Nivolumab in Children and Adults With Nasopharyngeal Carcinoma

Официальное название

Nivolumab in Combination With Cisplatin and 5-Fluorouracil as Induction Therapy in Children and Adults With EBV-positive Nasopharyngeal Carcinoma

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат Nivolumab
  Nivolumab during induction chemotherapy in all groups and during radiochemotherapy in patients with SD or PD after induction or metastases
• Препарат Cisplatin
  Cisplatin during induction chemotherapy and during radiochemotherapy in all groups
• Препарат 5-Fluorouracil
  5-Fluoruracil during induction chemotherapy in all groups except of adults \> 25 years with metastatic disease at diagnosis
• Препарат Gemcitabine
  Gemcitabine during induction chemotherapy in patients \> 25 years with metastatic disease at diagnosis
• Лучевая терапия Radiotherapy
  After induction therapy in all patients
• Препарат Interferon beta-1a
  In patients \< 26 years after end of radiochemotherapy for 6 months
• Процедура MRI
  At diagnosis and 17 to 22 days after the beginning of cycle 3 of induction therapy
• Процедура PET
  At diagnosis and 17 to 22 days after the beginning of cycle 3 of induction therapy, either as PET-CT or PET-MRI
• Поведенческое Patient-Reported Outcomes
  For all patients at baseline, before radiochemotherapy, at day 100, and 2 years after enrolment

Первичные конечные точки

• Complete remission rate after induction therapy [Срок оценки: MRI and PET will be done 17-22 days after start of induction therapy cycle 3 (each cycle is 21 days)]

Вторичные конечные точки (3)

• Overall and Event-free Survival [Срок оценки: 2 years after study enrolment]
• Number of Treatment-Related Adverse Events [Срок оценки: 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]
• Efficacy based on PD-L1 expression in tumor tissue [Срок оценки: 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]

Критерии участия

Критерии включения

• 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
• Stage II or higher in patients ≤ 25 years of age, stage III and IV in patients > 25 years of age (AJCC, 8th edition)
• Measurable disease by MRI per RECIST 1.1 criteria
• 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
• Written informed consent by legal guardians (if patient not ≥ 18 years) and patient prior to study participation

Критерии исключения

• Newly diagnosed nasopharyngeal carcinoma, Stage I in all patients, Stage II in patients > 25 years of age
• Recurrent nasopharyngeal carcinoma
• Nasopharyngeal carcinoma diagnosed as second malignancy and preceding chemotherapy and/or radiotherapy
• Prior chemotherapy and/or radiotherapy
• Other active malignancy
• 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.
• The subject received an investigational drug within 30 days prior to inclusion into this study
• Subjects who are enrolled in another clinical trial
• Subjects with prior organ allograft or allogenic bone marrow transplantation
• 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.
• 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.
• Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection
• Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
• Inadequate hematologic, renal or hepatic function defined by any of the following screening laboratory values:

• WBC < 2 000/µl
• Neutrophils < 1 500/µl
• Platelets < 100 x 10e3/µL
• Hemoglobin < 9.0 g/dL
• Creatinine >1.5 x ULN or creatinine clearance < 50 mL/min (using the Cockcroft Gault formula or Schwartz formula in patients < 18 years)
• AST/ALT > 3 x ULN (> 5 x ULN if liver metastases)
• Total Bilirubin > 1.5 x ULN (except subjects with Gilbert Syndrome who must have a total bilirubin level ≥ 3.0 x ULN)
• Hearing loss > 20 dB loss at 3 kHz due to an inner ear disorder and not caused by tumour burden
• History of allergy or hypersensitivity to platinum-containing compounds or other study drug components
• 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).
• Vaccinated with live attenuated vaccines within 4 weeks of the first dose of the study drug.
• Adequate performance status (Karnofsky score ≥ 60 for patients (age ≥ 16), Lansky score ≥ 60 (age < 16).
• 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.
• 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.
• 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)
• Lactating females
• Subjects, who are committed to an institution by virtue of an order issued either by the judicial or the administrative authorities
• The subject is unwilling or unable to follow the procedures outlined in the protocol
• The subject is mentally or legally incapacitated.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Германия · 31 центр

• Uniklinik RWTH Aachen, Department of Internal Medicine — Aachen
• Uniklinik RWTH Aachen, Division of Pediatric Hematology, Oncology, Stem Cell Transplantati — Aachen
• Department of Pediatric Oncology and Hematology, Charité University Medicine Berlin — Berlin
• Evangelisches Klinikum Bethel, Children's Hospital — Bielefeld
• Department of Pediatric Hematology and Oncology, University Hospital — Bonn
• Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne — Cologne
• Children's Hospital, Carl-Thiem Klinikum Cottbus — Cottbus
• Clinic for Children and Adolescent Medicine, Klinikum Dortmund — Dortmund
• … и ещё 23 центра

Идентификаторы

NCT: NCT06019130 · EUCT: 2022-500676-59-00

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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