A Study Using Nivolumab, in Combination With Chemotherapy Drugs to Treat Nasopharyngeal Carcinoma (NPC)

Phase 2

Recruiting

• Conditions: Stage IV Nasopharyngeal Carcinoma AJCC v8; Stage II Nasopharyngeal Carcinoma AJCC v8; Stage III Nasopharyngeal Carcinoma AJCC v8
• Interventions: Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Procedure: Chest Radiography; Drug: Cisplatin; Procedure: Computed Tomography; Procedure: Echocardiography Test; Other: Electronic Health Record Review; Other: Fluciclovine F18; Drug: Gemcitabine; Procedure: Magnetic Resonance Imaging; Procedure: Multigated Acquisition Scan; Biological: Nivolumab; Procedure: Positron Emission Tomography; Other: Quality-of-Life Assessment; Other: Questionnaire Administration; Radiation: Radiation Therapy; Procedure: X-Ray Imaging

• Registration Number: NCT06064097
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

This phase II trial tests effects of nivolumab in combination with chemotherapy drugs prior to radiation therapy patients with nasopharyngeal carcinoma (NPC). Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as gemcitabine and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Researchers want to find out what effects, good and/or bad, adding nivolumab to chemotherapy has on patients with newly diagnosed NPC. In addition, they want to find out if children with NPC may be treated with less radiation therapy and whether this decreases the side effects of therapy.

Detailed Description

PRIMARY OBJECTIVE:

I. To evaluate safety of combining chemotherapy (cisplatin and gemcitabine) with an anti-PD1 immune checkpoint inhibitor (nivolumab) in children, adolescents and young adults with nasopharyngeal carcinoma (NPC) by determining the rate of Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher immune related adverse events (irAEs).

SECONDARY OBJECTIVES:

I. To estimate the 2-year event-free survival (EFS) of children, adolescents and young adults with NPC who are treated with induction chemoimmunotherapy (CIT), followed by consolidation chemoradioimmunotherapy (CRIT, cisplatin, nivolumab and response-adjusted, dose de-escalated radiation therapy), and nivolumab maintenance therapy.

II. To evaluate the objective response rate (ORR) including complete responders and partial responders (complete response \[CR\] + partial response \[PR\]) of neoadjuvant CIT.

III. To evaluate feasibility of combining chemotherapy (cisplatin and gemcitabine) with an anti-PD1 immune checkpoint inhibitor (nivolumab) in children, adolescents and young adults with nasopharyngeal carcinoma (NPC).

IV. To evaluate the cumulative incidence of local and distant relapse.

EXPLORATORY OBJECTIVES:

I. To estimate 5-year EFS and overall survival (OS) of children with NPC who are treated with induction CIT followed by consolidation CRIT, and nivolumab maintenance therapy.

II. To compare response assessed by fludeoxyglucose F18 (FDG) positron emission tomography (PET) versus magnetic resonance imaging (MRI).

III. To determine treatment outcomes for patients treated with radiation per protocol versus (vs) deviation.

IV. To evaluate outcomes comparing patients receiving intensity modulated radiation therapy (IMRT) to proton therapy.

V. To objectively measure both acute and long-term toxicity including immune related adverse events and radiation late effects.

VI. To evaluate swallowing dysfunction using patient reported outcome (PRO) measures for children and adults throughout the protocol for up to 5 years.

VII. To evaluate quality of life (QOL) using Patient-Reported Outcomes Measurement Information System (PROMIS) multidimensional questionnaire throughout the protocol for up to 5 years.

VIII. To correlate the lymphocyte to monocyte ratio on complete blood counts (CBCs) with treatment response and outcomes.

IX. To collect and bank specimens (including tumor, blood and stool) for future research studies.

OUTLINE:

INDUCTION THERAPY: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1 of each cycle, gemcitabine IV over 30 minutes on days 1 and 8 of each cycle, and cisplatin IV over 3-6 hours on day 1 of each cycle. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION THERAPY: Patients receive nivolumab IV over 30 minutes on day 1 of each cycle and cisplatin IV over 3-6 hours on day 1 of cycles 1-2. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive concurrent radiation therapy on trial.

MAINTENANCE THERAPY: Patients receive nivolumab IV over 30 minutes on day 1 of each cycle. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity.

Patients also undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) during screening and as clinically indicated on trial. Patients undergo MRI, FDG PET, and computed tomography (CT) throughout the trial and chest x-ray during follow-up. Patients also undergo dental x-ray imaging on the trial. Patients may optionally undergo tissue biopsy, blood and stool sample collection during screening and on trial.

After completion of study treatment, patients are followed up every 3 months for 12 months, every 6 months until 24 months off therapy, and then yearly until 5 years off therapy.

Study Timeline

• Study First Submitted: 2023-09-29
• Study First Submitted QC: 2023-09-29
• Study First Posted: 2023-10-03
• Study Start: 2024-06-25
• Status Verified: 2025-04
• Last Update Submitted: 2025-05-16
• Last Update Posted: 2025-05-18
• Primary Completion: 2026-12-31
• Study Completion: 2026-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 50

Inclusion Criteria

• Patients must be ≤ 21 years of age at the time of study enrollment

• Newly diagnosed American Joint Committee on Cancer (AJCC) stage II-IV nasopharyngeal carcinoma (NPC)

  • Patients must have had histologic verification of the malignancy at original diagnosis
  • Although submission of tumor tissue for the molecular characterization initiative is not required for eligibility, it is strongly recommended

• Patients must have had histologic verification of the malignancy at original diagnosis

• Although submission of tumor tissue for the molecular characterization initiative is not required for eligibility, it is strongly recommended

• Patients must have a Lansky (for patients ≤ 16 years of age) or Karnofsky (for patients > 16 years of age) performance status score of ≥ 60%

• Peripheral absolute neutrophil count (ANC) ≥ 1000/uL (within 7 days prior to start of protocol therapy)

• Platelet count ≥ 100,000/uL (transfusion independent) (within 7 days prior to start of protocol therapy)

• Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m^2 or (within 7 days prior to start of protocol therapy)

• A serum creatinine based on age/gender (within 7 days prior to start of protocol therapy) Age: Maximum serum creatinine (mg/dL)

  1 month to < 6 months: 0.4 mg/dL (male); 0.4 mg/dL (female) 6 months to < 1 year: 0.5 mg/dL (male); 0.5 mg/dL (female)

  1 to < 2 years: 0.6 mg/dL (male); 0.6 mg/dL (female) 2 to < 6 years: 0.8 mg/dL (male); 0.8 mg/dL (female) 6 to < 10 years 1 mg/dL (male); 1 mg/dL (female) 10 to <13 years: 1.2 mg/dL (male); 1.2 mg/dL (female) 13 to < 16 years: 1.5 mg/dL (male); 1.4 mg/dL (female)

  ≥ 16 years: 1.7 mg/dL (male); 1.4 mg/dL (female)

• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age, and (within 7 days prior to start of protocol therapy)

• Serum glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) ≤ 135 U/L* (within 7 days prior to start of protocol therapy)

  • Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L

• Shortening fraction of ≥ 27% by echocardiogram, or

• Ejection fraction of ≥ 50% by radionuclide angiogram

• No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% if there is clinical indication for determination

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months and T-cell count above the lower limit of normal are eligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load

Exclusion Criteria

• Patients who received prior radiotherapy to the head or neck

• Patients who received prior chemotherapy or radiation for the treatment of any cancer in the last 3 years. These patients must also be in remission

• Patients with a diagnosis of immunodeficiency

• Patients with an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive agents). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.

  • Note: Patients with well-controlled asthma and no need for systemic steroids for the treatment of asthma in the last 12 months will not be excluded

• Patients with a condition requiring systemic treatment with either corticosteroids (> 0.25 mg/kg (10 mg) daily prednisone equivalent) within 14 days or other immunosuppressive medications within 30 days of enrollment. Inhaled or topical steroids, and adrenal replacement steroid doses > 0.25 mg/kg (10 mg) daily prednisone equivalent, are permitted in the absence of active autoimmune disease

• Patients with a history of (non-infectious) pneumonitis that required steroids or current pneumonitis

• Patients with detectable viral load of human immunodeficiency virus (HIV), hepatitis B or hepatitis C, or active tuberculosis

• Patients who have undergone solid organ or allogeneic hematopoietic transplant at any time

• Due to risks of fetal and teratogenic adverse events as seen in animal studies, a negative pregnancy test must be obtained in females of childbearing potential, defined as females who are post-menarchal. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

• Females of childbearing potential that are sexually active must agree to either practice 2 medically accepted highly-effective methods of contraception at the same time or abstain from heterosexual intercourse from the time of signing the informed consent through 5 months after the last dose of nivolumab, 6 months after the last dose of gemcitabine, and 14 months after the last dose of cisplatin, whichever is longer

• Males of childbearing potential that are sexually active must agree to either practice a medically accepted highly-effective methods of contraception or abstain from heterosexual intercourse from the time of signing the informed consent through 3 months after the last dose of gemcitabine, and 11 months after the last dose of cisplatin, whichever is longer

• Lactating females are not eligible unless they have agreed not to breastfeed their infants starting with the first dose of study therapy through 5 months after the last dose of nivolumab

• All patients and/or their parents or legal guardians must sign a written informed consent

• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (nivolumab, gemcitabine, cisplatin, radiattion)	Biopsy Procedure	See Detailed Description
Treatment (nivolumab, gemcitabine, cisplatin, radiattion)	Biospecimen Collection	See Detailed Description
Treatment (nivolumab, gemcitabine, cisplatin, radiattion)	Chest Radiography	See Detailed Description
Treatment (nivolumab, gemcitabine, cisplatin, radiattion)	Computed Tomography	See Detailed Description
Treatment (nivolumab, gemcitabine, cisplatin, radiattion)	Echocardiography Test	See Detailed Description
Treatment (nivolumab, gemcitabine, cisplatin, radiattion)	Cisplatin	See Detailed Description
Treatment (nivolumab, gemcitabine, cisplatin, radiattion)	Electronic Health Record Review	See Detailed Description
Treatment (nivolumab, gemcitabine, cisplatin, radiattion)	Fluciclovine F18	See Detailed Description
Treatment (nivolumab, gemcitabine, cisplatin, radiattion)	Positron Emission Tomography	See Detailed Description
Treatment (nivolumab, gemcitabine, cisplatin, radiattion)	Gemcitabine	See Detailed Description
Treatment (nivolumab, gemcitabine, cisplatin, radiattion)	Questionnaire Administration	See Detailed Description
Treatment (nivolumab, gemcitabine, cisplatin, radiattion)	Radiation Therapy	See Detailed Description
Treatment (nivolumab, gemcitabine, cisplatin, radiattion)	X-Ray Imaging	See Detailed Description
Treatment (nivolumab, gemcitabine, cisplatin, radiattion)	Magnetic Resonance Imaging	See Detailed Description
Treatment (nivolumab, gemcitabine, cisplatin, radiattion)	Multigated Acquisition Scan	See Detailed Description
Treatment (nivolumab, gemcitabine, cisplatin, radiattion)	Nivolumab	See Detailed Description
Treatment (nivolumab, gemcitabine, cisplatin, radiattion)	Quality-of-Life Assessment	See Detailed Description

Primary Outcome Measures

Name	Time	Method
Incidence of grade 3 or higher immune-related adverse events (irAE) during induction chemoimmunotherapy (CIT)	Until the end of consolidation therapy	Will be assessed by Common Terminology Criteria for Adverse Events. IrAEs include diarrhea (noninfectious), colitis (noninfectious), pneumonitis (noninfectious), myocarditis, elevated alanine aminotransferase, elevated aspartate aminotransferase, pancreatitis, elevated blood bilirubin, hypophysitis and hyperthyroid considered possibly, probably, or definitely related to nivolumab.

Secondary Outcome Measures

Name	Time	Method
Objective response rate	At the end of induction CIT	Will be defined as the rate of responders among evaluable patients using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Event-free survival (EFS)	From date of enrollment to the earliest occurrence of date of relapse, disease progression, second malignant neoplasm or death due to any cause, assessed at 2 years	EFS along with the 95% confidence intervals will be estimated using the Kaplan-Meier method. The EFS will be reported separately for patients with non-metastatic disease and those with metastatic disease (if there are enough patients with metastatic disease enrolled).
Feasibility success of the induction regimen	At the end of induction CIT	Will be defined as the completion of three cycles of induction without delay of greater than 30 days for radiation initiation due to toxicity in 80% of patients.
Cumulative incidence of local or distant relapse	Up to 5 years	Defined as a function of time since enrollment will be estimated by the method of Gray.

Trial Locations

Locations (53)

Children's Hospital of Alabama; 🇺🇸 Birmingham, Alabama, United States

Arkansas Children's Hospital; 🇺🇸 Little Rock, Arkansas, United States

Kaiser Permanente Downey Medical Center; 🇺🇸 Downey, California, United States

Loma Linda University Medical Center; 🇺🇸 Loma Linda, California, United States

Valley Children's Hospital; 🇺🇸 Madera, California, United States

UCSF Benioff Children's Hospital Oakland; 🇺🇸 Oakland, California, United States

Kaiser Permanente-Oakland; 🇺🇸 Oakland, California, United States

Rady Children's Hospital - San Diego; 🇺🇸 San Diego, California, United States

UCSF Medical Center-Mission Bay; 🇺🇸 San Francisco, California, United States

Children's Hospital Colorado; 🇺🇸 Aurora, Colorado, United States

Alfred I duPont Hospital for Children; 🇺🇸 Wilmington, Delaware, United States

Children's National Medical Center; 🇺🇸 Washington, District of Columbia, United States

University of Florida Health Science Center - Gainesville; 🇺🇸 Gainesville, Florida, United States

Nemours Children's Clinic-Jacksonville; 🇺🇸 Jacksonville, Florida, United States

Nicklaus Children's Hospital; 🇺🇸 Miami, Florida, United States

Arnold Palmer Hospital for Children; 🇺🇸 Orlando, Florida, United States

Nemours Children's Hospital; 🇺🇸 Orlando, Florida, United States

Saint Joseph's Hospital/Children's Hospital-Tampa; 🇺🇸 Tampa, Florida, United States

Children's Healthcare of Atlanta - Arthur M Blank Hospital; 🇺🇸 Atlanta, Georgia, United States

Lurie Children's Hospital-Chicago; 🇺🇸 Chicago, Illinois, United States

Riley Hospital for Children; 🇺🇸 Indianapolis, Indiana, United States

Johns Hopkins University/Sidney Kimmel Cancer Center; 🇺🇸 Baltimore, Maryland, United States

Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital; 🇺🇸 Grand Rapids, Michigan, United States

Mayo Clinic in Rochester; 🇺🇸 Rochester, Minnesota, United States

University of Mississippi Medical Center; 🇺🇸 Jackson, Mississippi, United States

Children's Mercy Hospitals and Clinics; 🇺🇸 Kansas City, Missouri, United States

Washington University School of Medicine; 🇺🇸 Saint Louis, Missouri, United States

Children's Hospital and Medical Center of Omaha; 🇺🇸 Omaha, Nebraska, United States

University of Nebraska Medical Center; 🇺🇸 Omaha, Nebraska, United States

Hackensack University Medical Center; 🇺🇸 Hackensack, New Jersey, United States

Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital; 🇺🇸 New Brunswick, New Jersey, United States

Newark Beth Israel Medical Center; 🇺🇸 Newark, New Jersey, United States

Albany Medical Center; 🇺🇸 Albany, New York, United States

Sanford Broadway Medical Center; 🇺🇸 Fargo, North Dakota, United States

Rainbow Babies and Childrens Hospital; 🇺🇸 Cleveland, Ohio, United States

University of Oklahoma Health Sciences Center; 🇺🇸 Oklahoma City, Oklahoma, United States

Children's Hospital of Philadelphia; 🇺🇸 Philadelphia, Pennsylvania, United States

Children's Hospital of Pittsburgh of UPMC; 🇺🇸 Pittsburgh, Pennsylvania, United States

Prisma Health Richland Hospital; 🇺🇸 Columbia, South Carolina, United States

Saint Jude Children's Research Hospital; 🇺🇸 Memphis, Tennessee, United States

Vanderbilt University/Ingram Cancer Center; 🇺🇸 Nashville, Tennessee, United States

Dell Children's Medical Center of Central Texas; 🇺🇸 Austin, Texas, United States

UT Southwestern/Simmons Cancer Center-Dallas; 🇺🇸 Dallas, Texas, United States

Cook Children's Medical Center; 🇺🇸 Fort Worth, Texas, United States

Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center; 🇺🇸 Houston, Texas, United States

M D Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

Children's Hospital of San Antonio; 🇺🇸 San Antonio, Texas, United States

University of Virginia Cancer Center; 🇺🇸 Charlottesville, Virginia, United States

Children's Hospital of The King's Daughters; 🇺🇸 Norfolk, Virginia, United States

Virginia Commonwealth University/Massey Cancer Center; 🇺🇸 Richmond, Virginia, United States

Seattle Children's Hospital; 🇺🇸 Seattle, Washington, United States

Mary Bridge Children's Hospital and Health Center; 🇺🇸 Tacoma, Washington, United States

Centre Hospitalier Universitaire Sainte-Justine; 🇨🇦 Montreal, Quebec, Canada