Individualized Treatment in Treating Patients With Stage II-IVB Nasopharyngeal Cancer Based on EBV DNA

Epstein-Barr Virus Infection Clinical Trial

Official title:

Randomized Phase II and Phase III Studies of Individualized Treatment for Nasopharyngeal Carcinoma Based on Biomarker Epstein Barr Virus (EBV) Deoxyribonucleic Acid (DNA)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02135042
• Other study ID #: NRG-HN001
• Secondary ID: NCI-2014-00635NR
• Status: Active, not recruiting
• Phase: Phase 2/Phase 3
• Start date: April 21, 2014
• Est. completion date: February 2031

Study information

• Verified date: October 2023
• Source: NRG Oncology
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

There are two study questions we are asking in this randomized phase II/III trial based on a blood biomarker, Epstein Barr virus (EBV) deoxyribonucleic acid (DNA) for locoregionally advanced non-metastatic nasopharyngeal cancer. All patients will first undergo standard concurrent chemotherapy and radiation therapy. When this standard treatment is completed, if there is no detectable EBV DNA in their plasma, then patients are randomized to either standard adjuvant cisplatin and fluorouracil chemotherapy or observation. If there is still detectable levels of plasma EBV DNA, patients will be randomized to standard cisplatin and fluorouracil chemotherapy versus gemcitabine and paclitaxel. Radiation therapy uses high energy x rays to kill tumor cells. Drugs used in chemotherapy, such as cisplatin, fluorouracil, gemcitabine hydrochloride, and paclitaxel 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. It is not yet known whether giving cisplatin and fluorouracil is more effective than gemcitabine hydrochloride and paclitaxel after radiation therapy in treating patients with nasopharyngeal cancer.

Description:

PRIMARY OBJECTIVES:

I. To determine whether substituting adjuvant concurrent high dose cisplatin (CDDP) and fluorouracil (5-FU) with gemcitabine (gemcitabine hydrochloride) and paclitaxel will result in superior progression-free survival. (Detectable Plasma Epstein Barr Virus [EBV] Deoxyribonucleic Acid [DNA] Cohort randomized Phase II) II. To determine whether omitting adjuvant CDDP and 5-FU (observation alone in the adjuvant setting) will result in non-inferior overall survival as compared with those patients receiving adjuvant CDDP and 5-FU chemotherapy. (Undetectable Plasma EBV DNA Cohort Phase III)

SECONDARY OBJECTIVES:

I. Time to distant metastasis. (Randomized Phase II and Phase III) II. Time to local progression. (Randomized Phase II and Phase III) III. Time to regional progression. (Randomized Phase II and Phase III) IV. Progression-free survival (Undetectable Cohort). V. Overall survival (Detectable Cohort). VI. Acute and late toxicity profiles based on clinician-reported Common Terminology Criteria for Adverse Events (CTCAE), version (v.) 4. (Randomized Phase II and Phase III) VII. Death during or within 30 days of end of protocol treatment. (Randomized Phase II and Phase III) VIII. Quality of life (general and physical well-being). (Randomized Phase II and Phase III) IX. Quality of life (hearing). (Randomized Phase II and Phase III) X. Quality of life (peripheral neuropathy). (Randomized Phase II and Phase III) XI. Cost effectiveness. (Randomized Phase II and Phase III)

OUTLINE:

Patients undergo intensity modulated radiation therapy (IMRT) once daily (QD) 5 days a week for 6.5 weeks and receive low-dose cisplatin intravenously (IV) over 30-60 minutes once weekly during IMRT. Beginning 1 week after chemoradiation, plasma samples are collected for EBV DNA analysis.

PHASE II: Patients with detectable EBV DNA from pre-treatment analysis are randomized to 1 of 2 treatment arms.

ARM I: Patients receive PF regimen comprising cisplatin IV over 60-120 minutes and fluorouracil IV over 96 hours continuously beginning at least 4 weeks after completion of IMRT. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive GT regimen comprising paclitaxel IV over 1 hour and gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 at least 4 weeks after completion of IMRT. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

PHASE III:

Patients with undetectable EBV DNA from pre-treatment analysis are randomized to 1 of 2 treatment arms.

ARM III: Patients receive PF regimen as in Arm I.

ARM IV: Patients undergo clinical observation.

After completion of study treatment, patients are followed up every 4 months for 2 years, every 6 months for 3 years, and then annually thereafter.

Other known NCT identifiers

• NCT02179164

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 685
• Est. completion date: February 2031
• Est. primary completion date: February 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Biopsy proven (from primary lesion and/or lymph nodes) diagnosis of cancer of the nasopharynx

• Sites are required to complete Step 1 registration before submitting specimens for EBV DNA analysis.

• Patients must have detectable pretreatment plasma EBV DNA, determined by the central lab prior to Step 2 registration (see Section 10.2 for details of specimen submission).

• For patients who have detectable plasma EBV DNA tested at one of the credentialed central labs (listed on the EBV DNA Testing Specimen Transmittal form) within 28 days prior to Step 1 registration: that test result can be used for eligibility without the need for re-testing. To use this test result for eligibility, the central lab must enter the test result through the pathology portal, and the site must follow the instructions in Section 5.4.

• Stage II-IVB disease (AJCC, 7th ed.) with no evidence of distant metastasis, based upon the following minimum diagnostic workup:

• History/physical examination by a Medical Oncologist or Clinical Oncologist or Radiation Oncologist or ENT, which must include an endoscopic evaluation, a complete list of current medications, and assessment of weight and weight loss in the past 6 months within 21 days prior to registration;

• Evaluation of tumor extent required within 28 days prior to registration:

• MRI of the nasopharynx and neck; or CT of the nasopharynx and neck with = 3 mm contiguous slices with contrast and bone windows (to evaluate base of skull involvement).

Note: If a treatment planning CT scan is used, it must be with = 3 mm contiguous slices with contrast and be read by a radiologist.

Please refer to section 6.3.2 for MRI requirement for target delineation.

• To rule out distant metastasis, patients must undergo the following imaging within 28 days prior to registration:

1. a CT scan with contrast of the chest and abdomen (required), and the pelvis (optional), or a total body PET/CT scan (non-contrast PET/CT is acceptable);

2. a bone scan only when there is suspicion of bone metastases (a PET/CT scan can substitute for the bone scan).

• Zubrod performance status 0-1 within 21 days prior to registration

• Absolute neutrophil count (ANC) = 1,500 cells/mm^3

• Platelets = 100,000 cells/mm^3

• Hemoglobin = 8.0 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] = 8.0 g/dl is acceptable)

• Total bilirubin = 1.5 x institutional upper limit of normal (ULN)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 1.5 x institutional ULN

• Alkaline phosphatase = 1.5 x institutional ULN

• Serum creatinine = 1.5 mg/dl or calculated creatinine clearance (CC) = 50 ml/min determined by 24-hour urine collection or estimated by Cockcroft-Gault formula

• Negative serum pregnancy test within 14 days prior to registration for women of childbearing potential

• Women of childbearing potential and male participants who are sexually active must agree to use a medically effective means of birth control throughout protocol treatment

• Patient must provide study specific informed consent prior to study entry, including the mandatory pre-treatment plasma EBV DNA assay

Exclusion Criteria:

• Prior invasive malignancy (except node negative, non-melanomatous skin cancer) unless disease free for a minimum of 1095 days (3 years) (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible)

• Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable; however, at least 6-weeks recovery is necessary if the last regimen included nitrosourea or mitomycin

• Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields

• Patients with hearing loss assessed to be primarily sensorineural in nature, requiring a hearing aid, or intervention (i.e. interfering in a clinically significant way with activities of daily living); a conductive hearing loss that is tumor-related is allowed

• = Grade 2 peripheral sensory neuropathy (CTCAE, v. 4.0)

• Severe, active co-morbidity, defined as follows:

• Major medical or psychiatric illness, which in the investigator's opinion would interfere with the completion of therapy and follow up or with full understanding of the risks and potential complications of the therapy

• Unstable angina and/or uncontrolled congestive heart failure within the past 6 months

• Myocardial infarction within the last 6 months

• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration; note that patients switched from IV antibiotics and currently on oral antibiotics whose infection is assessed to be adequately treated or controlled are eligible

• Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days prior to registration

• Acquired Immune Deficiency Syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that Human Immunodeficiency Virus (HIV) testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive.

• Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception

• Prior allergic reaction to the study drug(s) involved in this protocol

• Patients with undetectable pre-treatment plasma EBV DNA

Related Conditions & MeSH terms

• Carcinoma
• Epstein-Barr Virus Infection
• Epstein-Barr Virus Infections
• Nasopharyngeal Carcinoma
• Stage II Nasopharyngeal Carcinoma
• Stage III Nasopharyngeal Carcinoma
• Stage IVA Nasopharyngeal Carcinoma
• Stage IVB Nasopharyngeal Carcinoma

Intervention

Drug:
• Cisplatin
Given IV

Other:
• Clinical Observation
Undergo clinical observation

Drug:
• Fluorouracil
Given IV
• Gemcitabine Hydrochloride
Given IV

Radiation:
• Intensity-Modulated Radiation Therapy
Undergo IMRT

Other:
• Laboratory Biomarker Analysis
Correlative studies

Drug:
• Paclitaxel
Given IV

Other:
• Quality-of-Life Assessment
Ancillary studies

Locations

Country	Name	City	State
Australia	Peter MacCallum Cancer Centre	Melbourne	Victoria
Canada	Tom Baker Cancer Centre	Calgary	Alberta
Canada	Cross Cancer Institute	Edmonton	Alberta
Canada	London Regional Cancer Program	London	Ontario
Canada	Jewish General Hospital	Montreal	Quebec
Canada	McGill University Department of Oncology	Montreal	Quebec
Canada	The Research Institute of the McGill University Health Centre (MUHC)	Montreal	Quebec
Canada	University Health Network-Princess Margaret Hospital	Toronto	Ontario
China	Zhongshan Hospital Fudan University	Guangdong Province	Shanghai
China	Sun Yat-sen University Cancer Center	Guangzhou
China	Chinese University of Hong Kong-Prince of Wales Hospital	Shatin	Hong Kong
Hong Kong	Pamela Youde Nethersole Eastern Hospital	Chai Wan
Puerto Rico	Centro Comprensivo de Cancer de UPR	San Juan
Singapore	National Cancer Centre Singapore	Singapore
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Chang Gung Hospital-Lin Kou Medical Center	Taoyuan
United States	The Cancer Center of Hawaii-Pali Momi	'Aiea	Hawaii
United States	Cleveland Clinic Akron General	Akron	Ohio
United States	American Fork Hospital / Huntsman Intermountain Cancer Center	American Fork	Utah
United States	Saint Joseph Mercy Hospital	Ann Arbor	Michigan
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	Langlade Hospital and Cancer Center	Antigo	Wisconsin
United States	Emory Proton Therapy Center	Atlanta	Georgia
United States	Emory Saint Joseph's Hospital	Atlanta	Georgia
United States	Emory University Hospital Midtown	Atlanta	Georgia
United States	Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia
United States	Sutter Cancer Centers Radiation Oncology Services-Auburn	Auburn	California
United States	Rush - Copley Medical Center	Aurora	Illinois
United States	Greater Baltimore Medical Center	Baltimore	Maryland
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	Memorial Sloan Kettering Basking Ridge	Basking Ridge	New Jersey
United States	McLaren Cancer Institute-Bay City	Bay City	Michigan
United States	Alta Bates Summit Medical Center-Herrick Campus	Berkeley	California
United States	The Kirklin Clinic at Acton Road	Birmingham	Alabama
United States	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama
United States	Prisma Health Cancer Institute - Spartanburg	Boiling Springs	South Carolina
United States	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho
United States	Boston Medical Center	Boston	Massachusetts
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Tufts Medical Center	Boston	Massachusetts
United States	Montefiore Medical Center - Moses Campus	Bronx	New York
United States	Montefiore Medical Center-Einstein Campus	Bronx	New York
United States	Maimonides Medical Center	Brooklyn	New York
United States	New York-Presbyterian/Brooklyn Methodist Hospital	Brooklyn	New York
United States	Henry Ford Cancer Institute-Downriver	Brownstown	Michigan
United States	Mills-Peninsula Medical Center	Burlingame	California
United States	Fairview Ridges Hospital	Burnsville	Minnesota
United States	Minnesota Oncology - Burnsville	Burnsville	Minnesota
United States	Saint James Community Hospital and Cancer Treatment Center	Butte	Montana
United States	Sutter Cancer Centers Radiation Oncology Services-Cameron Park	Cameron Park	California
United States	Saint Joseph Mercy Canton	Canton	Michigan
United States	Saint Francis Medical Center	Cape Girardeau	Missouri
United States	Sandra L Maxwell Cancer Center	Cedar City	Utah
United States	Christiana Care Health System-Concord Health Center	Chadds Ford	Pennsylvania
United States	Geauga Hospital	Chardon	Ohio
United States	John H Stroger Jr Hospital of Cook County	Chicago	Illinois
United States	Northwestern University	Chicago	Illinois
United States	University of Cincinnati Cancer Center-UC Medical Center	Cincinnati	Ohio
United States	McLaren Cancer Institute-Clarkston	Clarkston	Michigan
United States	Case Western Reserve University	Cleveland	Ohio
United States	Cleveland Clinic Cancer Center/Fairview Hospital	Cleveland	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Henry Ford Macomb Hospital-Clinton Township	Clinton Township	Michigan
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Memorial Sloan Kettering Commack	Commack	New York
United States	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Cancer Care Specialists of Illinois - Decatur	Decatur	Illinois
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Iowa Methodist Medical Center	Des Moines	Iowa
United States	Henry Ford Hospital	Detroit	Michigan
United States	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	Kaiser Permanente Dublin	Dublin	California
United States	HSHS Sacred Heart Hospital	Eau Claire	Wisconsin
United States	Marshfield Medical Center-EC Cancer Center	Eau Claire	Wisconsin
United States	Crossroads Cancer Center	Effingham	Illinois
United States	Mercy Cancer Center-Elyria	Elyria	Ohio
United States	Inova Schar Cancer Institute	Fairfax	Virginia
United States	Inova Fairfax Hospital	Falls Church	Virginia
United States	Weisberg Cancer Treatment Center	Farmington Hills	Michigan
United States	McLaren Cancer Institute-Flint	Flint	Michigan
United States	Singh and Arora Hematology Oncology PC	Flint	Michigan
United States	Fresno Cancer Center	Fresno	California
United States	Unity Hospital	Fridley	Minnesota
United States	SCL Health Cancer Centers of Colorado - Lutheran Medical Center	Golden	Colorado
United States	North Colorado Medical Center	Greeley	Colorado
United States	Prisma Health Cancer Institute - Eastside	Greenville	South Carolina
United States	Prisma Health Cancer Institute - Faris	Greenville	South Carolina
United States	Saint Francis Cancer Center	Greenville	South Carolina
United States	Gibbs Cancer Center-Pelham	Greer	South Carolina
United States	Prisma Health Cancer Institute - Greer	Greer	South Carolina
United States	Legacy Mount Hood Medical Center	Gresham	Oregon
United States	Memorial Sloan Kettering Westchester	Harrison	New York
United States	Queen's Medical Center	Honolulu	Hawaii
United States	The Cancer Center of Hawaii-Liliha	Honolulu	Hawaii
United States	M D Anderson Cancer Center	Houston	Texas
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	Baptist MD Anderson Cancer Center	Jacksonville	Florida
United States	Gundersen Lutheran Medical Center	La Crosse	Wisconsin
United States	UC San Diego Moores Cancer Center	La Jolla	California
United States	Karmanos Cancer Institute at McLaren Greater Lansing	Lansing	Michigan
United States	Mid-Michigan Physicians-Lansing	Lansing	Michigan
United States	Sparrow Hospital	Lansing	Michigan
United States	McLaren Cancer Institute-Lapeer Region	Lapeer	Michigan
United States	Radiation Oncology Centers of Nevada Central	Las Vegas	Nevada
United States	Radiation Oncology Centers of Nevada Southeast	Las Vegas	Nevada
United States	Geisinger Medical Oncology-Lewisburg	Lewisburg	Pennsylvania
United States	Lewistown Hospital	Lewistown	Pennsylvania
United States	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan
United States	Logan Regional Hospital	Logan	Utah
United States	McKee Medical Center	Loveland	Colorado
United States	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin
United States	Cleveland Clinic Cancer Center Mansfield	Mansfield	Ohio
United States	Minnesota Oncology Hematology PA-Maplewood	Maplewood	Minnesota
United States	Marshfield Medical Center	Marshfield	Wisconsin
United States	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin
United States	Memorial Sloan Kettering Monmouth	Middletown	New Jersey
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Abbott-Northwestern Hospital	Minneapolis	Minnesota
United States	Hennepin County Medical Center	Minneapolis	Minnesota
United States	Marshfield Clinic-Minocqua Center	Minocqua	Wisconsin
United States	Memorial Medical Center	Modesto	California
United States	Memorial Sloan Kettering Bergen	Montvale	New Jersey
United States	McLaren Cancer Institute-Macomb	Mount Clemens	Michigan
United States	McLaren Cancer Institute-Central Michigan	Mount Pleasant	Michigan
United States	Intermountain Medical Center	Murray	Utah
United States	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey
United States	Yale University	New Haven	Connecticut
United States	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	New York Proton Center	New York	New York
United States	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York
United States	Christiana Care Health System-Christiana Hospital	Newark	Delaware
United States	Helen F Graham Cancer Center	Newark	Delaware
United States	Rutgers New Jersey Medical School	Newark	New Jersey
United States	Kaiser Permanente Oakland-Broadway	Oakland	California
United States	McKay-Dee Hospital Center	Ogden	Utah
United States	Mercy Hospital Oklahoma City	Oklahoma City	Oklahoma
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Nebraska Methodist Hospital	Omaha	Nebraska
United States	UC Irvine Health/Chao Family Comprehensive Cancer Center	Orange	California
United States	Palo Alto Medical Foundation Health Care	Palo Alto	California
United States	Stanford Cancer Institute Palo Alto	Palo Alto	California
United States	Parker Adventist Hospital	Parker	Colorado
United States	McLaren Cancer Institute-Northern Michigan	Petoskey	Michigan
United States	Saint Joseph Mercy Oakland	Pontiac	Michigan
United States	McLaren-Port Huron	Port Huron	Michigan
United States	Legacy Good Samaritan Hospital and Medical Center	Portland	Oregon
United States	Naval Medical Center - Portsmouth	Portsmouth	Virginia
United States	Geisinger Cancer Services-Pottsville	Pottsville	Pennsylvania
United States	Utah Valley Regional Medical Center	Provo	Utah
United States	Kaiser Permanente-Rancho Cordova Cancer Center	Rancho Cordova	California
United States	Renown Regional Medical Center	Reno	Nevada
United States	Saint Mary's Regional Medical Center	Reno	Nevada
United States	Marshfield Medical Center-Rice Lake	Rice Lake	Wisconsin
United States	Riverton Hospital	Riverton	Utah
United States	North Memorial Medical Health Center	Robbinsdale	Minnesota
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	University of Rochester	Rochester	New York
United States	Rohnert Park Cancer Center	Rohnert Park	California
United States	Delbert Day Cancer Institute at PCRMC	Rolla	Missouri
United States	Sutter Cancer Centers Radiation Oncology Services-Roseville	Roseville	California
United States	The Permanente Medical Group-Roseville Radiation Oncology	Roseville	California
United States	South Sacramento Cancer Center	Sacramento	California
United States	Sutter Medical Center Sacramento	Sacramento	California
United States	University of California Davis Comprehensive Cancer Center	Sacramento	California
United States	Ascension Saint Mary's Hospital	Saginaw	Michigan
United States	Saint George Regional Medical Center	Saint George	Utah
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Siteman Cancer Center-South County	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Regions Hospital	Saint Paul	Minnesota
United States	Siteman Cancer Center at Saint Peters Hospital	Saint Peters	Missouri
United States	Utah Cancer Specialists-Salt Lake City	Salt Lake City	Utah
United States	California Pacific Medical Center-Pacific Campus	San Francisco	California
United States	UCSF Medical Center-Mission Bay	San Francisco	California
United States	UCSF Medical Center-Mount Zion	San Francisco	California
United States	North Coast Cancer Care	Sandusky	Ohio
United States	Kaiser Permanente Medical Center - Santa Clara	Santa Clara	California
United States	Prisma Health Cancer Institute - Seneca	Seneca	South Carolina
United States	Memorial Sloan Kettering Sleepy Hollow	Sleepy Hollow	New York
United States	Memorial Hospital of South Bend	South Bend	Indiana
United States	City of Hope South Pasadena	South Pasadena	California
United States	Kaiser Permanente Cancer Treatment Center	South San Francisco	California
United States	Spartanburg Medical Center	Spartanburg	South Carolina
United States	CoxHealth South Hospital	Springfield	Missouri
United States	Memorial Medical Center	Springfield	Illinois
United States	Mercy Hospital Springfield	Springfield	Missouri
United States	Ascension Saint Michael's Hospital	Stevens Point	Wisconsin
United States	Marshfield Medical Center-River Region at Stevens Point	Stevens Point	Wisconsin
United States	Cleveland Clinic Cancer Center Strongsville	Strongsville	Ohio
United States	Palo Alto Medical Foundation-Sunnyvale	Sunnyvale	California
United States	ProMedica Flower Hospital	Sylvania	Ohio
United States	Moffitt Cancer Center	Tampa	Florida
United States	Banner University Medical Center - Tucson	Tucson	Arizona
United States	Memorial Sloan Kettering Nassau	Uniondale	New York
United States	Carle Cancer Center	Urbana	Illinois
United States	Sutter Cancer Centers Radiation Oncology Services-Vacaville	Vacaville	California
United States	Legacy Salmon Creek Hospital	Vancouver	Washington
United States	Aspirus Regional Cancer Center	Wausau	Wisconsin
United States	Henry Ford West Bloomfield Hospital	West Bloomfield	Michigan
United States	University of Cincinnati Cancer Center-West Chester	West Chester	Ohio
United States	Reading Hospital	West Reading	Pennsylvania
United States	UHHS-Westlake Medical Center	Westlake	Ohio
United States	Diagnostic and Treatment Center	Weston	Wisconsin
United States	Marshfield Medical Center - Weston	Weston	Wisconsin
United States	SCL Health Lutheran Medical Center	Wheat Ridge	Colorado
United States	Ascension Via Christi Hospitals Wichita	Wichita	Kansas
United States	Wesley Medical Center	Wichita	Kansas
United States	Geisinger Wyoming Valley/Henry Cancer Center	Wilkes-Barre	Pennsylvania
United States	Rice Memorial Hospital	Willmar	Minnesota
United States	Aspirus Cancer Care - Wisconsin Rapids	Wisconsin Rapids	Wisconsin
United States	Cleveland Clinic Wooster Family Health and Surgery Center	Wooster	Ohio

Sponsors (2)

Lead Sponsor	Collaborator
NRG Oncology	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Australia,  Canada,  China,  Hong Kong,  Puerto Rico,  Singapore,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival (OS) (Undetectable Plasma EBV DNA Cohort Phase III)	Estimated using the Kaplan-Meier method for each arm. Their distributions will be compared between treatment arms with a 1-sided log rank test. The confidence interval approach will be used for the final analysis of OS.	Up to 7 years
Primary	Progression-free survival (PFS) (Detectable Plasma EBV DNA Cohort Phase II)	Estimated using the Kaplan-Meier method for each arm. Their distributions will be compared between treatment arms with a 1-sided log rank test. A one-sided log rank test will be used to compare the PFS at a significance level of 0.1379.	Up to 7 years
Secondary	Changes in pure tone audiometry (Phase II and III)	Correlation between categorical measures will be summarized by odds ratios, chi-square tests, and associated measures. Adjusted correlation may be derived from analysis of covariance (ANCOVA) models or derived directly using nonparametric analysis of variance (ANOVA) models if normality assumption is violated. Correlations between HHIE-S PRO scores and PTA and FACT-NP hearing, and PTA will be compared as dependent statistics	Baseline to up to 1 year
Secondary	Changes in QOL (hearing) as assessed by the Hearing Handicap Inventory for the Elderly-Screening version (HHIE-S) (Phase II and III)	QOL analysis including overall score and change from baseline will be summarized using mean and standard deviation at each time point for each arm. Overall and nasopharyngeal-specific QOL, hearing QOL (FACT-NP hearing domain, HHIE-S scores), peripheral neuropathy QOL over the short and long term and pure-tone audiometry (PTA) scores will be compared using a two sample independent t test and paired t test if the comparison is within the experimental arm between different time points.	Baseline to up to 24 months
Secondary	Changes in QOL (peripheral neuropathy) as assessed by the FACT-Taxane (Phase II and III)		Baseline to up to 24 months
Secondary	Changes in quality of life (QOL) (general and physical well-being) assessed using the Functional Assessment of Cancer Therapy (FACT)-Nasopharyngeal (NP) (Phase II and III)	Changes in patient reported outcome (PRO) scores will be correlated to clearance or non-clearance of EBV titers. Descriptive statistics derived from FACT-NP will be used to enrich the understanding of QOL as it pertains to the 2 phase III arms of observation versus additional adjuvant chemotherapy. Univariable and multivariable analysis will be performed using the Cox proportional hazards model for OS and distant metastasis. Pearson correlation will be estimated between general and physical well-being. QOL measures and change from baseline will be correlated to EBV DNA.	Baseline to up to 24 months
Secondary	Cost effectiveness as assessed by the health-related QOL (HRQOL) from the EuroQol (EQ-5D) instrument (Phase II and III)	Incremental cost effectiveness ratios will be compared to determine the probability of cost effectiveness of various interventions, with sensitivity analyses to identify model weaknesses. The expected value of perfect information will be determined to delimit the upper boundary for cost-effective future investment in this area of research.	Up to 24 months
Secondary	Incidence of acute grade 3-5 adverse events (Phase II and III)	Rates of specific acute toxicity profiles and late toxicity profiles will be estimated using a binomial distribution along with their associated 95% confidence intervals and will be compared using Fisher's exact test between the 2 treatment arms.	Up to 7 years
Secondary	Incidence of death (Phase II and III)		Up to 30 days of end of protocol treatment
Secondary	Incidence of late grade 3-5 adverse events (Phase II and III)	Rates of specific acute toxicity profiles and late toxicity profiles will be estimated using a binomial distribution along with their associated 95% confidence intervals and will be compared using Fisher's exact test between the 2 treatment arms.	Up to 7 years
Secondary	OS (Detectable Plasma EBV DNA Cohort Phase II)	Estimated using the Kaplan-Meier method for each arm. Their distributions will be compared between treatment arms with a 1-sided log rank test.	Up to 7 years
Secondary	PFS (Undetectable Plasma EBV DNA Cohort Phase III)	Estimated using the Kaplan-Meier method for each arm. Their distributions will be compared between treatment arms with a 1-sided log rank test.	Up to 7 years
Secondary	Time to distant metastasis (DM) (Phase II and III)	The cumulative incidence method will be used to estimate local, regional, and distant failure rates. The failure rates for the experimental treatment will be compared against the control using a failure-specific log-rank test. Multivariate analysis will be performed using the Cox proportional hazards model.	Up to 7 years
Secondary	Time to local progression (Phase II and III)	The cumulative incidence method will be used to estimate local, regional, and distant failure rates. The failure rates for the experimental treatment will be compared against the control using a failure-specific log-rank test. Multivariate analysis will be performed using the Cox proportional hazards model.	Up to 7 years
Secondary	Time to regional progression (Phase II and III)	Defined as an estimated increase in the size of the tumor (product of the perpendicular diameters of the two largest dimensions) of greater than 25%, taking as reference the smallest value of all previous measurements or appearance of new areas of malignant disease. The cumulative incidence method will be used to estimate local, regional, and distant failure rates. The failure rates for the experimental treatment will be compared against the control using a failure-specific log-rank test. Multivariate analysis will be performed using the Cox proportional hazards model.	Up to 7 years