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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02135042




Registration number
NCT02135042
Ethics application status
Date submitted
7/05/2014
Date registered
9/05/2014
Date last updated
2/06/2020

Titles & IDs
Public title
Individualized Treatment in Treating Patients With Stage II-IVB Nasopharyngeal Cancer Based on EBV DNA
Scientific title
Randomized Phase II and Phase III Studies of Individualized Treatment for Nasopharyngeal Carcinoma Based on Biomarker Epstein Barr Virus (EBV) Deoxyribonucleic Acid (DNA)
Secondary ID [1] 0 0
NCI-2014-00635
Secondary ID [2] 0 0
NRG-HN001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Epstein-Barr Virus Infection 0 0
Stage II Nasopharyngeal Carcinoma 0 0
Stage III Nasopharyngeal Carcinoma 0 0
Stage IVA Nasopharyngeal Carcinoma 0 0
Stage IVB Nasopharyngeal Carcinoma 0 0
Condition category
Condition code
Infection 0 0 0 0
Other infectious diseases
Cancer 0 0 0 0
Non melanoma skin cancer
Cancer 0 0 0 0
Kidney
Cancer 0 0 0 0
Head and neck

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Cisplatin
Other interventions - Clinical Observation
Treatment: Drugs - Fluorouracil
Treatment: Drugs - Gemcitabine Hydrochloride
Treatment: Other - Intensity-Modulated Radiation Therapy
Other interventions - Laboratory Biomarker Analysis
Treatment: Drugs - Paclitaxel
Other interventions - Quality-of-Life Assessment

Active Comparator: Arm I (chemoradiation, cisplatin, fluorouracil) - 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.

Experimental: Arm II (chemoradiation, gemcitabine hydrochloride, paclitaxel) - 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.

Active Comparator: Arm III (chemoradiation, cisplatin, fluorouracil) - Patients receive PF regimen as in Arm I of Phase II.

Experimental: Arm IV (chemoradiation, observation) - Patients undergo clinical observation.


Treatment: Drugs: Cisplatin
Given IV

Other interventions: Clinical Observation
Undergo clinical observation

Treatment: Drugs: Fluorouracil
Given IV

Treatment: Drugs: Gemcitabine Hydrochloride
Given IV

Treatment: Other: Intensity-Modulated Radiation Therapy
Undergo IMRT

Other interventions: Laboratory Biomarker Analysis
Correlative studies

Treatment: Drugs: Paclitaxel
Given IV

Other interventions: Quality-of-Life Assessment
Ancillary studies

Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Other interventions
Intervention code [3] 0 0
Treatment: Other
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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.
Timepoint [1] 0 0
Up to 7 years
Primary outcome [2] 0 0
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.
Timepoint [2] 0 0
Up to 7 years
Secondary outcome [1] 0 0
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
Timepoint [1] 0 0
Baseline to up to 1 year
Secondary outcome [2] 0 0
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.
Timepoint [2] 0 0
Baseline to up to 24 months
Secondary outcome [3] 0 0
Changes in QOL (peripheral neuropathy) as assessed by the FACT-Taxane (Phase II and III)
Timepoint [3] 0 0
Baseline to up to 24 months
Secondary outcome [4] 0 0
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.
Timepoint [4] 0 0
Baseline to up to 24 months
Secondary outcome [5] 0 0
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.
Timepoint [5] 0 0
Up to 24 months
Secondary outcome [6] 0 0
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.
Timepoint [6] 0 0
Up to 7 years
Secondary outcome [7] 0 0
Incidence of death (Phase II and III)
Timepoint [7] 0 0
Up to 30 days of end of protocol treatment
Secondary outcome [8] 0 0
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.
Timepoint [8] 0 0
Up to 7 years
Secondary outcome [9] 0 0
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.
Timepoint [9] 0 0
Up to 7 years
Secondary outcome [10] 0 0
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.
Timepoint [10] 0 0
Up to 7 years
Secondary outcome [11] 0 0
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.
Timepoint [11] 0 0
Up to 7 years
Secondary outcome [12] 0 0
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.
Timepoint [12] 0 0
Up to 7 years
Secondary outcome [13] 0 0
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.
Timepoint [13] 0 0
Up to 7 years

Eligibility
Key inclusion criteria
- Biopsy proven (from primary lesion and/or lymph nodes) diagnosis of cancer of the
nasopharynx

- Patients must have detectable pretreatment plasma EBV DNA, determined by the central
lab prior to Step 2 registration

- Stage II-IVB disease (American Joint Committee on Cancer [AJCC], 7th edition [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 Ear, Nose, Throat specialist (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 with magnetic resonance imaging (MRI) of the
nasopharynx and neck within 28 days prior to registration; if MRI is medically
contraindicated, obtain computed tomography (CT) scan 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

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

- A CT scan with contrast of the chest, abdomen, and/or pelvis or a total body
positron emission tomography (PET)/CT scan (non-contrast PET/CT is
acceptable)

- 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) or 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
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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

- 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2/Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment postcode(s) [1] 0 0
3000 - Melbourne
Recruitment outside Australia
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United States of America
State/province [1] 0 0
Alabama
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United States of America
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Arizona
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California
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Colorado
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Connecticut
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Delaware
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Florida
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Georgia
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Hawaii
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Idaho
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Illinois
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Indiana
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Iowa
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Kansas
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Maryland
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Massachusetts
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Michigan
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Minnesota
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Missouri
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Nebraska
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Nevada
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New Jersey
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New York
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Ohio
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Oklahoma
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Oregon
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Pennsylvania
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South Carolina
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Texas
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Utah
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Virginia
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Washington
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United States of America
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Wisconsin
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Canada
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Alberta
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Canada
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Ontario
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Canada
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Quebec
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China
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Hong Kong
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China
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Shanghai
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China
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Guangzhou
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Hong Kong
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Chai Wan
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Puerto Rico
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San Juan
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Singapore
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Singapore
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Taiwan
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Taipei
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Taiwan
State/province [44] 0 0
Taoyuan

Funding & Sponsors
Primary sponsor type
Other
Name
NRG Oncology
Address
Country
Other collaborator category [1] 0 0
Government body
Name [1] 0 0
National Cancer Institute (NCI)
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief 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.
Trial website
https://clinicaltrials.gov/show/NCT02135042
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Nancy Lee
Address 0 0
NRG Oncology
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT02135042