NPC-Nivo: Nivolumab in Children and Adults With Nasopharyngeal Carcinoma

Sponsor

German Society for Pediatric Oncology and Hematology GPOH gGmbH (Other)

Overall Status

Recruiting

CT.gov ID

NCT06019130

Collaborator

Deutsche Krebshilfe e.V., Bonn (Germany) (Other)

Enrollment

Locations

Arms

Anticipated Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Nasopharyngeal Carcinoma Nasopharyngeal Cancer Nasopharyngeal Neoplasms Nasopharynx Cancer	Drug: Nivolumab Drug: Cisplatin Drug: 5-Fluorouracil Drug: Gemcitabine Radiation: Radiotherapy Drug: Interferon beta-1a Procedure: MRI Procedure: PET Behavioral: Patient-Reported Outcomes	Phase 2

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

57 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

A phase-II optimum Simon design with alpha=0.1 and beta=0.2 will be used.A phase-II optimum Simon design with alpha=0.1 and beta=0.2 will be used.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jan 10, 2023

Anticipated Primary Completion Date :

Jan 9, 2026

Anticipated Study Completion Date :

Jan 9, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Patients < 26 years with non-metastatic disease with CR or PR after induction therapy Participants receive Nivolumab (4.5 mg/kg BW (max. 360 mg) every three weeks) during induction chemotherapy for a total of 3 doses, starting on day 1 of cycle 1 of induction standard chemotherapy with cisplatin 100 mg/m2 on day 1, plus 5-fluorouracil 1,000 mg/m2/d from day 1-5. After induction therapy patients will undergo standard radiochemotherapy. Primary PTV1 including elective irradiated LN-levels, will be 45Gy, with a boost ad 59.4Gy in patients with PR or a reduced boost at 54Gy in patients with CR. Cisplatin will be administered at 3x20mg/m2 in the first and last week of radiotherapy, each. Radiochemotherapy is followed by maintenance therapy with recombinant interferon-ß1a at 3x6Mio IU/week s.c. for 6 months.	Drug: Nivolumab Nivolumab during induction chemotherapy in all groups and during radiochemotherapy in patients with SD or PD after induction or metastases Other Names: Opdivo Drug: Cisplatin Cisplatin during induction chemotherapy and during radiochemotherapy in all groups Other Names: Cisplatin Teva Drug: 5-Fluorouracil 5-Fluoruracil during induction chemotherapy in all groups except of adults > 25 years with metastatic disease at diagnosis Other Names: Fluorouracil-GRY Radiation: Radiotherapy After induction therapy in all patients Drug: Interferon beta-1a In patients < 26 years after end of radiochemotherapy for 6 months Other Names: Rebif Procedure: MRI At diagnosis and 17 to 22 days after the beginning of cycle 3 of induction therapy Procedure: PET At diagnosis and 17 to 22 days after the beginning of cycle 3 of induction therapy, either as PET-CT or PET-MRI Behavioral: Patient-Reported Outcomes For all patients at baseline, before radiochemotherapy, at day 100, and 2 years after enrolment
Experimental: Patients < 26 y with no metastases and SD or PD after induction therapy or patients with metastases Participants receive Nivolumab (4.5 mg/kg BW (max. 360 mg) every three weeks) during induction chemotherapy for a total of 3 doses, starting on day 1 of cycle 1 of induction standard chemotherapy with cisplatin 100 mg/m2 on day 1, plus 5-fluorouracil 1,000 mg/m2/d from day 1-5. Patients with metastases responding to induction therapy may have a fourth cycle of induction therapy, including a fourth dose of Nivolumab. After induction therapy patients will undergo standard radiochemotherapy. Primary PTV1 including elective irradiated LN-levels, will be 45Gy, with a boost ad 59.4Gy. Cisplatin will be administered at 3x20mg/m2 in the first and last week of radiotherapy, each. Nivolumab (4.5 mg/kg BW (max. 360 mg) every three weeks) will be continued during radiochemotherapy, adding a total of 3 further doses of Nivolumab. Radiochemotherapy is followed by maintenance therapy with recombinant interferon-ß1a at 3x6Mio IU/week s.c. for 6 months.	Drug: Nivolumab Nivolumab during induction chemotherapy in all groups and during radiochemotherapy in patients with SD or PD after induction or metastases Other Names: Opdivo Drug: Cisplatin Cisplatin during induction chemotherapy and during radiochemotherapy in all groups Other Names: Cisplatin Teva Drug: 5-Fluorouracil 5-Fluoruracil during induction chemotherapy in all groups except of adults > 25 years with metastatic disease at diagnosis Other Names: Fluorouracil-GRY Radiation: Radiotherapy After induction therapy in all patients Drug: Interferon beta-1a In patients < 26 years after end of radiochemotherapy for 6 months Other Names: Rebif Procedure: MRI At diagnosis and 17 to 22 days after the beginning of cycle 3 of induction therapy Procedure: PET At diagnosis and 17 to 22 days after the beginning of cycle 3 of induction therapy, either as PET-CT or PET-MRI Behavioral: Patient-Reported Outcomes For all patients at baseline, before radiochemotherapy, at day 100, and 2 years after enrolment
Experimental: Patients >25 years with non-metastatic disease with CR or PR after induction therapy Participants receive Nivolumab (4.5 mg/kg BW (max. 360 mg) every three weeks) during induction chemotherapy for a total of 3 doses, starting on day 1 of cycle 1 of induction standard chemotherapy with cisplatin 100 mg/m2 on day 1, plus 5-fluorouracil 1,000 mg/m2/d from day 1-5. After induction therapy patients will undergo standard radiochemotherapy as outlined in current international guidelines (e.g. NCCN, ESMO).	Drug: Nivolumab Nivolumab during induction chemotherapy in all groups and during radiochemotherapy in patients with SD or PD after induction or metastases Other Names: Opdivo Drug: Cisplatin Cisplatin during induction chemotherapy and during radiochemotherapy in all groups Other Names: Cisplatin Teva Drug: 5-Fluorouracil 5-Fluoruracil during induction chemotherapy in all groups except of adults > 25 years with metastatic disease at diagnosis Other Names: Fluorouracil-GRY Radiation: Radiotherapy After induction therapy in all patients Procedure: MRI At diagnosis and 17 to 22 days after the beginning of cycle 3 of induction therapy Procedure: PET At diagnosis and 17 to 22 days after the beginning of cycle 3 of induction therapy, either as PET-CT or PET-MRI Behavioral: Patient-Reported Outcomes For all patients at baseline, before radiochemotherapy, at day 100, and 2 years after enrolment
Experimental: Patients > 25 years with non-metastatic disease with SD or PD after induction therapy Participants receive Nivolumab (4.5 mg/kg BW (max. 360 mg) every three weeks) during induction chemotherapy for a total of 3 doses, starting on day 1 of cycle 1 of induction standard chemotherapy with cisplatin 100 mg/m2 on day 1, plus 5-fluorouracil 1,000 mg/m2/d from day 1-5. After induction therapy patients will undergo standard radiochemotherapy as outlined in current international guidelines (e.g. NCCN, ESMO). Nivolumab (4.5 mg/kg BW (max. 360 mg) every three weeks) will be continued during radiochemotherapy, adding a total of 3 further doses of Nivolumab.	Drug: Nivolumab Nivolumab during induction chemotherapy in all groups and during radiochemotherapy in patients with SD or PD after induction or metastases Other Names: Opdivo Drug: Cisplatin Cisplatin during induction chemotherapy and during radiochemotherapy in all groups Other Names: Cisplatin Teva Drug: 5-Fluorouracil 5-Fluoruracil during induction chemotherapy in all groups except of adults > 25 years with metastatic disease at diagnosis Other Names: Fluorouracil-GRY Radiation: Radiotherapy After induction therapy in all patients Procedure: MRI At diagnosis and 17 to 22 days after the beginning of cycle 3 of induction therapy Procedure: PET At diagnosis and 17 to 22 days after the beginning of cycle 3 of induction therapy, either as PET-CT or PET-MRI Behavioral: Patient-Reported Outcomes For all patients at baseline, before radiochemotherapy, at day 100, and 2 years after enrolment
Experimental: Patients > 25 years with metastatic disease at diagnosis Participants receive Nivolumab (4.5 mg/kg BW (max. 360 mg) every three weeks) during induction chemotherapy for a total of 3 doses, starting on day 1 of cycle 1 of induction standard chemotherapy with cisplatin 80 mg/m2 on day 1, plus gemcitabine 1,000 mg/m2/d on day 1 and day 8, respectively. Patients responding to induction therapy may have a fourth cycle of induction therapy, including a fourth dose of Nivolumab. After induction therapy patients will undergo standard radiochemotherapy as outlined in current international guidelines (e.g. NCCN, ESMO). Nivolumab (4.5 mg/kg BW (max. 360 mg) every three weeks) will be continued during radiochemotherapy, adding a total of 3 further doses of Nivolumab.	Drug: Nivolumab Nivolumab during induction chemotherapy in all groups and during radiochemotherapy in patients with SD or PD after induction or metastases Other Names: Opdivo Drug: Cisplatin Cisplatin during induction chemotherapy and during radiochemotherapy in all groups Other Names: Cisplatin Teva Drug: Gemcitabine Gemcitabine during induction chemotherapy in patients > 25 years with metastatic disease at diagnosis Other Names: Gemcitabin-GRY Radiation: Radiotherapy After induction therapy in all patients Procedure: MRI At diagnosis and 17 to 22 days after the beginning of cycle 3 of induction therapy Procedure: PET At diagnosis and 17 to 22 days after the beginning of cycle 3 of induction therapy, either as PET-CT or PET-MRI Behavioral: Patient-Reported Outcomes For all patients at baseline, before radiochemotherapy, at day 100, and 2 years after enrolment

Outcome Measures

Primary Outcome Measures

Complete remission rate after induction therapy [MRI and PET will be done 17-22 days after start of induction therapy cycle 3 (each cycle is 21 days)]
Complete response by MRI and PET will be determined as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria

Secondary Outcome Measures

Overall and Event-free Survival [2 years after study enrolment]
Overall and event-free survival rates will be analysed with suitable descriptive methods (Kaplan Meyer estimates with confidence intervals) and compared with historical data using descriptive log-rank tests
Number of Treatment-Related Adverse Events [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]
Adverse events will be classified using the National Cancer Institute Common Toxicity Criteria (NCI-CTCAE) version 5.0 by investigator assessment. Descriptive methods (frequency tables, rates of AE's and SAE's with 95% confidence intervals) will be applied
Efficacy based on PD-L1 expression in tumor tissue [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]
PD-L1-stained % of tumor cells at the time of diagnosis will be associated to the rate of response after induction therapy and EFS and OS

Eligibility Criteria

Criteria

Ages Eligible for Study:

3 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

Exclusion Criteria:

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.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Uniklinik RWTH Aachen, Department of Internal Medicine	Aachen	Germany	52074
2	Uniklinik RWTH Aachen, Division of Pediatric Hematology, Oncology, Stem Cell Transplantation	Aachen	Germany	52074
3	Department of Pediatric Oncology and Hematology, Charité University Medicine Berlin	Berlin	Germany	13353
4	Evangelisches Klinikum Bethel, Children's Hospital	Bielefeld	Germany	33617
5	Department of Pediatric Hematology and Oncology, University Hospital	Bonn	Germany	53127
6	Children's Hospital, Carl-Thiem Klinikkum Cottbus	Cottbus	Germany	03048
7	Clinic for Children and Adolescent Medicine, Klinikum Dortmund	Dortmund	Germany	44145
8	Department of Internal Medicine, Klinikum Dortmund	Dortmund	Germany	44145
9	Department fo Radiotherapy, University Hospital	Erlangen	Germany	91054
10	Department of Pediatrics, University Hospital Erlangen	Erlangen	Germany	91054
11	Department of Medical Oncology, West German Cancer Center, University Hospital Essen	Essen	Germany	45147
12	Department of Pediatric Hematology and Oncology, University Hospital Essen	Essen	Germany	45147
13	Department of Pediatrics, University Hospital	Frankfurt	Germany	60590
14	Department of Pediatric Hematology/Oncology, University Hospital Freiburg	Freiburg	Germany	79106
15	Department of Pediatric Oncology, Justus-Liebig University of Giessen	Giessen	Germany	35392
16	Department of Pediatric Hematology/Oncology, University Medicine Greifswald	Greifswald	Germany	17475
17	Department of Pediatric Oncology, University Hospital	Göttingen	Germany	37075
18	Universitätsklinikum Halle, Klinik für Pädiatrie I	Halle	Germany	06120
19	Department of Pediatric Oncology, University Children's Hospital	Hamburg	Germany
20	Department of Otorhinolaryngology, Jena University Hospital	Jena	Germany	07743
21	Department of Pediatric Oncology, University Hospital Kiel	Kiel	Germany	24105
22	Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne	Köln	Germany	50937
23	Department of Pediatrics, University Hospital Mageburg	Magdeburg	Germany	39120
24	Pediatric Hematology/Oncology, University Medicine Mainz	Mainz	Germany	55131
25	Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Mannheim,	Mannheim	Germany	68167
26	Department of Pediatric Hematology and Oncology, University Children's Hospital	Münster	Germany	48149
27	Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, University Hospital	Regensburg	Germany	93053
28	Universitätsklinikum Tübingen, Klinik für Pädiatrie I	Tübingen	Germany	72076
29	Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, University Children's Hospital, University of Würzburg	Würzburg	Germany	97080