Clinical trial NCT06019130: Nivolumab in Children and Adults With Nasopharyngeal Carcinoma
Official title: Nivolumab in Combination With Cisplatin and 5-Fluorouracil as Induction Therapy in Children and Adults With EBV-positive Nasopharyngeal Carcinoma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Nasopharyngeal Carcinoma
Nasopharyngeal Cancer
Nasopharyngeal Neoplasms
Nasopharynx Cancer
Keywords: Immunotherapy
Nivolumab
Children
Adults
Chemotherapy
Immune Checkpoint Inhibitor
Lead sponsor: German Society for Pediatric Oncology and Hematology GPOH gGmbH
Sponsor class: OTHER
Collaborators: name: Deutsche Krebshilfe e.V., Bonn (Germany)
First posted: 2023-08-31
Enrollment: 57
Sex: ALL
Minimum age (years): 3
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A phase-II optimum Simon design with alpha=0.1 and beta=0.2 will be used.
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to assess whether the addition of the immune checkpoint inhibitor Nivolumab to induction chemotherapy will increase the percentage of patients with a complete response on MRI and PET after 3 cycles of induction therapy.

Detailed description: After being informed about the study and potential risks, all patients will undergo a 2-week screening period to determine eligibility for study entry. After informed consent has been obtained, all patients ≤ 25 years and patients \> 25 years without metastases will receive Nivolumab (4.5 mg/kg BW (max. 360 mg) q 3 weeks) added to standard induction chemotherapy (3 blocks of cisplatin/5-fluorouracil). In patients not responding to induction chemotherapy, the application of Nivolumab will be extended throughout the period of radiochemotherapy.

Patients \> 25 years with metastatic disease will receive Nivolumab (4.5 mg/kg BW (max. 360 mg) q 3 weeks) added to induction chemotherapy with 3 blocks of cisplatin/gemcitabine.

All patients with metastatic disease will continue to receive Nivolumab during radiochemotherapy.

Eligibility criteria: Inclusion Criteria:

1. Histologically confirmed new diagnosis of nasopharyngeal carcinoma according to the current WHO classification in children and adolescents, aged between 3 years and 17 years, OR histologically confirmed new diagnosis of EBV-positive nasopharyngeal carcinoma, WHO stage II or III, in subjects ≥ 18 years
2. Stage II or higher in patients ≤ 25 years of age, stage III and IV in patients \> 25 years of age (AJCC, 8th edition)
3. Measurable disease by MRI per RECIST 1.1 criteria
4. Sufficient tumor tissue to be sent for central review, including PD-L1 staining, either as 1 or 2 full blocks (preferred) or a minimum of 25 slides, obtained from core biopsy, punch biopsy, excisional biopsy or surgical specimen
5. Written informed consent by legal guardians (if patient not ≥ 18 years) and patient prior to study participation

Exclusion Criteria:

1. Newly diagnosed nasopharyngeal carcinoma, Stage I in all patients, Stage II in patients \> 25 years of age
2. Recurrent nasopharyngeal carcinoma
3. Nasopharyngeal carcinoma diagnosed as second malignancy and preceding chemotherapy and/or radiotherapy
4. Prior chemotherapy and/or radiotherapy
5. Other active malignancy
6. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
7. The subject received an investigational drug within 30 days prior to inclusion into this study
8. Subjects who are enrolled in another clinical trial
9. Subjects with prior organ allograft or allogenic bone marrow transplantation
10. Subjects with an active, known or suspected autoimmune disease. Participants with 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 to enrol.
11. Subjects with a 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.
12. Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection
13. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
14. Inadequate hematologic, renal or hepatic function defined by any of the following screening laboratory values:

    1. WBC \< 2 000/µl
    2. Neutrophils \< 1 500/µl
    3. Platelets \< 100 x 10e3/µL
    4. Hemoglobin \< 9.0 g/dL
    5. Creatinine \>1.5 x ULN or creatinine clearance \< 50 mL/min (using the Cockcroft Gault formula or Schwartz formula in patients \< 18 years)
    6. AST/ALT \> 3 x ULN (\> 5 x ULN if liver metastases)
    7. Total Bilirubin \> 1.5 x ULN (except subjects with Gilbert Syndrome who must have a total bilirubin level ≥ 3.0 x ULN)
15. Hearing loss \> 20 dB loss at 3 kHz due to an inner ear disorder and not caused by tumour burden
16. History of allergy or hypersensitivity to platinum-containing compounds or other study drug components
17. 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).
18. Vaccinated with live attenuated vaccines within 4 weeks of the first dose of the study drug.
19. Adequate performance status (Karnofsky score ≥ 60 for patients (age ≥ 16), Lansky score ≥ 60 (age \< 16).
20. The subject has a history of any other illness, which, in the opinion of the Investigator, might pose an unacceptable risk by administering study medication.
21. The subject has any current or past medical condition and/or required medication to treat a condition that could affect the evaluation of the study.
22. Pregnant females as determined by positive \[serum or urine\] hCG test at Screening or prior to dosing. Participants of child-bearing age should use adequate contraception as defined in the study protocol. (Please refer to section 4.4)
23. Lactating females
24. Subjects, who are committed to an institution by virtue of an order issued either by the judicial or the administrative authorities
25. The subject is unwilling or unable to follow the procedures outlined in the protocol
26. The subject is mentally or legally incapacitated.

Primary outcomes:
measure: Complete remission rate after induction therapy
timeFrame: MRI and PET will be done 17-22 days after start of induction therapy cycle 3 (each cycle is 21 days)
Secondary outcomes:
measure: Overall and Event-free Survival
timeFrame: 2 years after study enrolment
measure: Number of Treatment-Related Adverse Events
timeFrame: At day 0 of chemotherapy cycles 1, 2 and 3, each; at day 20-25 after beginning of chemotherapy cycle 3 (each cycle is 21 days); within 2-3 weeks after the last dose of radiotherapy; 100 days following the last dose of Nivolumab
measure: Efficacy based on PD-L1 expression in tumor tissue
timeFrame: Response to induction therapy will be measured 17-22 days after start of induction therapy cycle 3 (each cycle is 21 days), event-free and overall survival will be determined 2 years after study enrolment
Other outcomes:
Locations:
city: Aachen
country: Germany
facility: Uniklinik RWTH Aachen, Department of Internal Medicine
city: Aachen
country: Germany
facility: Uniklinik RWTH Aachen, Division of Pediatric Hematology, Oncology, Stem Cell Transplantation
city: Berlin
country: Germany
facility: Department of Pediatric Oncology and Hematology, Charité University Medicine Berlin
city: Bielefeld
country: Germany
facility: Evangelisches Klinikum Bethel, Children's Hospital
city: Bonn
country: Germany
facility: Department of Pediatric Hematology and Oncology, University Hospital
city: Cottbus
country: Germany
facility: Children's Hospital, Carl-Thiem Klinikum Cottbus
city: Dortmund
country: Germany
facility: Clinic for Children and Adolescent Medicine, Klinikum Dortmund
city: Dortmund
country: Germany
facility: Department of Internal Medicine, Klinikum Dortmund
city: Dresden
country: Germany
facility: Department of Pediatrics, University Hospital, Technische Universität Dresden
city: Erlangen
country: Germany
facility: Department fo Radiotherapy, University Hospital
city: Erlangen
country: Germany
facility: Department of Pediatrics, University Hospital Erlangen
city: Essen
country: Germany
facility: Department of Medical Oncology, West German Cancer Center, University Hospital Essen
city: Essen
country: Germany
facility: Department of Pediatric Hematology and Oncology, University Hospital Essen
city: Frankfurt
country: Germany
facility: Department of Pediatrics, University Hospital
city: Freiburg
country: Germany
facility: Department of Pediatric Hematology/Oncology, University Hospital Freiburg
city: Giessen
country: Germany
facility: Department of Pediatric Oncology, Justus-Liebig University of Giessen
city: Greifswald
country: Germany
facility: Department of Pediatric Hematology/Oncology, University Medicine Greifswald
city: Göttingen
country: Germany
facility: Department of Pediatric Oncology, University Hospital
city: Halle
country: Germany
facility: Universitätsklinikum Halle, Klinik für Pädiatrie I
city: Hamburg
country: Germany
facility: Department of Otorhinolaryngology, University Medical Center Hamburg-Eppendorf,
city: Hamburg
country: Germany
facility: Department of Pediatric Oncology, University Children's Hospital
city: Jena
country: Germany
facility: Department of Otorhinolaryngology, Jena University Hospital
city: Kiel
country: Germany
facility: Department of Pediatric Oncology, University Hospital Kiel
city: Köln
country: Germany
facility: Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne
city: Magdeburg
country: Germany
facility: Department of Pediatrics, University Hospital Mageburg
city: Mainz
country: Germany
facility: Pediatric Hematology/Oncology, University Medicine Mainz
city: Mannheim
country: Germany
facility: Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Mannheim,
city: Münster
country: Germany
facility: Department of Pediatric Hematology and Oncology, University Children's Hospital
city: Regensburg
country: Germany
facility: Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, University Hospital
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen, Klinik für Pädiatrie I
city: Würzburg
country: Germany
facility: Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, University Children's Hospital, University of Würzburg
Study officials:
affiliation: Uniklinik RWTH Aachen
name: Udo Kontny, MD
role: PRINCIPAL_INVESTIGATOR
References: