Clinical trial NCT06455410: GP Plus Adebrelimab Versus GP Neoadjuvant Chemotherapy for Nasopharyngeal Carcinoma
Official title: GP Plus Adebrelimab Versus GP Neoadjuvant Chemotherapy Followed by Concurrent Chemoradiotherapy for High-risk Locoregionally Advanced Nasopharyngeal Carcinoma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Nasopharyngeal Carcinoma
Lead sponsor: Sun Yat-sen University
Sponsor class: OTHER
First posted: 2024-06-12
Enrollment: 216
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to explore the efficacy and safety of neoadjuvant GP chemotherapy plus adebrelimab versus neoadjuvant GP chemotherapy in treating high-risk locoregionally advanced nasopharyngeal carcinoma patients.

Detailed description: Platinum-based neoadjuvant chemotherapy plus concurrent chemoradiotherapy (CCRT) is the standard of care for patients with locoregionally advanced nasopharyngeal carcinoma (NPC). Gemcitabine plus cisplatin(GP) has been demonstrated an effective chemotherapy regimen for NPC patients in previous studies. Three cycles of GP neoadjuvant chemotherapy resulted in 10% of complete response rate, and GP neoadjuvant chemotherapy added to chemoradiotherapy significantly improved recurrence-free survival (85.3% vs 76.5%) and overall survival (94.6% vs 90.3%) among locoregionally advanced NPC patients , as compared with concurrent chemoradiotherapy alone. Therefore, GP has been established as the highest level of evidence-based neoadjuvant chemotherapy regimen in the 2020 National Comprehensive Cancer Network (NCCN) guidelines. Recently, immune checkpoint inhibitors, such as anti-programmed cell death-1 (PD-1) monoclonal antibody has shown promising efficacy in NPC patients. Clinical trials have shown objective response rates of 20.5%-34% in patients with recurrent or metastatic NPC patients receiving anti PD-1 monoclonal antibody immunotherapy including pembrolizumab, nivolumab, camrelizumab, and toripalimab. GP chemotherapy combined with anti PD-1 antibody were hence considered in treating locoregionally advanced NPC. Concurrent radiotherapy might cause T-cell dysfunction, and larger-volume elective nodal irradiation might hinder immunotherapy effects by directly depleting memory T cells. No survival benefit was observed when PD-1 blockade was added concurrently to the CCRT phase for treating head and neck cancers. On the contrary, several studies have demonstrated that administration of immunotherapy in the neoadjuvant setting modified the primary tumor into an antigen source for T-cell expansion and priming, thereby resulting in stronger effects than those of adjuvant therapy. Currently there were 3 trials exploring the addition of immunotherapy to chemoradiotherapy, the preliminary results of which were recently published. These trials had different trial designs, with two trials utilized anti PD-1 inhibitors in all treatment phases including neoadjuvant, concurrent and adjuvant phases, The third trial, which was conducted by our team, gave anti PD-1 inhibitor only in the neoadjuvant phase, and promising efficacy was observed in our study.

Adebrelimab is a recombinant humanized IgG4 monoclonal antibody with specificity for PD-L1. In a phase III clinical trial of extensive stage small-cell lung cancer, the addition of adebrelimab significantly improved the median overall survival compared with the control group (15.3 vs. 12.8，HR 0.72, P=0.0017). So we hypothesize that GP neoadjuvant chemotherapy combined with adebrelimab could further improve the survival of patients with high-risk locoregionally advanced NPC (diagnosed with T4 or N2-3 disease). Therefore, we designed this phase II multi-center randomized controlled trial to evaluate whether GP neoadjuvant chemotherapy combined with adebrelimab plus cisplatin-based CCRT improve the complete response rate of high-risk locoregionally advanced NPC patients compared with GP neoadjuvant chemotherapy plus CCRT.

Eligibility criteria: Inclusion Criteria:

1. Patients must be informed of the investigational nature of this study and give written informed consent.
2. Age ≥ 18 years and ≤65 years, men or non-pregnant women.
3. Patients with histologically confirmed Nonkeratinizing carcinoma of the nasopharynx (differentiated or undifferentiated type, WHO II or III).
4. Tumor staged as T4N0-1M0 or T1-4N2-3M0 (AJCC 8th).
5. No previous anti-tumor treatment.
6. Eastern Cooperative Oncology Group (ECOG) score 0 or 1.
7. Adequate marrow function: White blood cell count (WBC)≥4.0×109 /L, Hemoglobin ≥ 90g/L, Platelet count ≥100×109/L.
8. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum total bilirubin (TBIL) ≤2×upper limit of normal (ULN).
9. Adequate renal function: creatinine clearance rate ≥ 60 ml/min or Creatinine ≤ 1.5× upper limit of normal value.

Exclusion Criteria:

1. Patients with recurrent or metastatic nasopharyngeal carcinoma.
2. Histologically confirmed with keratinizing squamous cell carcinoma of the nasopharynx.
3. Prior therapy with radiation or systemic chemotherapy.
4. Women in the period of pregnancy, lactation, or reproductive without effective contraceptive measures.
5. Seropositivity for human immunodeficiency virus (HIV).
6. Known history of other malignancies (except cured basal cell carcinoma or carcinoma in situ of the cervix).
7. Prior exposure to immune checkpoint inhibitors,including anti-PD-1, anti- PD-L1, anti-CTLA-4 antibodies.
8. Patients with immunodeficiency disease or a history of organ transplantation.
9. Received large doses of glucocorticoids, anticancer monoclonal antibodies, or other immunosuppressants within 4 weeks.
10. Patients with severe dysfunction of heart, liver, lung, kidney or marrow.
11. Patients with severe, uncontrolled disease or infections.
12. Received other research drugs or in other clinical trials at the same time.
13. Refuse or fail to sign the informed consent .
14. Patients with other treatment contraindications.
15. Patients with personality or mental disorders, incapacity or limited capacity for civil conduct.
16. Hepatitis B surface antigen (HBsAg) positive and peripheral blood HBV deoxyribonucleic acid (HBV DNA) ≥1000cps/ml or 200 IU/ml.
17. Patients with positive HCV antibody test will only be enrolled in this study if the PCR test for HCV RNA is negative.

Primary outcomes:
measure: Complete response (CR) rate
timeFrame: 11weeks
Secondary outcomes:
measure: Event-free survival(EFS)
timeFrame: 2 years
measure: Overall survival (OS)
timeFrame: 2 years
measure: Locoregional relapse-free survival（LRRFS）
timeFrame: 2 years
measure: Distant metastasis-free survival (DMFS)
timeFrame: 2 years
measure: Toxicity profiles
timeFrame: Up to 2 years
Other outcomes:
Locations:
city: Foshan
country: China
facility: Foshan First People's Hospital
state: Guangdong
city: Guangzhou
country: China
facility: Affiliated cancer hospital and institute of guangzhou medical university
city: Guangzhou
country: China
facility: Sun Yat-Sen Memorial Hospital
city: Guangzhou
country: China
facility: The affiliated panyu central hospital of guangzhou medical university
city: Guangzhou
country: China
facility: ZhuJiang Hospital of Southern Medical University
city: Liuzhou
country: China
facility: Liuzhou Workers Hospital
city: Nanning
country: China
facility: Guangxi Medical University Affiliated Cancer Hospital
city: Shantou
country: China
facility: Cancer hospital of Shantou university medical college
city: Shenzhen
country: China
facility: Cancer hospital Chinese academy of medical sciences, Shenzhen center
city: Shenzhen
country: China
facility: The second people's hospital of Shenzhen
city: Shenzhen
country: China
facility: The university of Hongkong - Shenzhen hospital
city: Zhangjiang
country: China
facility: Guangdong Medical School First Affiliated Hospital
Study officials:
References: