression, or death from any cause, whichever occurred first, as assessed by the IRC per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Kaplan-Meier methodology was used to estimate the median PFS.	Through the study interim data analysis cutoff date of March 26th, 2021 (maximum time on study follow-up was 23 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR) as Assessed by the IRC	Defined as the percentage of participants who had complete response or partial response as assessed by the IRC per RECIST v1.1 in all randomized participants with measurable disease at Baseline.	Through the study interim data analysis cutoff date of March 26th, 2021 (maximum time on study follow-up was 23 months)
Duration of Response (DOR) as Assessed by the IRC	Defined as the time from the first occurrence of a documented objective response to the time of relapse, or death from any cause, whichever occurred first, as assessed by the IRC per RECIST v1.1 in all randomized participants with documented objective responses.	Through the study interim data analysis cutoff date of March 26th, 2021 (maximum time on study follow-up was 23 months)
Overall Survival (OS) as Assessed by the IRC	Defined as the time from the date of randomization to the date of death due to any cause.	Through study completion data cut-off date of December 8th, 2023 or last available date showing participants alive (maximum time on study follow-up was 53 months)
PFS as Assessed by the Investigator	Defined as the time from randomization to the first objectively documented disease progression, or death from any cause, whichever occurred first, as assessed by the investigator per RECIST v1.1.	Through the interim analysis data cut-off date of March 26th, 2021 (up to approximately 23 months)
Progression-free Survival After Next Line of Treatment (PFS2) as Assessed by the Investigator	Defined as the time from randomization to second/subsequent disease progression after initiation of new anticancer therapy, or death from any cause, whichever occurred first. Median PFS was estimated using the Kaplan-Meier method.	Through the study completion data cut-off date of December 8th, 2023 (maximum time on study follow-up was 53 months)
Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Global Health Status	Change from baseline in EORTC QLQ-C30 Global Health Status/Quality of Life score. The EORTC QLQ-C30 v3.0 is a questionnaire that assesses quality of life of participants with cancer. It includes global health status and quality of life questions related to overall health in which participants respond based on a 7-point scale, where 1 is very poor and 7 is excellent. Raw scores are transformed into a 0 to 100 scale via linear transformation. A higher score indicates better health outcomes.	Baseline to Cycle 6 (Each cycle is 21 days)
Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Head and Neck-351 (EORTC QLQ-H&N35) Index Score	The QLQ-H&N35 consists of thirty-five questions that are associated with eighteen symptom scales (pain, swallowing, senses, speech, social eating, social contact, sexuality, problem with teeth, problem opening mouth, dry mouth, problem with sense smell, cough, felt ill, pain med, nutritional supplements, feeding tube, weight loss and weight gain).. Raw scores are transformed into a 0 to 100 scale via linear transformation. The index score is calculated as an average of the 18 symptom scales. A negative change from baseline score indicates improvement in symptoms.	Baseline to Cycle 6 (Each cycle is 21 days)
Number of Participants With Adverse Events	Number of participants with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), including laboratory tests, vital signs, electrocardiograms (ECGs), and physical examinations (PEs ), graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. For Arm B, only adverse events reported prior to participants crossing over to receive tislelizumab monotherapy are included.	From first dose to 30 days after last dose or new anticancer therapy, or until Dec 8, 2023 data cut-off; max treatment duration: 231 weeks (Arm A), 202 weeks (Arm B).

Collaborators and Investigators

• Sponsor: BeiGene
• Investigators: Principal Investigator: Li Zhang, MD, Sun Yat-sen University

Publications and helpful links

General Publications

• Zhang L, Liu T, Wang H, Shi S, Yang Y. A Phase 3 Trial in Progress Comparing Tislelizumab Plus Chemotherapy With Placebo Plus Chemotherapy in Chinese Patients With Recurrent or Metastatic Nasopharyngeal Cancer. Abstract published at: 22nd Annual Meeting of the Chinese Society of Clinical Oncology; September, 2019; Xiamen, China.

Study record dates

Study Major Dates

• Study Start (Actual): March 27, 2019
• Primary Completion (Actual): March 26, 2021
• Study Completion (Actual): December 8, 2023

Study Registration Dates

• First Submitted: March 21, 2019
• First Submitted That Met QC Criteria: April 22, 2019
• First Posted (Actual): April 23, 2019

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 8, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Stomatognathic Diseases; Pathologic Processes; Neoplasms by Site; Neoplasms; Disease Attributes; Neoplasms by Histologic Type; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Carcinoma; Otorhinolaryngologic Diseases; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Nasopharyngeal Diseases; Pharyngeal Diseases; Nasopharyngeal Carcinoma; Recurrence; Nasopharyngeal Neoplasms; Antineoplastic Agents, Immunological; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Gemcitabine; Tislelizumab
• Other Study ID Numbers: BGB-A317-309; CTR20182534 (Registry Identifier: ChinaDrugTrials)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No