Radiation Therapy, Amifostine, and Chemotherapy in Treating Young Patients With Newly Diagnosed Nasopharyngeal Cancer

Study Overview
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Brief Summary
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This phase III trial is studying how well radiation therapy, amifostine, and chemotherapy work in treating young patients with newly diagnosed nasopharyngeal cancer. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs, such as amifostine, may protect normal cells from the side effects of radiation therapy. Drugs used in chemotherapy, such as cisplatin and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving radiation therapy together with amifostine and chemotherapy may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the response rate, overall survival, and event-free survival of children with advanced nasopharyngeal carcinoma who are treated with induction chemotherapy followed by concurrent chemoradiotherapy and amifostine. SECONDARY OBJECTIVES: I. Characterize the role of Epstein-Barr virus (EBV) in the pathogenesis of nasopharyngeal carcinoma in children. II. Investigate the predictive value of the detection of EBV DNA in the peripheral blood of children with nasopharyngeal carcinoma. III. Determine the incidence of NUT rearrangements in childhood nasopharyngeal carcinoma. IV. Determine the radioprotective effect of amifostine when given daily prior to radiation therapy. OUTLINE: This is a nonrandomized, multicenter study. Patients are stratified according to stage of disease (I or IIA [stratum I] vs IIB-IV [stratum II]). STRATUM I: Patients undergo radiotherapy 5 days a week for 8 weeks. Patients also receive amifostine subcutaneously on the same days they undergo radiotherapy. STRATUM II: INDUCTION THERAPY (weeks 1-9): Patients receive cisplatin IV over 6 hours on day 1 and fluorouracil IV continuously on days 1-4. Treatment repeats every 3 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. Patients with responding or stable disease proceed to consolidation therapy. CONSOLIDATION THERAPY (weeks 10-18): Patients undergo radiotherapy and receive amifostine as in stratum I. Patients also receive cisplatin IV over 6 hours on days 1 and 22 (2 courses). After completion of study treatment, patients are followed periodically for 10 years.

Official Title
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Treatment of Childhood Nasopharyngeal Carcinoma With Neoadjuvant Chemotherapy and Concomitant Chemoradiotherapy: A Groupwide Phase III Study

Conditions
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Stage I Nasopharyngeal Keratinizing Squamous Cell Carcinoma AJCC v7, Stage I Nasopharyngeal Undifferentiated Carcinoma AJCC v7, Stage II Nasopharyngeal Keratinizing Squamous Cell Carcinoma AJCC v7, Stage II Nasopharyngeal Undifferentiated Carcinoma AJCC v7, Stage III Nasopharyngeal Keratinizing Squamous Cell Carcinoma AJCC v7, Stage III Nasopharyngeal Undifferentiated Carcinoma AJCC v7, Stage IV Nasopharyngeal Keratinizing Squamous Cell Carcinoma AJCC v7, Stage IV Nasopharyngeal Undifferentiated Carcinoma AJCC v7

Intervention / Treatment
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* Drug: Amifostine
* Drug: Cisplatin
* Drug: Fluorouracil
* Other: Laboratory Biomarker Analysis
* Radiation: Radiation Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological diagnosis of nasopharyngeal carcinoma WHO type II or III Stage I-IV disease Newly diagnosed disease Performance status Patients ≤ 16 years of age: Lansky 60-100% Patients > 16 years of age: Karnofsky 60-100% Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min Creatinine based on age/gender as follows: No greater than 0.4 mg/dL (for patients 1 month to < 6 months of age) No greater than 0.5 mg/dL (for patients 6 months to < 1 year of age) No greater than 0.6 mg/dL (for patients 1-2 years of age) No greater than 0.8 mg/dL (for patients < 6 years of age) No greater than 1.0mg/dL (for patients 6 to < 10 years of age) No greater than 1.2 mg/dL (for patients 10 to < 13 years of age) No greater than 1.4 mg/dL (for female patients 13 to ≥ 16 years of age) No greater than 1.5 mg/dL (for male patients 13 to < 16 years of age) No greater than 1.7 mg/dL (for male patients ≥ 16 years of age) Bilirubin ≤ 1.5 times upper limit of normal (ULN) for age AST or ALT < 2.5 times ULN for age Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No prior chemotherapy or radiotherapy to the nasopharynx or neck for the treatment of nasopharyngeal carcinoma

Ages Eligible for Study
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Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stratum I (radiotherapy, chemoprotective agent)<br>Patients undergo radiotherapy 5 days a week for 8 weeks. Patients also receive amifostine subcutaneously on the same days they undergo radiotherapy. | Drug: Amifostine<br>* Given subcutaneously<br>* Other names: YM-08310;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Radiation: Radiation Therapy<br>* Undergo radiotherapy<br>* Other names: Therapy, Radiation;|
| Experimental: Stratum II (chemotherapy, chemoprotective agent, radiotherapy)<br>Patients receive cisplatin IV over 6 hours on day 1 and fluorouracil IV continuously on days 1-4. Treatment repeats every 3 weeks for 3 courses. In weeks 10-18, patients undergo radiotherapy and receive amifostine as in stratum I. Patients also receive 3 courses of cisplatin as before. | Drug: Amifostine<br>* Given subcutaneously<br>* Other names: YM-08310;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Fluorouracil<br>* Given IV<br>* Other names: Ro-2-9757;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Radiation: Radiation Therapy<br>* Undergo radiotherapy<br>* Other names: Therapy, Radiation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Two Year Event-free Survival (EFS) | The two-year event-free survival will be compared with a standard established from adult oncology data and the results of POG-9486. The two-year Kaplan-Meier estimate of event-free survival will be compared with 70% using a 1-sided test of size 0.05 using the asymptotic distribution of the complementary log-log distribution of the estimate. | Up to Two Year After Enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Predictive Value of Epstein-Barr Virus (EBV) DNA as Measured by Quantitative Detection at Enrollment on EFS 2 Years After Treatment | Presence of EBV DNA in serum. | At study enrollment | 
| Prognostic Significance of EBV Viral Load | Viral load in blood. | At study enrollment | 
| Predictive Value of the Detection of EBV DNA in the Peripheral Blood | The prognostic value of the presence of EBV DNA will be assessed using the log-rank test, adjusted by initial stage of disease, if appropriate. The proposed analysis will take place at the analytic endpoint of the clinical trial. | Up to 6 years | 
| Protective Effects of Amifostine Assessed Primarily by Sialometry | Weight of stimulated saliva production in grams. | At study enrollment | 
| Protective Effects of Amifostine Assessed Primarily by Sialometry: Weight of Unstimulated Saliva Production in Grams. | Weight of unstimulated saliva production in grams. | At study enrollment |