Phase II Trial of Neoadjuvant and Adjuvant Anti-PD-1 Antibody Toripalimab Combined With CCRT in NPC Patients

Phase 2

Active, not recruiting

• Conditions: Nasopharyngeal Carcinoma
• Interventions: Drug: Cisplatin+placebo; Drug: Cisplatin+Toripalimab

• Registration Number: NCT03925090
• Lead Sponsor: Sun Yat-sen University

Brief Summary

This is a randomized Phase II trial to study the effectiveness and toxicity of neoadjuvant and adjuvant PD-1 antibody Toripalimab combined with concurrent cisplatin chemoradiotherapy versus cisplatin concurrent chemoradiotherapy plus placebo in treating patients with high risk locoregionally advanced nasopharyngeal carcinoma.

Detailed Description

Nasopharyngeal carcinoma (NPC) is endemic in Southern China and Southeast Asia. For locoregionally advanced NPC, especially for the high risk NPC (plasma EBV DNA ≥ 1500 copies/ml), the incidence of treatment failure is still high. Although concurrent chemoradiotherapy (CCRT) can improve the treatment outcomes of these patients, approximately 25% of locoregionally advanced NPCs still develop relapse and metastasis.

Hence, there is an urgent need for novel therapies to improve survival and reduce treatment-related toxicity in NPC patients. Accumulating evidence shows that PD-1 antibody is effective for treating recurrent/metastastic NPC patients. This is a Phase II randomized trial to study the effectiveness and toxicity of neoadjuvant and adjuvant PD-1 antibody Toripalimab combined with CCRT versus CCRT plus placebo in treating patients with high risk NPC (Stage III-IVa, AJCC 8th and EBV DNA ≥ 1500 copies/ml).

Study Timeline

• Study First Submitted: 2019-03-28
• Study First Submitted QC: 2019-04-20
• Study First Posted: 2019-04-23
• Study Start: 2019-12-08
• Primary Completion: 2021-12-06
• Status Verified: 2023-06
• Last Update Submitted: 2023-06-29
• Last Update Posted: 2023-07-03
• Study Completion: 2023-10

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 150

Inclusion Criteria

1. Patients with newly histologically confirmed non-keratinizing nasopharyngeal carcinoma, including WHO II or III Original clinical staged as III-IVa （according to the 8th AJCC edition）
2. No evidence of distant metastasis (M0)
3. Plasm EB Virus DNA≥1500copies/ml
4. Male and no pregnant female
5. Satisfactory performance status: ECOG (Eastern Cooperative OncologyGroup) scale 0-1
6. WBC ≥ 4×109 /L and PLT ≥4×109 /L and HGB ≥90 g/L
7. With normal liver function test (ALT、AST ≤ 2.5×ULN, TBIL≤ 2.0×ULN)
8. With normal renal function test ( creatinine clearance ≥60 ml/min)

Exclusion Criteria

1. Patients have evidence of relapse or distant metastasis
2. Histologically confirmed keratinizing squamous cell carcinoma (WHO I)
3. Receiving radiotherapy or chemotherapy previously
4. The presence of uncontrolled life-threatening illness
5. Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant.
6. Suffered from other malignant tumors (except the cure of basal cell carcinoma or uterine cervical carcinoma in situ) previously.
7. Patients who have been treated with inhibitors of immune regulation (CTLA-4, PD-1, PD-L1, etc.).
8. Patients with immunodeficiency disease and history of organ transplantation.
9. Patients who have used large doses of glucocorticoids, anti-cancer monoclonal antibodies, and other immunosuppressive agents within 4 weeks.
10. HIV positive.
11. Patients with significantly lower heart, liver, lung, kidney and bone marrow function.
12. Severe, uncontrolled medical conditions and infections.
13. At the same time using other test drugs or in other clinical trials.
14. Refusal or inability to sign informed consent to participate in the trial.
15. Other treatment contraindications.
16. Emotional disturbance or mental illness, no civil capacity or limited capacity for civil conduct.
17. Hepatitis B surface antigen (HBsAg) positive and HBVDNA ≥1000cps/ml.
18. Patients with positive HCV antibody test results can only be included in the study when the polymerase chain reaction of HCV RNA is negative.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Neoadjuvant and Adjuvant Placebo+CCRT	Cisplatin+placebo	Drug: Cisplatin cisplatin 100mg/m2(every three weeks),D1,D22,D43 of intensity modulated radiotherapy Other Names: DDP Drug: placebo placebo 240mg every 2 weeks with a total of 2 cycles as neoadjuvant treatment; placebo 240mg every 3 weeks with a total of 8 cycles as adjuvant treatment 2 weeks after CCRT.
Neoadjuvant and Adjuvant Toripalimab+CCRT	Cisplatin+Toripalimab	Drug: Cisplatin cisplatin 100mg/m2(every three weeks),D1,D22,D43 of intensity modulated radiotherapy Other Names: DDP Drug: Toripalimab Toripalimab 240mg every 2 weeks with a total of 2 cycles as neoadjuvant anti-PD-1 immunotherapy; Toripalimab240mg every 3 weeks with a total of 8 cycles as adjuvant anti-PD-1 immunotherapy 2 weeks after CCRT Other Names:anti-PD-1 antibody, JS001

Primary Outcome Measures

Name	Time	Method
Progress-free survival (PFS)	2 years	Defined from date of randomization to date of first documentation of progression or death due to any cause, whichever occurred first.

Secondary Outcome Measures

Name	Time	Method
Overall Survival (OS)	2 years	Defined as the time from randomisation to death.
Incidence rate of adverse events (AEs)	2 years	Analysis of adverse events (AEs) are based on treatment-related AEs (trAEs) and immune-related AEs (irAEs), and all-grade AEs and grade 3-4 AEs. AEs are evaluated by investigators according to the Common Terminology Criteria for Adverse Events, version 5.0
Number of subjects with major pathologic response (MPR)	21-28 days	Major pathologic response rate (MPR) is defined as \> 90% decrease in viable tumor.
Distant Metastasis-Free Survival (DMFS)	2 years	Defined as the time from randomisation to documented distant metastasis or death due to any cause.
Objective Response Rate （ORR）	After the completion of the neoadjuvant PD-1 antibody and chemoradiotherapy treatment	An objective response is defined as either a confirmed CR or a PR, as determined by the investigator using RECIST v1.1Response Evaluation Criteria in Solid Tumors (RECIST) from the National Cancer Institute (NCI).
Correlation between the plasma EBV DNA level and PFS	2 years	The plasma EBV DNA level of the patients will be assessed.
Locoregional Relapse-Free Survival (LRRFS)	2 years or until the date of the last follow-up visit.	Defined as the time from the randomisation to documented locoregional recurrence or death due to any cause.
Correlation between the percentage of tumor-infiltrating lymphocytes (TILs) and PFS	2 years	TILs are lymphoid cells (T cells) that infiltrate solid tumors (intra-tumoral TILs) and stroma (stromal TILs), which play important roles in the tumor microenvironment.
Correlation between pre-treatment PD-L1 expression level and PFS	2 years	Pre-treatment PD-L1 expression level is evaluated centrally by means of immunohistochemical testing.
Change of QoL (quality of life)	1 year	QoL scores were assessed by using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTCQLQ-C30) before neoadjuvant PD-1 antibody, before radiotherapy, at the end of radiotherapy, at 3 months after radiotherapy, at 6 months after radiotherapy and 12 months after radiotherapy.

Trial Locations

Locations (1)

Sun Yat-sen Universitty Cancer Center; 🇨🇳 Guangzhou, Guangdong, China