Nivolumab in combination with cisplatin and 5-fluorouracil as induction therapy in children and adults with EBV-positive nasopharyngeal carcinoma
- Trial ID
- 2022-500676-59-00
- Protocol
- NPC-Nivo
- Sponsor
- GPOH gGmbH
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to increase the percentage of patients with **EBV-positive nasopharyngeal carcinoma** achieving a complete response (CR) on magnetic resonance imaging (MRI) and PET-CT following induction chemotherapy. This objective is clinically significant as it aims to reduce the dosage of radiotherapy from 59.4 Gy to 54 Gy in children, adolescents, and young adults aged 25 years or younger with locoregional disease, potentially minimizing treatment-related side effects while maintaining therapeutic efficacy.
Secondary objectives include:
- Investigating the safety of **Nivolumab** in combination with standard induction chemotherapy in both children and adults with nasopharyngeal carcinoma.
- Assessing the safety of Nivolumab in combination with radiochemotherapy in patients not responding to induction therapy or with metastases.
- Evaluating event-free and overall survival of patients.
Participants
The clinical trial focuses on participants diagnosed with **EBV-positive nasopharyngeal carcinoma**. The study population includes both male and female subjects, ranging in age from 3 to 25 years. Participants are required to have a histologically confirmed new diagnosis of nasopharyngeal carcinoma, with specific staging criteria based on age. The trial does not involve a vulnerable population. The sponsor has not provided the total number of participants. The selection process for the trial population involves specific inclusion criteria, such as measurable disease by MRI per RECIST 1.1 criteria and sufficient tumor tissue for central review. Participants' general health status and lifestyle considerations, such as diet and physical activity, are not specified in the available data.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of **nivolumab** in combination with **cisplatin** and **fluorouracil** as induction therapy for patients with EBV-positive nasopharyngeal carcinoma. This trial is structured as a randomized, double-blind, controlled study, with an estimated duration from September 2022 to August 2028. The primary objective is to increase the complete response rate on MRI and PET-CT after induction chemotherapy, potentially allowing a reduction in radiotherapy dosage for eligible patients. The trial will include multiple study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed nasopharyngeal carcinoma and measurable disease by MRI per RECIST 1.1 criteria.
Participants will undergo regular follow-up visits to monitor treatment response and safety, with assessments including imaging studies and laboratory tests. The end-of-study visit will evaluate the overall treatment outcomes and any long-term effects. The expected length of participant involvement is up to nine months, corresponding to the maximum treatment period for the investigational products. Conditions that may lead to early termination from the study include the occurrence of serious adverse events, disease progression, or withdrawal of consent by the participant or their legal guardians. The trial aims to provide comprehensive data on the primary endpoint of complete remission rate and secondary endpoints such as event-free survival, overall survival, and safety and tolerability of the treatment regimen.
Treatment
The clinical trial involves the administration of several **experimental medications** and **non-experimental treatments**. The primary experimental medication is **Nivolumab**, which is provided as a concentrate for solution for infusion. It is administered intravenously at a dosage of 4.5 mg/kg, with a maximum total dose of 360 mg/kg over a treatment period of 9 weeks. Nivolumab is utilized as a test product in this study.
**Cisplatin** is used as an auxiliary treatment in the trial. It is administered as a solution for infusion, with an intravenous route of administration. The dosage is set at 100 mg/m², with a maximum total dose of 300 mg/m² over a 9-week period. Cisplatin is classified as an antineoplastic agent.
Another auxiliary treatment is **Fluorouracil**, which is also administered as a solution for infusion via intravenous use. The dosage is 1000 mg/m², with a maximum total dose of 15000 mg/m² over 9 weeks. Fluorouracil is recognized for its antineoplastic properties.
**Interferon Beta-1a** is included in the study as an auxiliary treatment. It is provided as a solution for injection and administered subcutaneously. The dosage is 22 µg, with a maximum total dose of 576 µg over a 6-week period. This medication is not classified as an antineoplastic agent.
**Carboplatin** is administered as a solution for infusion, with an intravenous route. The dosage is 500 mg/m², with a maximum total dose of 1500 mg/m² over a 9-week period. It is used as an auxiliary treatment and is classified as an antineoplastic agent.
**Gemcitabine** is also used as an auxiliary treatment in the trial. It is administered as a solution for infusion via intravenous use. The dosage is 1000 mg/m², with a maximum total dose of 6000 mg/m² over 9 weeks. Gemcitabine is recognized for its antineoplastic properties.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The study aims to evaluate the efficacy of these treatments in combination, particularly focusing on the response of patients with EBV-positive nasopharyngeal carcinoma.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the **Complete Remission Rate (CRR)**, which is defined as the proportion of subjects achieving a complete response on magnetic resonance imaging (MRI) and PET-CT after induction chemotherapy with 5-fluorouracil and cisplatin in combination with Nivolumab, evaluated according to RECIST 1.1 criteria. Secondary endpoints include Event-Free Survival (EFS), Overall Survival (OS), and efficacy based on PD-L1 expression in tumor tissue. Safety and tolerability will also be monitored through the recording of adverse events (AEs) and serious adverse events (SAEs).
The efficacy parameters will be measured and collected at specified timepoints throughout the trial. The complete response will be assessed using MRI and PET-CT scans, which are standard imaging techniques for evaluating tumor response. The RECIST 1.1 criteria will be employed to ensure a consistent and validated approach to measuring tumor response. The trial aims to increase the percentage of nasopharyngeal carcinoma patients with a complete response, thereby potentially allowing a reduction in radiotherapy dosage for children, adolescents, and young adults with locoregional disease.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Histologically confirmed new diagnosis of nasopharyngeal carcinoma according to the current WHO classification in children and adolescents aged between 3 and 17 years
- Alternatively to (1): 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
- Written informed consent by legal guardians (if patient not ≥ 18 years) and patient prior to study participation
- Sufficient tumor tissue to be sent for central review, including PD-L1 staining, either as 2 full blocks or a minimum of 25 slides, obtained from core biopsy, punch biopsy, excisional biopsy or surgical specimen
Exclusion Criteria
- Newly diagnosed nasopharyngeal carcinoma, Stage I in all patients, Stage II in patients > 25 years of age
- 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
- Hearing loss > 20 dB loss at 3 kHz
- 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
- Recurrent nasopharyngeal carcinoma
- 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
- Lactating females
- The subject is unwilling or unable to follow the procedures outlined in the protocol
- The subject is mentally or legally incapacitated
- 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 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
- Subjects who are enrolled in another clinical trial
- Subjects with prior organ allograft or allogenic bone marrow transplantation
- Subjects, who are committed to an institution by virtue of an order issued either by the judicial or the administrative authorities
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Recruiting | 01 Sept 2022 | 57 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
CARBOPLATIN | Other | — | INTRAVENOUS USE | 500 | 9 | SUB06614MIG |
CISPLATIN | Other | PHF00230MIG | INTRAVENOUS USE | 100 | 9 | SCP26873719 |
GEMCITABINE | Other | — | INTRAVENOUS USE | 1000 | 9 | SUB07892MIG |
NIVOLUMAB | Test | — | INTRAVENOUS USE | 4.5 | 9 | SUB122750 |
FLUOROURACIL | Other | PHF00230MIG | INTRAVENOUS USE | 1000 | 9 | SCP7587892 |
INTERFERON BETA-1A | Other | — | SUBCUTANEOUS | 22 | 6 | SUB12440MIG |