Reduced-dose RT With/Without CCT Versus Standard CCRT for High-risk LANPC Who Achieved CR Post Induction Chemotherapy

Reduced-dose Radiotherapy With/Without Concurrent Chemotherapy Versus Standard Chemoradiotherapy for High-risk Locoregionally Advanced Nasopharyngeal Carcinoma Who Achieved Complete Response After Induction Chemotherapy Plus Immunotherapy: a Randomized, Open-label, Multicenter, Phase III Trial

This prospective trial aims to enroll patients with high-risk stage III-IVA (AJCC 8th, except T3N0) locoregionally-advanced nasopharyngeal carcinoma (LANPC). Under the condition of full course of PD-1/PD-L1 blockades, patients who achieved both radiological and biological complete response after 3 cycles of platinum-based chemotherapy plus PD-1/PD-L1 blockades will be randomized in a 1:1:1 ratio to receive reduced-dose radiotherapy (60Gy/30F) alone or reduced-dose radiotherapy plus concurrent chemotherapy or standard dose radiotherapy (70Gy/33F) with concurrent chemotherapy. To solve the urgent problem of whether patients with high-risk advanced nasopharyngeal carcinoma are suitable for downgrade treatment.

Study Overview

• Status: Recruiting
• Conditions: Nasopharyngeal Carcinoma; De-escalation Therapy
• Intervention / Treatment: Drug: Cisplatin-based induction chemotherapy; Drug: Full course of PD-1/PD-L1 blockades; Radiation: Standard-dose IMRT; Drug: Concurrent Chemotherapy; Radiation: Reduced-dose IMRT

• Study Type: Interventional
• Enrollment (Estimated): 504
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Ming-Yuan Chen, MD,PhD; Phone Number: +86-20-87343361; Email: chenmy@sysucc.org.cn
• Study Contact Backup: Name: Rui You, MD,PhD; Phone Number: +86-13580439820; Email: yourui@sysucc.org.cn

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510060
      • Recruiting
      • Sun Yat-sen University Cancer Center
      • Contact: Ming-Yuan Chen, MD,PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Histologically confirmed non-keratinizing nasopharyngeal carcinoma (differentiated or undifferentiated type, i.e., WHO type II or type III).
2. Tumor staged as III-IVA (AJCC 8th, except T3N0).
3. Patients who achieved both radiological and biological CR according to the RECIST criteria on the basis of MRI, PET-CT and endoscopic biopsy, and EBV DNA load =0 copies/mL (or lower than the test line) after 3 cycles of induction therapy of platinum-based chemotherapy plus immunotherapy.
4. Eastern Cooperative Oncology Group performance status ≤1.

5. Adequate organ function:

   Adequate marrow function: neutrocyte count≥4×10e9/L, hemoglobin ≥90g/L and platelet count ≥100×10e9/L.

   Adequate liver and kidney function: Alanine Aminotransferase (ALT)/Aspartate Aminotransferase (AST) ≤2.5×upper limit of normal (ULN), and bilirubin ≤ 2.5×ULN.; creatinine clearance rate ≥ 60 ml/min or creatinine of no more than 1.5 times the upper normal limit.

6. Patients must be informed of the investigational nature of this study and give written informed consent.

Exclusion Criteria:

1. Patients who are evaluated as PR or SD or PD or EBV DNA load of >0 copies/mL after 3 cycles of induction therapy of platinum-based chemotherapy plus PD-1/PD-L1 blockades.
2. The laboratory examination value does not meet the relevant standards within 7 days before enrollment.
3. Patients have received prior chemotherapy, immunotherapy, targeted therapy, or surgery (other than diagnostic treatment).
4. Subjects who underwent anti-PD-1 /PD-L1 antibody or anti-CTLA-4 antibody (or any other antibody acting on T cell synergistic stimulation or checkpoint pathway) and anti-angiogenic drugs.
5. Active central nervous system (CNS) metastases (indicated by clinical symptoms, cerebral edema, steroid requirement, or progressive disease).
6. Grade ≥2 epistaxis (defined as the need for medical intervention such as nasal tamponade, cautery, topical vasoconstrictors, according to CTCAE 5.0) within 1 month prior to enrollment; Macroscopic hemoptysis or hematemesis) is defined as ≥1/2 teaspoon of bright red blood, or a blood clot with little/no sputum on each cough). (Patients with mixed sputum-blood occasionally may be enrolled).
7. Patients with hypertension who cannot be reduced to the normal range by antihypertensive drug treatment (systolic blood pressure > 140 mmHg/diastolic blood pressure > 90 mmHg), patients with ≥ grade II coronary heart disease, arrhythmia (including QTc interval prolongation > 450 ms in men and > 470 ms in women) and cardiac insufficiency.
8. Patients currently take warfarin, heparin, aspirin (> 325 mg/day) or other NSAIDs known to inhibit platelet function, ticlopidine, clopidogrel, or cilostazol. (Patients can be enrolled if they discontinue these drugs 10 days prior to the commence of study and meet the requirements of coagulation in the enrollment criteria).
9. Patients with other malignancies (except for cervical cancer, basal cell carcinoma or squamous cell carcinoma of the skin, localized prostate cancer, and ductal carcinoma in situ who have undergone curative treatment).
10. Has a known history of interstitial lung disease.
11. Known history of hypersensitivity to any components of the PD-1/PD-L1 blockades formulation or other monoclonal antibodies.
12. Has a known history of allergic reactions to the drugs in the study (gemcitabine, cisplatin, docetaxel, abraxane, paclitaxel ).
13. Has active autoimmune disease or any condition that requires systemic corticosteroid or immunosuppressive therapy, including but not limited to the following: rheumatoid arthritis, pneumonitis, colitis (inflammatory bowel disease), hepatitis, hypophysitis, nephritis, hyperthyroidism, and hypothyroidism, except for subjects with vitiligo or resolved childhood asthma/atopy. Subjects with the following conditions will not be excluded from this study: asthma that requires intermittent use of bronchodilators, hypothyroidism stable on hormone replacement, vitiligo, Graves' disease, or Hashimoto's disease. Additional exceptions may be made with medical monitor approval.
14. Complications requiring long-term use of immunosuppressive drugs or systemic or local use of immunosuppressive-dose corticosteroids.
15. HIV positive; HBsAg positive and HBV DNA copy number positive (quantitative detection ≥ 1000 cps/ml); chronic hepatitis C with blood screening positive (HCV antibody positive).
16. Has a known history of active TB (bacillus tuberculosis) within 1 year; anti-TB treatment is ongoing or within 1 year prior to screening.
17. Has received a live vaccine; or a systematic glucocorticoid therapy ; or any anti-infective vaccine (e.g. influenza vaccine, varicella vaccine, etc.) ; any Chinese anti-tumor herbs within 4 weeks prior to enrollment.
18. Pregnancy or breastfeeding.
19. Other patients who were considered unsuitable by the treating physicians.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Induction chemotherapy plus conventional concurrent chemoradiotherapy	Drug: Cisplatin-based induction chemotherapy; Cisplatin-based induction chemotherapy will be given every 3 weeks for 3 cycles before radiotherapy including GP, TP, and TPF regimen.; Drug: Full course of PD-1/PD-L1 blockades; a) Camrelizumab 200mg, b) Toripalimab 240mg, or c) Adebrelimab 1200mg will be started on day 1 of induction chemotherapy and given every 3 weeks for up to 12 cycles, or until intolerable toxicity, or disease progression or withdrawal from the treatment.; Radiation: Standard-dose IMRT; GTVnx：69.96Gy/33Fr/2.12Gy；CTV1：60.60Gy/33Fr/1.82y；CTV2：54.12Gy/33Fr/1.64Gy; Drug: Concurrent Chemotherapy; Cisplatin 100mg/m2 every 3 weeks for 2 cycles
Experimental: Induction chemotherapy plus reduced-dose radiotherapy and concurrent chemotherapy	Drug: Cisplatin-based induction chemotherapy; Cisplatin-based induction chemotherapy will be given every 3 weeks for 3 cycles before radiotherapy including GP, TP, and TPF regimen.; Drug: Full course of PD-1/PD-L1 blockades; a) Camrelizumab 200mg, b) Toripalimab 240mg, or c) Adebrelimab 1200mg will be started on day 1 of induction chemotherapy and given every 3 weeks for up to 12 cycles, or until intolerable toxicity, or disease progression or withdrawal from the treatment.; Drug: Concurrent Chemotherapy; Cisplatin 100mg/m2 every 3 weeks for 2 cycles; Radiation: Reduced-dose IMRT; GTVnx:60Gy/30F/2.0Gy，CTV1:54Gy/30F/1.8Gy，CTV2:48Gy/30F/1.6Gy
Experimental: Induction chemotherapy plus reduced-dose radiotherapy alone	Drug: Cisplatin-based induction chemotherapy; Cisplatin-based induction chemotherapy will be given every 3 weeks for 3 cycles before radiotherapy including GP, TP, and TPF regimen.; Drug: Full course of PD-1/PD-L1 blockades; a) Camrelizumab 200mg, b) Toripalimab 240mg, or c) Adebrelimab 1200mg will be started on day 1 of induction chemotherapy and given every 3 weeks for up to 12 cycles, or until intolerable toxicity, or disease progression or withdrawal from the treatment.; Radiation: Reduced-dose IMRT; GTVnx:60Gy/30F/2.0Gy，CTV1:54Gy/30F/1.8Gy，CTV2:48Gy/30F/1.6Gy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progress-Free Survival (PFS)	Defined as time from randomization to locoregional or distant metastasis relapse or death from any cause, whichever occurred first.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	Defined as the time interval from randomization to death due to any cause.	3 years
Distant Metastasis-Free Survival (DMFS)	Defined as the time interval from randomisation to the date of first distant metastases.	3 years
Locoregional Relapse-Free Survival (LRRFS)	Defined as the time from randomisation to the date of first locoregional relapse.	3 years
Score of survival quality according to the EORTC Quality of Life Questionnaire (QLQ)-C30 (V3.0)	Score of survival quality according to the EORTC Quality of Life Questionnaire (QLQ)-C30 (V3.0) before treatment, during treatment, after treatment.	3 years
Score of survival quality according to the EORTC Quality of Life Questionnaire Head and Neck (The QLQ-H&N35)	Score of survival quality according to the EORTC Quality of Life Questionnaire Head and Neck (The QLQ-H&N35) before treatment, during treatment, after treatment.	3 years
The proportion of patients with treatment related acute complications	The proportion of patients with treatment related acute complications according to NCI-CTC5.0 criteria and RTOG criteria.	1 year
The proportion of patients with treatment related late complications	The proportion of patients with treatment related late complications according to NCI-CTC5.0 criteria and RTOG criteria.	3 years

Collaborators and Investigators

• Sponsor: Sun Yat-sen University
• Collaborators: First Affiliated Hospital, Sun Yat-Sen University; Tongji Hospital; Hunan Cancer Hospital; Second Affiliated Hospital, Sun Yat-Sen University; Guangdong Provincial People's Hospital; Affiliated Cancer Hospital & Institute of Guangzhou Medical University; Zhongshan People's Hospital, Guangdong, China; The fifth Affiliated Hospital of Guangzhou Medcial University
• Investigators: Principal Investigator: Ming-Yuan Chen, MD,PhD, Sun Yat-sen University

Study record dates

Study Major Dates

• Study Start (Actual): October 9, 2023
• Primary Completion (Estimated): October 30, 2029
• Study Completion (Estimated): October 30, 2031

Study Registration Dates

• First Submitted: October 16, 2023
• First Submitted That Met QC Criteria: October 16, 2023
• First Posted (Actual): October 23, 2023

Study Record Updates

• Last Update Posted (Actual): December 15, 2023
• Last Update Submitted That Met QC Criteria: December 10, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Head and Neck Neoplasms; Nasopharyngeal Diseases; Pharyngeal Diseases; Stomatognathic Diseases; Otorhinolaryngologic Diseases; Nasopharyngeal Neoplasms; Carcinoma; Nasopharyngeal Carcinoma; Antineoplastic Agents; Cisplatin
• Other Study ID Numbers: SYSUCC-CMY-2023-09-25

Drug and device information, study documents

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