Administrative information
Title {1} | Nivolumab in combination with cisplatin and 5‑fluorouracil as induction therapy in children and adults with EBV-positive nasopharyngeal carcinoma |
Trial registration {2a and 2b} | EudraCT (European Union Drug Regulating Authorities Clinical Trials Database) No. 2021-006477-32; DRKS (German Clinical Trials Register): DRKS00027098; ClinicalTrials.gov: NCT06019130 |
Protocol version {3} | Version 1.3 Final, March 3, 2023 |
Funding {4} | This investigator-initiated clinical trial is funded by the Deutsche Krebshilfe (German Cancer Aid) as is the Center for Integrated Oncology at Aachen-Bonn-Cologne-Düsseldorf (CIOABCD). Bristol-Myers Squibb provides support for this trial by providing nivolumab |
Author details {5a} | Coordinating (chief) investigator: Udo Kontny |
Assistant investigator: Tristan Römer | |
Both: Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD) | |
Trial reference centers | |
Pathology | |
Christian Vokuhl, Section of Pediatric Pathology, Department of Pathology, University Hospital Bonn, Bonn, Germany, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD) | |
Radiology | |
Gundula Staatz, Section of Pediatric Radiology, University Medical Center Mainz, Mainz, Germany | |
Nuclear Medicine | |
Felix M. Mottaghy, Department of Nuclear Medicine, Medical Faculty, RWTH Aachen University, Aachen, Germany, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD) | |
Radiotherapy | |
Hans Christiansen, Department of Radiotherapy and Radiation Oncology, Hannover Medical School, Hannover, Germany | |
Michael J. Eble, Department of Radiation Oncology, RWTH Aachen University, Aachen, Germany, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD) | |
Beate Timmermann, Department of Particle Therapy, University Hospital Essen, West German Proton Therapy Centre Essen (WPE), West German Cancer Centre (WTZ), Essen, Germany | |
Head and Neck Surgery | |
Jens Peter Klussmann, ENT Clinic of the University Hospital of Cologne, Cologne, Germany, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD) | |
Pharmacogenomics | |
Miriam Elbracht, Institute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University, Aachen, Germany, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD) | |
Patient-reported Outcome | |
Gabriele Calaminus, Division of Pediatric Hematology and Oncology, University Hospital Bonn, Bonn, Germany, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD) | |
Biostatistics | |
Martin Zimmermann, Division of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany | |
Additional steering committee members | |
Tim H. Brümmendorf, Department of Hematology, Oncology, Hemostaseology, Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD) | |
Tobias Feuchtinger, Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany | |
Project management and monitoring: | |
Helena Kerp, Pediatric Research Network gGmbH, University of Duisburg-Essen, Essen, Germany | |
Name and contact information for the trial sponsor {5b} | German Society for Pediatric Oncology and Hematology (GPOH) gGmbH, registered at: Chausseestraße 128/129, 10115 Berlin, Germany; Sponsor office: Holsterhauser Platz 2, 45147 Essen, Germany |
Role of sponsor {5c} | n/a: The funders have no role in study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication, and they do not have ultimate authority over any of these activities |
Introduction
Background and rationale {6a}
Objectives {7}
Trial design {8}
Methods: participants, interventions, and outcomes
Study setting {9}
Eligibility criteria {10}
Inclusion criteria
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Histologically confirmed new diagnosis of NPC according to the current World Health Organization (WHO) classification in children and adolescents aged between 3 and 17 years, or histologically confirmed new diagnosis of EBV-positive NPC, WHO type II or III, in individuals aged ≥ 18 years
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Stage II or higher in patients ≤ 25 years, stage III and IV in patients > 25 years (according to American Joint Committee on Cancer [AJCC], 8th edition)
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Measurable disease by MRI per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
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Sufficient tumor tissue to be sent for central review, including PD-L1 staining, either as one or two full blocks (preferred) or a minimum of 25 slides, obtained from core biopsy, punch biopsy, excisional biopsy, or surgical specimen
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Written informed consent of patient and legal guardian (if patient not ≥ 18 years)
Exclusion criteria
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Newly diagnosed NPC stage I in all patients, stage II in patients > 25 years
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Recurrent NPC
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NPC diagnosed as second malignancy after preceding chemotherapy and/or radiotherapy
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Prior chemotherapy and/or radiotherapy
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Other active malignancy
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Prior treatment with an anti-PD‑1, anti-PD-L1, anti-PD-L2, anti-cytotoxic T‑lymphocyte-associated antigen (CTLA)‑4 antibody, or any other antibody or drug specifically targeting T‑cell co-stimulation or checkpoint pathways
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Investigational drug within 30 days prior to inclusion
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Enrolment in another clinical trial
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Prior organ allograft or allogenic bone marrow transplantation
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Active, known or suspected autoimmune disease; type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted for enrollment
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Condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days before start of therapy; inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease
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Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection
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Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
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Inadequate hematological, renal, or hepatic function defined by any of the following screening laboratory values:
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White blood cells (WBC) < 2000/μL
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Neutrophils < 1500/μL
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Platelets < 100 × 103/μL
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Hemoglobin < 9.0g/dL
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Creatinine > 1.5 x upper limit of normal (ULN) or creatinine clearance < 50 mL/min (using the Cockcroft–Gault formula or Schwartz formula in patients < 18 years)
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Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 3 x ULN (> 5 x ULN if liver metastases)
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Total bilirubin > 1.5 x ULN (except patients with Gilbert syndrome who must have a total bilirubin level ≥ 3.0 x ULN)
-
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Hearing loss > 20 dB loss at 3 kHz, due to an inner ear disorder and not caused by tumor burden
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History of allergy or hypersensitivity to platinum-containing compounds or other study drug components
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Clinically significant, uncontrolled heart disease (including history of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality within 12 months of screening)
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Vaccinated with live attenuated vaccines within 4 weeks of the first dose of the study drug
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Inadequate performance status (Karnofsky score < 60 for patients ≥ 16 years, Lansky score < 60 for patients < 16 years)
Who will take informed consent? {26a}
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Interventions
Explanation for the choice of comparators {6b}
Intervention description {11a}
Criteria for discontinuing or modifying allocated interventions {11b}
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Patient’s or parent/legal guardian’s request to stop treatment
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Withdrawal of consent to data collection
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Confirmed radiographic disease progression during induction therapy
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Any clinical adverse event (AE), laboratory abnormality, or intercurrent illness that, in the opinion of the investigator, indicates that continued participation in the study is not in the best interest of the patient
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Less than one dose of nivolumab during induction therapy
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Loss of ability to freely provide consent through imprisonment or involuntarily incarceration for treatment of either a psychiatric or physical illness
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Non-compliance
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Pregnancy
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For additional protocol-specified reasons for treatment discontinuation, please refer to the full protocol that is provided by the coordinating investigator
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Unjustifiable risk and/or toxicity in risk–benefit analysis (decision taken by sponsor or its representative), e.g., when AEs occur, unknown to date in terms of their nature, severity, duration, or frequency in relation to the current established safety profile (substantial changes in risk–benefit considerations), and therefore medical and/or ethical reasons affect the continued performance of the trial or for a specific patient cohort or specific the subgroup
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New scientific evidence becomes available during the study that could affect the patient’s safety (benefit–risk analysis no longer positive), e.g., new insights from other clinical trials
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Request of the sponsor or regulatory agency, e.g., as a consequence of monitoring or inspection
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In the case of difficulties in the recruitment of the planned number of participants in the indicated time (insufficient recruitment rate)
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Permanently unavailability of an investigational medicinal product (IMP) or withdrawal of the license to manufacture or of the permission to import an IMP
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The maximal sum insured cannot be adjusted, although required
Strategies to improve adherence to interventions {11c}
Relevant concomitant care permitted or prohibited during the trial {11d}
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Immunosuppressive agents within 14 days of starting study treatment
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Immunosuppressive doses of systemic corticosteroids (> 10 mg daily prednisone equivalent), except as stated above
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Any concurrent anti-neoplastic therapy (i.e., chemotherapy, hormonal therapy, immunotherapy, radiotherapy other than specified in this protocol)
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Surgical resection of tumor
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Any botanical preparation (e.g., herbal supplements or traditional Chinese medicines) intended to treat the disease under study or to provide supportive care
Provisions for post-trial care {30}
Outcomes {12}
Primary outcome
Secondary outcomes
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Event-free and overall survival
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Safety of nivolumab in combination with standard induction chemotherapy in children and adults with NPC
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Safety of nivolumab in combination with CCRT in children and adults with NPC not responding to induction therapy or with initial distant metastases
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Correlation of efficacy of nivolumab with PD-L1 expression in tumor tissue (as measured by CPS [21])
Participant timeline {13}
Phase | Pre-study | Treatment | Off treatment | Follow-up | ||||
---|---|---|---|---|---|---|---|---|
Study period | Screening | Chemo Cycle 1 | Chemo Cycle 2 | Chemo Cycle 3 | Radiotherapy1 | |||
Visit no. | 1 | 2 | 3 | 4 | 5 | 5add1 | 6 | |
Activity | Baseline | Response evaluation | Response evaluation1 | Disease status | ||||
Visit window ± calendar days19 | Day -14–0 | Day 1 | Day 0–1 | Day 0–1 | Day 17–22 | 12 weeks after last dose of radiotherapy1 | 100 days ±3 days after last dose of nivolumab | Every 3 months until 2 years from enrolment |
Written informed consent | X | |||||||
Inclusion/exclusion criteria | X | X | ||||||
Tumor tissue sample2 | X | |||||||
Demographics and medical history | X | |||||||
Concomitant medication | X | X | X | X | X | X | X | |
Physical examination | X | X | X | X | X | X | X | |
Vital signs3 | X | X | X | X | X | X | X | |
Height (cm) | X | X | ||||||
Weight (kg) | X | X | X | X | X | X | X | |
Performance status4 | X | X | X | X | X | X | X | |
12-lead ECG5 | X | X | ||||||
Echocardiography5 | X | X | ||||||
Creatinine-clearance (24‑h urine)5 | X | X | X | X | ||||
Audiometry5,18 | X | X | X | X | X | |||
Dental exam5 | X | X | ||||||
Ophthalmological exam5 | X | X | ||||||
Pregnancy test5,6 (WOCBP only) | X | X | X | X | X | |||
Laboratory tests5,7 | X | X | X | X | X | X | X | |
Hepatitis screening5,8 | X | X | ||||||
HIV testing5 | X | X | ||||||
DPD genetics5,9 | X | |||||||
EBV-PCR5,10 | X11 | X | X | X | X | X | ||
Biomarkers (blood)12 | X11 | X | X | X | X | X | ||
Biomarkers (saliva)12 | X11 | X | X | X | ||||
MRI head/neck5,13 | X | X | X | X | ||||
PET-CT or PET-MRI5,14 | X | X | X | |||||
MRI abdomen5,15 | X | |||||||
Study drug administration | X | X | X | |||||
AE evaluation16 | X | X | X | X | X | |||
Disease and event status | X | |||||||
PROs Assessment | X | X | X | X17 |
Sample size {14}
Recruitment {15}
Assignment of interventions: allocation
Sequence generation {16a}, concealment mechanism {16b}, and implementation {16c}
Assignment of interventions: blinding
Who will be blinded {17a}
Procedure for unblinding if needed {17b}
Data collection and management
Plans for assessment and collection of outcomes {18a}
Plans to promote participant retention and complete follow-up {18b}
Data management {19}
Confidentiality {27}
Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
Interim analyses {21b}
Methods for additional analyses (e.g., subgroup analyses) {20b}
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
Plans to give access to the full protocol, participant level-data, and statistical code {31c}
Oversight and monitoring
Composition of the coordinating center and trial steering committee {5d}
Composition of the data monitoring committee, its role, and reporting structure {21a}
Adverse event reporting and harms {22}
Frequency and plans for auditing trial conduct {23}
Plans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees) {25}
Dissemination plans {31a}
Discussion
Trial status
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Protocol version: v1.3, March 20, 2023
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First patient enrolled: January 10, 2023
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Estimated recruitment completion: Q1 2025
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Current status: First five patients enrolled