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

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ClinicalTrials.gov Identifier: NCT03984357
Recruitment Status : Not yet recruiting
First Posted : June 13, 2019
Last Update Posted : July 31, 2019
Sponsor:
Collaborators:
Bristol-Myers Squibb
Varian Medical Systems, Inc.
Information provided by (Responsible Party):
Jun Ma, MD, Sun Yat-sen University

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 138 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 138 participants
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
Estimated Study Start Date : December 2019
Estimated Primary Completion Date : June 2024
Estimated Study Completion Date : June 2026

Resource links provided by the National Library of Medicine


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
  1. 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.
  2. Adjuvant PD-1 blocking antibody: every 4 weeks × 6 cycles; 480 mg, day 1
Other Name: PD-1 blockade

Drug: Gemcitabine
Gemcitabine as induction chemotherapy, 1000 mg/m2 day 1, 8 per cycle, every 3 weeks for 3 cycles
Other Name: GEM

Drug: Cisplatin
Cisplatin as induction chemotherapy, 80 mg/m2 day 1 per cycle, every 3 weeks for 3 cycles
Other Name: DDP

Radiation: Intensity-modulated radiotherapy
Definitive IMRT of 70 Gy, 33 fractions, 5 fractions/week, 1 fraction/day
Other Name: IMRT




Primary Outcome Measures :
  1. Failure-free survival (FFS) [ Time Frame: 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 :
  1. Overall survival (OS) [ Time Frame: 3-year ]
    Overall survival is measured from day of diagnosis until death due to any cause or the latest known date alive

  2. Locoregional failure-free survival (LRFFS) [ Time Frame: 3-year ]
    Locoregional failure-free survival is measured from day of diagnosis until local or regional recurrence

  3. Distant failure-free survival (DFFS) [ Time Frame: 3-year ]
    Distant failure-free survival is measured from day of diagnosis until distant metastasis

  4. Incidence rate of investigator-reported adverse events (AEs) [ Time Frame: 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

  5. Incidence rate of patient-reported adverse events (AEs) [ Time Frame: 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

  6. Quality of life (QoL): questionnaire [ Time Frame: 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 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). Scores for the module range 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:
  1. Correlation between pre-treatment PD-L1 expression level and FFS [ Time Frame: 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.

  2. Correlation between pre-treatment PD-L1 expression level and OS [ Time Frame: 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.

  3. Correlation between the percentage of tumor-infiltrating lymphocytes (TILs) and PFS [ Time Frame: 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.

  4. Correlation between the percentage of tumor-infiltrating lymphocytes (TILs) and OS [ Time Frame: 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.

  5. Evaluate failure-free survival in the subgroup of age at diagnosis (year) [ Time Frame: 3-year ]
    Subgroup analysis

  6. Evaluate failure-free survival in the subgroup of gender (male and female) [ Time Frame: 3-year ]
    Subgroup analysis

  7. Evaluate failure-free survival in the subgroup of plasma Epstein-Barr virus DNA level [ Time Frame: 3-year ]
    Subgroup analysis

  8. Evaluate failure-free survival in the subgroup of clinical stage [ Time Frame: 3-year ]
    Subgroup analysis



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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;
  7. 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;
  8. 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) or 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 psychotropic disease, alcoholism or drug abuse;
  14. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03984357


Contacts
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Contact: Jun Ma, M.D. +862087343469 majun@sysucc.org.cn

Sponsors and Collaborators
Sun Yat-sen University
Bristol-Myers Squibb
Varian Medical Systems, Inc.
Investigators
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Principal Investigator: Jun Ma, M.D. Sun Yat-sen University

Publications:

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Responsible Party: Jun Ma, MD, Principal Investigator, Sun Yat-sen University
ClinicalTrials.gov Identifier: NCT03984357     History of Changes
Other Study ID Numbers: CA209-7GC
First Posted: June 13, 2019    Key Record Dates
Last Update Posted: July 31, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: We currently have no plans to share individual participant data.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Jun Ma, MD, Sun Yat-sen University:
PD-1 blockade
immune checkpoint inhibitor
induction chemotherapy
radiotherapy

Additional relevant MeSH terms:
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Carcinoma
Nasopharyngeal Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Nasopharyngeal Neoplasms
Pharyngeal Neoplasms
Otorhinolaryngologic Neoplasms
Head and Neck Neoplasms
Neoplasms by Site
Nasopharyngeal Diseases
Pharyngeal Diseases
Stomatognathic Diseases
Otorhinolaryngologic Diseases
Cisplatin
Gemcitabine
Antibodies
Immunoglobulins
Antibodies, Blocking
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs