CANIRA: Concurrent and Adjuvant PD-1 Blockade Combined With Induction Chemotherapy Plus Radiotherapy in Nasopharyngeal Carcinoma

Sponsor

Sun Yat-sen University (Other)

Overall Status

Recruiting

CT.gov ID

NCT03984357

Collaborator

Bristol-Myers Squibb (Industry), Varian Medical Systems, Inc. (Other)

152

Enrollment

Locations

Arm

76.5

Anticipated Duration (Months)

25.3

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a phase 2, single-arm, multicenter clinical trial, with the purpose to evaluate the therapeutic efficacy and safety of PD-1 Blockade combined with induction chemotherapy and radiotherapy alone in high-risk locoregionally advanced nasopharyngeal carcinoma.

Condition or Disease	Intervention/Treatment	Phase
Nasopharyngeal Carcinoma	Drug: PD-1 blocking antibody Drug: Gemcitabine Drug: Cisplatin Radiation: Intensity-modulated radiotherapy	Phase 2

Detailed Description

This phase 2, single-arm, multicenter clinical trial plans to enroll 146 patients with newly-diagnosed, pathologically-proven, untreated locoregionally advanced nasopharyngeal carcinoma (LANPC) at high-risk of distant metastasis (T4N1 and T1-4N2-3, 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 4 weeks of the completion of IMRT, adjuvant nivolumab will begin every 4 weeks for 6 cycles.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

152 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Whole-course 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

Actual Study Start Date :

Mar 16, 2020

Anticipated Primary Completion Date :

Aug 1, 2024

Anticipated Study Completion Date :

Aug 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: PD-1 blocking antibody combined with IC+IMRT All participants will receive induction chemotherapy (IC; every 3 weeks × 3 cycles; gemcitabine 1000 mg/m2 day 1, 8 + cisplatin 80 mg/m2 day 1) followed by intensity-modulated radiotherapy (IMRT; 70 Gy, 33 fractions, 5 fractions/week, 1 fraction/day) alone. PD-1 blocking antibody (360 mg per cycle) 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 PD-1 blocking antibody are administrated concurrently with IC and IMRT, respectively. After 4 weeks of the completion of IMRT, adjuvant PD-1 blocking antibody (480 mg per cycle) will begin every 4 weeks for 6 cycles.	Drug: PD-1 blocking antibody Whole-course concurrent PD-1 blocking antibody: every 3 weeks × 6 cycles; 360 mg, day 1; 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. Adjuvant PD-1 blocking antibody: every 4 weeks × 6 cycles; 480 mg, day 1 Other Names: PD-1 blockade Drug: Gemcitabine Gemcitabine as induction chemotherapy, 1000 mg/m2 day 1, 8 per cycle, every 3 weeks for 3 cycles Other Names: GEM Drug: Cisplatin Cisplatin as induction chemotherapy, 80 mg/m2 day 1 per cycle, every 3 weeks for 3 cycles Other Names: DDP Radiation: Intensity-modulated radiotherapy Definitive IMRT of 70 Gy, 33 fractions, 5 fractions/week, 1 fraction/day Other Names: IMRT

Arm

Intervention/Treatment

Experimental: PD-1 blocking antibody combined with IC+IMRT

All participants will receive induction chemotherapy (IC; every 3 weeks × 3 cycles; gemcitabine 1000 mg/m2 day 1, 8 + cisplatin 80 mg/m2 day 1) followed by intensity-modulated radiotherapy (IMRT; 70 Gy, 33 fractions, 5 fractions/week, 1 fraction/day) alone. PD-1 blocking antibody (360 mg per cycle) 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 PD-1 blocking antibody are administrated concurrently with IC and IMRT, respectively. After 4 weeks of the completion of IMRT, adjuvant PD-1 blocking antibody (480 mg per cycle) will begin every 4 weeks for 6 cycles.

Drug: PD-1 blocking antibody

Whole-course concurrent PD-1 blocking antibody: every 3 weeks × 6 cycles; 360 mg, day 1; 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. Adjuvant PD-1 blocking antibody: every 4 weeks × 6 cycles; 480 mg, day 1

Other Names:

PD-1 blockade

Drug: Gemcitabine

Gemcitabine as induction chemotherapy, 1000 mg/m2 day 1, 8 per cycle, every 3 weeks for 3 cycles

Other Names:

GEM

Drug: Cisplatin

Cisplatin as induction chemotherapy, 80 mg/m2 day 1 per cycle, every 3 weeks for 3 cycles

Other Names:

DDP

Radiation: Intensity-modulated radiotherapy

Definitive IMRT of 70 Gy, 33 fractions, 5 fractions/week, 1 fraction/day

Other Names:

IMRT

Outcome Measures

Primary Outcome Measures

Failure-free survival (FFS) [3-year]
Failure-free survival is measured from day of diagnosis until treatment failure, death from any cause, or last follow-up visit, whichever occurred first

Secondary Outcome Measures

Overall survival (OS) [3-year]
Overall survival is measured from day of diagnosis until death due to any cause or the latest known date alive
Locoregional failure-free survival (LRFFS) [3-year]
Locoregional failure-free survival is measured from day of diagnosis until local or regional recurrence
Distant failure-free survival (DFFS) [3-year]
Distant failure-free survival is measured from day of diagnosis until distant metastasis
Incidence rate of investigator-reported adverse events (AEs) [3-year]
Analysis of investigator-reported 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
Incidence rate of patient-reported adverse events (AEs) [3-year]
Analysis of patient-reported 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 patients themselves
Quality of life (QoL): questionnaire [week 1, 20, 40, 64]
Changes in QoL of participants from initial treatment to 6 months after the completion of 6 cycles adjuvant PD-1 blocking antibody. QoL is evaluated with the use of (1) the head-and-neck-specific module (H&N35) of the Quality of Life Questionnaire-Core 30 module (QLQ-C30), which is established by European Organization for Research and Treatment of Cancer (EORTC) and (2) the general and head-and-neck-specific module of the evaluation tool developed by the Functional Assessment of Cancer Therapy (FACT). Scores for the module range of H&N35 QLQ-C30 from 0 to 100, with higher scores indicating better functioning or well-being or higher symptom burden (scales measuring symptom burden were reverse-scored to facilitate presentation)

Other Outcome Measures

Correlation between pre-treatment PD-L1 expression level and FFS [3-year]
Pre-treatment PD-L1 expression level of tumor cell is evaluated centrally by means of immunohistochemical testing. This is a single assessment with only one unit of measure, since the correlation is aimed to be roughly categorized into positive and negative.
Correlation between pre-treatment PD-L1 expression level and OS [3-year]
Pre-treatment PD-L1 expression level of tumor cell is evaluated centrally by means of immunohistochemical testing. This is a single assessment with only one unit of measure, since the correlation is aimed to be roughly categorized into positive and negative.
Correlation between the percentage of tumor-infiltrating lymphocytes (TILs) and PFS [3-year]
TILs are lymphoid cells (T cells) that infiltrate solid tumors (intra-tumoral TILs) and stroma (stromal TILs), which play an important role in the tumor microenvironment. This is a single assessment with only one unit of measure, since the correlation is aimed to be roughly categorized into positive and negative.
Correlation between the percentage of tumor-infiltrating lymphocytes (TILs) and OS [3-year]
TILs are lymphoid cells (T cells) that infiltrate solid tumors (intra-tumoral TILs) and stroma (stromal TILs), which play an important role in the tumor microenvironment. This is a single assessment with only one unit of measure, since the correlation is aimed to be roughly categorized into positive and negative.
Evaluate failure-free survival in the subgroup of age at diagnosis (year) [3-year]
Subgroup analysis
Evaluate failure-free survival in the subgroup of gender (male and female) [3-year]
Subgroup analysis
Evaluate failure-free survival in the subgroup of plasma Epstein-Barr virus DNA level [3-year]
Subgroup analysis
Evaluate failure-free survival in the subgroup of clinical stage [3-year]
Subgroup analysis

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age: 18 to 65;
Pathological type: non-keratinizing carcinoma (World Health Organization criteria);
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];
ECOG performance score: 0 to 1;
Normal bone marrow function: white blood cell count > 4×109/L, hemoglobin > 90g/L, platelet count > 100×109/L;
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.
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;
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;
Subjects with pregnancy ability must agree to use reliable contraceptive measures from screening to 1 year after treatment.

Exclusion Criteria:

Hepatitis B virus surface antigen (HBsAg) positive and HBV DNA > 1×10E3 copies/ml; anti-hepatitis C virus positive;
Anti-human immunodeficiency virus (HIV) positive or diagnosed with acquired immune deficiency syndrome (AIDS);
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;
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);
Previous interstitial lung disease or pneumonia requiring oral or intravenous steroid therapy;
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;
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;
Pregnant or lactating women (pregnancy test should be considered for women with sexual life and fertility);
Previous or concurrent with other malignant tumors, except for adequately treated non-melanoma skin cancer, cervical carcinoma in situ and thyroid papillary cancer;
Allergy to macromolecular protein preparations, or any component of nivolumab;
Active infection requiring systemic treatment;
Receiving live vaccine within 30 days of the initial nivolumab;
History of organ transplantation;
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.

Contacts and Locations

Locations

	Site	City	State	Country
1	Fujian Provinve Cancer Hospital	Fuzhou	Fujian Provinve	China
2	Cancer Hospital of Guizhou Medical University	Guiyang	Guizhou	China
3	Hubei Province Cancer Hosiptal	Wuhan	Hubei	China
4	Union Hospital Affiliated with Tongji Medical College of Huazhong University of Science and Technology	Wuhan	Hubei	China
5	Xiangya Hospital Central South University	Changsha	Hunan	China
6	Zhejiang Province Cancer Hospital	Hangzhou	Zhejiang	China