Nivolumab in Children and Adults With Nasopharyngeal Carcinoma (NPC-Nivo)

• ClinicalTrials.gov Identifier: NCT06019130
• Recruitment Status: Recruiting
• First Posted: August 31, 2023
• Last Update Posted: August 31, 2023
• Sponsor: German Society for Pediatric Oncology and Hematology GPOH gGmbH
• Collaborator: Deutsche Krebshilfe e.V., Bonn (Germany)
• Information provided by (Responsible Party): Prof. Dr. Udo Kontny, RWTH Aachen University

Tracking Information

• First Submitted Date: August 15, 2023
• First Posted Date: August 31, 2023
• Last Update Posted Date: August 31, 2023
• Actual Study Start Date: January 10, 2023
• Estimated Primary Completion Date: January 9, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 24, 2023)

Complete remission rate after induction therapy [ Time Frame: 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

• Original Primary Outcome Measures: Same as current
• Change History: No Changes Posted

Current Secondary Outcome Measures (submitted: August 24, 2023)

• Overall and Event-free Survival [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

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.

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

• Nasopharyngeal Carcinoma
• Nasopharyngeal Cancer
• Nasopharyngeal Neoplasms
• Nasopharynx Cancer

Intervention

• Drug: Nivolumab
  Nivolumab during induction chemotherapy in all groups and during radiochemotherapy in patients with SD or PD after induction or metastases
  Other Name: Opdivo
• Drug: Cisplatin
  Cisplatin during induction chemotherapy and during radiochemotherapy in all groups
  Other Name: Cisplatin Teva
• Drug: 5-Fluorouracil
  5-Fluoruracil during induction chemotherapy in all groups except of adults > 25 years with metastatic disease at diagnosis
  Other Name: Fluorouracil-GRY
• Drug: Gemcitabine
  Gemcitabine during induction chemotherapy in patients > 25 years with metastatic disease at diagnosis
  Other Name: Gemcitabin-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 Name: 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

Study Arms

• 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.

  Interventions:

  • Drug: Nivolumab
  • Drug: Cisplatin
  • Drug: 5-Fluorouracil
  • Radiation: Radiotherapy
  • Drug: Interferon beta-1a
  • Procedure: MRI
  • Procedure: PET
  • Behavioral: Patient-Reported Outcomes
• 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.

  Interventions:

  • Drug: Nivolumab
  • Drug: Cisplatin
  • Drug: 5-Fluorouracil
  • Radiation: Radiotherapy
  • Drug: Interferon beta-1a
  • Procedure: MRI
  • Procedure: PET
  • Behavioral: Patient-Reported Outcomes
• 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).

  Interventions:

  • Drug: Nivolumab
  • Drug: Cisplatin
  • Drug: 5-Fluorouracil
  • Radiation: Radiotherapy
  • Procedure: MRI
  • Procedure: PET
  • Behavioral: Patient-Reported Outcomes
• 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.

  Interventions:

  • Drug: Nivolumab
  • Drug: Cisplatin
  • Drug: 5-Fluorouracil
  • Radiation: Radiotherapy
  • Procedure: MRI
  • Procedure: PET
  • Behavioral: Patient-Reported Outcomes
• 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.

  Interventions:

  • Drug: Nivolumab
  • Drug: Cisplatin
  • Drug: Gemcitabine
  • Radiation: Radiotherapy
  • Procedure: MRI
  • Procedure: PET
  • Behavioral: Patient-Reported Outcomes

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 24, 2023): 57
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: January 9, 2028
• Estimated Primary Completion Date: January 9, 2026 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 3 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Helena Kerp, PhD; +49 201 74 94 96 14; h.kerp@forschung-paediatrie.de

Contact: Tristan Römer, MD.; +49 241 80 38063; troemer@ukaachen.de

• Listed Location Countries: Germany

Administrative Information

• NCT Number: NCT06019130
• Other Study ID Numbers: EUCT: 2022-500676-59-00
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Prof. Dr. Udo Kontny, RWTH Aachen University
• Original Responsible Party: Same as current
• Current Study Sponsor: German Society for Pediatric Oncology and Hematology GPOH gGmbH
• Original Study Sponsor: Same as current
• Collaborators: Deutsche Krebshilfe e.V., Bonn (Germany)

Investigators

• Principal Investigator: Udo Kontny, MD; Uniklinik RWTH Aachen

• PRS Account: German Society for Pediatric Oncology and Hematology GPOH gGmbH
• Verification Date: August 2023