A Study Using a New Drug, Nivolumab, in Combination With Chemotherapy Drugs to Treat a Type of Cancer Called Nasopharyngeal Carcinoma (NPC)

Study Overview
=================
Brief Summary
-----------------
This phase II trial tests how well nivolumab in combination with chemotherapy drugs along with radiation therapy works in treating patients with nasopharyngeal cancer. 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). 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 repeat 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.

Official Title
-----------------
A Phase 2 Study Using Chemoimmunotherapy With Gemcitabine, Cisplatin and Nivolumab in Newly Diagnosed Nasopharyngeal Carcinoma (NPC)

Conditions
-----------------
Stage II Nasopharyngeal Carcinoma AJCC v8, Stage III Nasopharyngeal Carcinoma AJCC v8, Stage IV Nasopharyngeal Carcinoma AJCC v8

Intervention / Treatment
-----------------
* Procedure: Biopsy
* Procedure: Biospecimen Collection
* Procedure: Chest Radiography
* Drug: Cisplatin
* Procedure: Computed Tomography
* Procedure: Echocardiography
* 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


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Maximum Age: 21 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (nivolumab, gemcitabine, cisplatin, radiattion)<br>See Detailed Description | Procedure: Biopsy<br>* Undergo tissue biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo blood and stool sample collection<br>* Other names: Specimen Collection;Procedure: Chest Radiography<br>* Undergo chest x-ray<br>* Other names: Chest X-ray;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Procedure: Computed Tomography<br>* Undergo CT<br>* Other names: tomography;Procedure: Echocardiography<br>* Undergo ECHO<br>* Other names: EC;Other: Electronic Health Record Review<br>* Ancillary studies<br>Other: Fluciclovine F18<br>* Given IV<br>* Other names: GE-148 F-18;Drug: Gemcitabine<br>* Given IV<br>* Other names: Difluorodeoxycytidine;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Procedure: Multigated Acquisition Scan<br>* Undergo MUGA<br>* Other names: Synchronized Multigated Acquisition Scanning;Biological: Nivolumab<br>* Given IV<br>* Other names: Opdivo;Procedure: Positron Emission Tomography<br>* Undergo PET<br>* Other names: PT;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Radiation: Radiation Therapy<br>* Receive radiation therapy<br>* Other names: Therapy, Radiation;Procedure: X-Ray Imaging<br>* Undergo dental x-ray<br>* Other names: X-Ray;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of grade 3 or higher immune-related adverse events (irAE) during induction chemoimmunotherapy (CIT) | 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. | Until the end of consolidation therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival (EFS) | 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). | 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 | 
| Objective response rate | Will be defined as the rate of responders among evaluable patients using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. | At the end of induction CIT | 
| Feasibility success of the induction regimen | 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. | At the end of induction CIT |