Clinical trial NCT03984357: Nivolumab Combined With Chemoradiotherapy Sparing Concurrent Cisplatin in Nasopharyngeal Carcinoma
Official title: Induction, Concurrent and Adjuvant Nivolumab Combined With Induction Chemotherapy Followed by Radiotherapy Alone in Locoregionally Advanced Nasopharyngeal Carcinoma: A Phase 2, Multi-center, Single-arm Clinical Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Nasopharyngeal Carcinoma
Keywords: PD-1 blockade
immune checkpoint inhibitor
induction chemotherapy
radiotherapy
Lead sponsor: Sun Yat-sen University
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
First posted: 2019-06-13
Enrollment: 152
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a phase 2, single-arm, multicenter clinical trial, with the purpose to evaluate the therapeutic efficacy, safety, and tolerability of PD-1 Blockade nivolumab combined with a deintensified chemoradiotherapy by sparing concurrent cisplatin from the standard induction chemotherapy plus concurrent chemoradiotherapy in high-risk locoregionally advanced nasopharyngeal carcinoma.

Detailed description: This phase 2, single-arm, multicenter clinical trial plans to enroll 152 patients with newly-diagnosed, pathologically-proven, untreated locoregionally advanced nasopharyngeal carcinoma (LANPC) at high-risk of distant metastasis (T4N1M0 or T1-4N2-3M0, according to American Joint Committee on Cancer \[AJCC\]/Union for International Cancer Control \[UICC\] 8th edition clinical staging system). Patients will receive 3 cycles of induction chemotherapy (IC; gemcitabine-cisplatin regimen) followed by intensity-modulated radiotherapy (IMRT) alone. Nivolumab injection OPDIVO® will start on day 1 of the first cycle IC and continue every 3 weeks for 6 cycles till the end of IMRT, involving the whole-course of IC + IMRT alone. The first and last 3 cycles of nivolumab are administrated concurrently with IC and IMRT, respectively. After the completion of IMRT, adjuvant nivolumab will begin every 4 weeks for 6 cycles.

Eligibility criteria: Inclusion Criteria:

1. Age: 18 to 65;
2. Pathological type: non-keratinizing carcinoma (World Health Organization criteria);
3. Diagnosed with LANPC (T4N1, T1-4N2-3) according to the 8th edition clinical staging system of the American Joint Committee on Cancer \[AJCC\]/Union for International Cancer Control \[UICC\];
4. ECOG performance score: 0 to 1;
5. Normal bone marrow function: white blood cell count \> 4×109/L, hemoglobin \> 90g/L, platelet count \> 100×109/L;
6. Normal values of thyroid function, amylase and lipase examination, pituitary function, inflammation and infection indicators, myocardial enzymes, and ECG results. For patients older than 50 years with a smoking history, normal lung function are required. Patients with abnormal ECG and/or a history of vascular disease (but not meeting the exclusion criteria listed in the exclusion criteria 7) need further testing and require normal results of myocardial function and color Doppler ultrasound.
7. Normal liver and kidney function: total bilirubin ≤ 1.5 × upper limit of normal (ULN); alanine transaminase and aspartate transaminase ≤ 2.5 × ULN; alkaline phosphatase ≤ 2.5 × ULN; creatinine clearance rate ≥ 60 ml/min;
8. Patients must sign informed consent and be willing and able to comply with the requirements of visits, treatment, laboratory tests and other research requirements stipulated in the research schedule;
9. Subjects with pregnancy ability must agree to use reliable contraceptive measures from screening to 1 year after treatment.

Exclusion Criteria:

1. Hepatitis B virus surface antigen (HBsAg) positive and HBV DNA \> 1×10E3 copies/ml; anti-hepatitis C virus positive;
2. Anti-human immunodeficiency virus (HIV) positive or diagnosed with acquired immune deficiency syndrome (AIDS);
3. Active tuberculosis: active tuberculosis in the past 1 year should be excluded regardless with treatment; history of active tuberculosis over 1 year should be excluded except that previous regulatory anti-tuberculosis treatment is proved;
4. Active, known or suspected autoimmune disease (including but not limited to uveitis, enteritis, hepatitis, pituitary, nephritis, vasculitis, hyperthyroidism, hypothyroidism and asthma requiring bronchiectasis). Exceptions are type I diabetes mellitus, hypothyroidism requiring hormone replacement therapy, skin disorders requiring no systemic treatment (such as vitiligo, psoriasis or alopecia);
5. Previous interstitial lung disease or pneumonia requiring oral or intravenous steroid therapy;
6. Chronic treatment with systemic glucocorticoid (dose equivalent to or over 10 mg prednisone per day) or any other form of immunosuppressive therapy. Subjects who used inhaled or topical corticosteroids were eligible;
7. Uncontrolled heart disease, for example: 1) heart failure (NYHA level ≥ 2); 2) unstable angina; 3) myocardial infarction in past 1 year; 4) supraventricular or ventricular arrhythmia requiring treatment or intervention;
8. Pregnant or lactating women (pregnancy test should be considered for women with sexual life and fertility);
9. Previous or concurrent with other malignant tumors, except for adequately treated non-melanoma skin cancer, cervical carcinoma in situ and thyroid papillary cancer;
10. Allergy to macromolecular protein preparations, or any component of nivolumab;
11. Active infection requiring systemic treatment;
12. Receiving live vaccine within 30 days of the initial nivolumab;
13. History of organ transplantation;
14. History of psychotropic disease, alcoholism or drug abuse; other situation assessed by the investigators that may compromise the safety or compliance of patients, such as serious disease requiring timely treatment (including mental illness), severe laboratory abnormalities, or family-social risk factors.

Primary outcomes:
measure: Failure-free survival (FFS)
timeFrame: 3-year
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: 3-year
measure: Locoregional failure-free survival (LRFFS)
timeFrame: 3-year
measure: Distant failure-free survival (DFFS)
timeFrame: 3-year
measure: Incidence rate of investigator-reported adverse events (AEs)
timeFrame: 3-year
measure: Incidence rate of patient-reported adverse events (AEs)
timeFrame: 3-year
measure: Quality of life (QoL): questionnaire
timeFrame: baseline, week 7, 14, 38, 62
Other outcomes:
measure: Correlation between pre-treatment PD-L1 expression level and FFS
timeFrame: 3-year
measure: Correlation between pre-treatment PD-L1 expression level and OS
timeFrame: 3-year
measure: Correlation between the percentage of tumor-infiltrating lymphocytes (TILs) and PFS
timeFrame: 3-year
measure: Correlation between the percentage of tumor-infiltrating lymphocytes (TILs) and OS
timeFrame: 3-year
measure: Evaluate failure-free survival in the subgroup of age at diagnosis (year)
timeFrame: 3-year
measure: Evaluate failure-free survival in the subgroup of gender (male and female)
timeFrame: 3-year
measure: Evaluate failure-free survival in the subgroup of plasma Epstein-Barr virus DNA level
timeFrame: 3-year
measure: Evaluate failure-free survival in the subgroup of clinical stage
timeFrame: 3-year
Locations:
city: Fuzhou
country: China
facility: Fujian Provinve Cancer Hospital
state: Fujian Provinve
city: Guiyang
country: China
facility: Cancer Hospital of Guizhou Medical University
state: Guizhou
city: Wuhan
country: China
facility: Hubei Province Cancer Hosiptal
state: Hubei
city: Wuhan
country: China
facility: Union Hospital Affiliated with Tongji Medical College of Huazhong University of Science and Technology
state: Hubei
city: Changsha
country: China
facility: Xiangya Hospital Central South University
state: Hunan
city: Hangzhou
country: China
facility: Zhejiang Province Cancer Hospital
state: Zhejiang
Study officials:
affiliation: Sun Yat-sen University
name: Jun Ma, M.D.
role: PRINCIPAL_INVESTIGATOR
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