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Trial record 1 of 1 for:    NCT02254278
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Reduced-Dose Intensity-Modulated Radiation Therapy With or Without Cisplatin in Treating Patients With Advanced Oropharyngeal Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
NRG Oncology
ClinicalTrials.gov Identifier:
NCT02254278
First received: September 29, 2014
Last updated: March 2, 2017
Last verified: March 2017
  Purpose
This randomized phase II trial studies the side effects and how well modestly reduced-dose intensity-modulated radiation therapy (IMRT) with or without cisplatin works in treating patients with oropharyngeal cancer that has spread to other places in the body (advanced). Radiation therapy uses high energy x rays to kill tumor cells. Drugs used in chemotherapy, such as 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. It is not yet known whether IMRT is more effective with or without cisplatin in treating patients with oropharyngeal cancer.

Condition Intervention Phase
Stage III Oropharyngeal Squamous Cell Carcinoma
Stage IVA Oropharyngeal Squamous Cell Carcinoma
Stage IVB Oropharyngeal Squamous Cell Carcinoma
Stage IVC Oropharyngeal Squamous Cell Carcinoma
Tongue Carcinoma
Drug: Cisplatin
Radiation: Intensity-Modulated Radiation Therapy
Other: Laboratory Biomarker Analysis
Other: Quality-of-Life Assessment
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single Blind (masked role unspecified)
Primary Purpose: Treatment
Official Title: A Randomized Phase II Trial for Patients With p16 Positive, Non-Smoking Associated, Locoregionally Advanced Oropharyngeal Cancer

Resource links provided by NLM:


Further study details as provided by NRG Oncology:

Primary Outcome Measures:
  • Incidence of grade >= 3 modified barium swallow (MBS) detected dysphagia assessed by Common Terminology Criteria for Adverse Events [CTCAE], version [v].4 [ Time Frame: 2 years after de-escalated IMRT ]
  • PFS [ Time Frame: Time of randomization to local-regional failure, distant metastasis, or death due to any causes, assessed at 2 years ]
    PFS rates will be estimated for all treatment arms using the Kaplan-Meier method. One sample binomial test will be used to test the 2-year PFS for each arm. Multivariate analysis will be performed using the Cox proportional hazards model.


Secondary Outcome Measures:
  • Distant metastasis [ Time Frame: At 6 months ]
    The cumulative incidence method will be used to estimate locoregional and distant failure rates and 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.

  • Distant metastasis [ Time Frame: At 2 years ]
    The cumulative incidence method will be used to estimate locoregional and distant failure rates and 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.

  • HPV DNA copy number [ Time Frame: Baseline to up to 2 weeks after the completion of treatment ]
    Correlation between HPV DNA copy number and the nodal metabolic volume will be calculated using Spearman's correlation coefficient and R2, and the corresponding 95% CI will be provided.

  • HPV DNA rate decline [ Time Frame: Baseline to up to 2 weeks after the completion of treatment ]
    With a two-sided type error rate of 5% and based on paired t test for means, there is 99% power to detect HPV DNA rate decline of 0.375 (effect size) within each arm (n=140). The HPV DNA rate for each group will be summarized using means and standard deviations.

  • Human papillomavirus (HPV) deoxyribonucleic acid (DNA) detection rate [ Time Frame: Baseline to up to 2 weeks after the completion of treatment ]
    With a two-sided type error rate of 5% and based on chi-squared test for proportions, there is a greater than 99% power to detect HPV DNA detection rate of 65% and 95% between the 2 groups (n=140 in each arm). The rate of detection for each group will be summarized based on binomial distributions and a 95% confidence intervals (CI) will be provided.

  • Incidence of acute toxicities (>= grade 3, CTCAE v.4) [ Time Frame: At 6 weeks ]
    Rates of adverse events (>= grade 3, CTCAE, v.4) for acute toxicities 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.

  • Incidence of acute toxicities (>= grade 3, CTCAE, v.4) [ Time Frame: At 1 month ]
    Rates of adverse events (>= grade 3, CTCAE, v.4) for acute toxicities 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.

  • Incidence of acute toxicities (>= grade 3, CTCAE, v.4) [ Time Frame: At 6 months ]
    Rates of adverse events (>= grade 3, CTCAE, v.4) for acute toxicities 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.

  • Incidence of late toxicities (>= grade 3, CTCAE, v.4) [ Time Frame: At 1 year ]
    Rates of adverse events (>= grade 3, CTCAE, v.4) for late toxicities 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.

  • Incidence of late toxicities (>= grade 3, CTCAE, v.4) [ Time Frame: At 2 years ]
    Rates of adverse events (>= grade 3, CTCAE, v.4) for late toxicities 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.

  • Local-regional failure [ Time Frame: At 6 months ]
    The failure rates for the experimental treatment will be compared against the control using a log rank test. The cumulative incidence method will be used to estimate locoregional and distant failure rates and 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.

  • Local-regional failure [ Time Frame: At 2 years ]
    The failure rates for the experimental treatment will be compared against the control using a log rank test. The cumulative incidence method will be used to estimate locoregional and distant failure rates and 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.

  • Negative predictive value (NPV) of FDG-PET/CT [ Time Frame: 12-14 weeks post-therapy ]
    The power is calculated to detect a minimum difference of 3% between the NPV under the null hypothesis of 90%-92% and the NPV under the alternative hypothesis of 93-95% using a one-sided Z-test at a significance level of 0.05.

  • Overall survival [ Time Frame: At 6 months ]
    Will be estimated using the Kaplan-Meier method.

  • Overall survival [ Time Frame: At 2 years ]
    Will be estimated using the Kaplan-Meier method.

  • Patient-reported swallowing outcomes as assessed by the mean individual change in total MDADI score [ Time Frame: Baseline to up to 1 year ]
    Correlation between MDADI and dysphagia as well as other variables will be calculated using Spearman's correlation coefficient and the corresponding p values will be reported. Correlation between categorical measures will be summarized by odds ratios, chi square tests, and associated measures. Adjusted correlation may be derived from ANCOVA models or derived directly using nonparametric ANOVA models if normality assumption is violated. If comparison to historical control is needed, a one-sample t test will be utilized.

  • Patient-reported swallowing outcomes as assessed by the mean individual change in total MDADI score [ Time Frame: Baseline to up to 2 years ]
    Correlation between MDADI and dysphagia as well as other variables will be calculated using Spearman's correlation coefficient and the corresponding p values will be reported. Correlation between categorical measures will be summarized by odds ratios, chi square tests, and associated measures. Adjusted correlation may be derived from ANCOVA models or derived directly using nonparametric ANOVA models if normality assumption is violated. If comparison to historical control is needed, a one-sample t test will be utilized.

  • Patient-reported swallowing outcomes as measured by the change in total MDADI score [ Time Frame: Baseline to up to 6 months ]
    Correlation between MDADI and dysphagia as well as other variables will be calculated using Spearman's correlation coefficient and the corresponding p values will be reported. 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. If comparison to historical control is needed, a one-sample t test will be utilized.

  • Variance for HPV DNA [ Time Frame: Baseline to up to 2 weeks after the completion of treatment ]
    Univariable and multivariable cause specific analysis will be performed using the Cox proportional hazards model for rate of relapse.


Other Outcome Measures:
  • Change in dysphagia scores as detected by modified barium swallow study and rated by Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) [ Time Frame: Baseline to 2 years after de-escalated RT ]
  • Predictive model for DIGEST grade >= 3 MBS detected dysphagia [ Time Frame: 2 years after de-escalated RT ]
    Will be developed per age, tumor characteristics, treatment parameters (including use of concurrent chemotherapy), early toxicity profiles (clinician and provider graded).


Enrollment: 295
Study Start Date: October 2014
Estimated Primary Completion Date: May 31, 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (IMRT, cisplatin)
Patients undergo IMRT QD five days a week for 6 weeks to a total dose of 60 Gy and receive cisplatin IV over 30-60 minutes weekly during radiation therapy for 6 doses in the absence of disease progression or unacceptable toxicity.
Drug: Cisplatin
Given IV
Other Names:
  • Abiplatin
  • Blastolem
  • Briplatin
  • CDDP
  • Cis-diammine-dichloroplatinum
  • Cis-diamminedichloridoplatinum
  • Cis-diamminedichloro Platinum (II)
  • Cis-diamminedichloroplatinum
  • Cis-dichloroammine Platinum (II)
  • Cis-platinous Diamine Dichloride
  • Cis-platinum
  • Cis-platinum II
  • Cis-platinum II Diamine Dichloride
  • Cismaplat
  • Cisplatina
  • Cisplatinum
  • Cisplatyl
  • Citoplatino
  • Citosin
  • Cysplatyna
  • DDP
  • Lederplatin
  • Metaplatin
  • Neoplatin
  • Peyrone's Chloride
  • Peyrone's Salt
  • Placis
  • Plastistil
  • Platamine
  • Platiblastin
  • Platiblastin-S
  • Platinex
  • Platinol
  • Platinol- AQ
  • Platinol-AQ
  • Platinol-AQ VHA Plus
  • Platinoxan
  • Platinum
  • Platinum Diamminodichloride
  • Platiran
  • Platistin
  • Platosin
Radiation: Intensity-Modulated Radiation Therapy
Undergo IMRT
Other Names:
  • IMRT
  • Intensity Modulated RT
  • Intensity-Modulated Radiotherapy
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment
Experimental: Arm II (IMRT)
Patients undergo IMRT five days a week for 5 weeks to a total dose of 60 Gy in the absence of disease progression or unacceptable toxicity.
Radiation: Intensity-Modulated Radiation Therapy
Undergo IMRT
Other Names:
  • IMRT
  • Intensity Modulated RT
  • Intensity-Modulated Radiotherapy
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Detailed Description:

PRIMARY OBJECTIVES:

I. To select the arm(s) achieving a 2-year progression-free survival rate of >= 85% without unacceptable swallowing toxicity at 1 year.

SECONDARY OBJECTIVES:

I. To determine patterns of failure (locoregional relapse versus distant) and survival (overall and progression-free) at 6 months and 2 years.

II. To determine acute toxicity profiles at the end of radiation therapy and at 1 and 6 months.

III. To determine late toxicity profiles at 1 and 2 years. IV. To determine patient-reported swallowing outcomes at 6 months and 1 and 2 years.

V. To determine the predictive value of 12-14 week, post-treatment fludeoxyglucose F 18 (FDG)-positron emission tomography (PET)/computed tomography (CT) for locoregional control and progression free survival (PFS) at 2 years.

VI. To determine the predictive value of blood and tissue biomarkers for disease outcomes at 2 years.

VII. To determine swallowing recovery per videofluoroscopy imaging at 2 years.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients undergo IMRT once daily (QD) five days a week for 6 weeks to a total dose of 60 Gy and receive cisplatin intravenously (IV) over 30-60 minutes weekly during radiation therapy for 6 doses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients undergo IMRT five days a week for 5 weeks to a total dose of 60 Gy in the absence of disease progression or unacceptable toxicity.

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

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • STEP 1: REGISTRATION
  • Pathologically (histologically or cytologically) proven diagnosis of squamous cell carcinoma (including the histological variants papillary squamous cell carcinoma and basaloid squamous cell carcinoma) of the oropharynx (tonsil, base of tongue, soft palate, or oropharyngeal walls); cytologic diagnosis from a cervical lymph node is sufficient in the presence of clinical evidence of a primary tumor in the oropharynx; clinical evidence should be documented, may consist of palpation, imaging, or endoscopic evaluation, and should be sufficient to estimate the size of the primary (for T stage)
  • Patients must have clinically or radiographically evident measurable disease at the primary site or at nodal stations; tonsillectomy or local excision of the primary without removal of nodal disease is permitted, as is excision removing gross nodal disease but with intact primary site; limited neck dissections retrieving =< 4 nodes are permitted and considered as non-therapeutic nodal excisions
  • Immunohistochemical staining for p16 must be performed on tissue, and this tissue must be submitted for central review; fine needle aspiration (FNA) biopsy specimens may be used as the sole diagnostic tissue if formalin-fixed paraffin-embedded cell block material is available for p16 immunohistochemistry; FNA specimens prepared with adequate p16 testing in this manner are acceptable to submit for central review; if the p16 preparation is not adequate, additional specimens will be required to establish p16 status; centers are encouraged to contact the pathology chairs for clarification
  • Clinical stage T1-T2, N1-N2b or T3, N0-N2b (American Joint Committee on Cancer [AJCC], 7th edition [ed.]) including no distant metastases based on the following diagnostic workup:

    • General history and physical examination within 56 days prior to registration
    • Fiberoptic exam with laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) within 70 days prior to registration
    • One of the following combinations of imaging is required within 56 days prior to registration:

      • A CT scan of the neck (with contrast) and a chest CT scan (with or without contrast)
      • Or a magnetic resonance imaging (MRI) of the neck (with contrast) and a chest CT scan (with or without contrast)
      • Or a CT scan of neck (with contrast) and a PET/CT of neck and chest (with or without contrast)
      • Or an MRI of the neck (with contrast) and a PET/CT of neck and chest (with or without contrast)

        • Note: a CT scan of neck and/or a PET/CT performed for the purpose of radiation planning may serve as both staging and planning tools
  • Patients must provide their personal smoking history prior to registration; the lifetime cumulative history cannot exceed 10 pack-years; the following formula is used to calculate the pack-years during the periods of smoking in the patient's life; the cumulative total of the number of pack-years during each period of active smoking is the lifetime cumulative history

    • Number of pack-years = (frequency of smoking [number of cigarettes per day] x duration of cigarette smoking [years])/20
    • Note: twenty cigarettes is considered equivalent to one pack; the effect of non-cigarette tobacco products on the survival of patients with p16-positive oropharyngeal cancers is undefined; cigar and pipe tobacco consumption is therefore not included in calculating the lifetime pack-years; marijuana consumption is likewise not considered in this calculation; there is no clear scientific evidence regarding the role of chewing tobacco-containing products in this disease; investigators are discouraged from enrolling patients with a history of very sustained use (such as several years or more) of non-cigarette tobacco products alone
  • Zubrod performance status of 0-1 within 56 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
  • Serum creatinine =< 1.5 mg/dl or creatinine clearance (CC) >= 50 ml/min determined by 24-hour collection or estimated by Cockcroft-Gault formula
  • Bilirubin =< 2 mg/dl
  • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 3 x the upper limit of normal
  • Negative serum pregnancy test within 14 days prior to registration for women of childbearing potential
  • Patients who are human immunodeficiency virus (HIV) positive but have no prior acquired immune deficiency syndrome (AIDS)-defining illness and have cluster of differentiation (CD)4 cells of at least 350/mm^3 are eligible; HIV-positive patients must not have multi-drug resistant HIV infection or other concurrent AIDS-defining conditions; patients must not be seropositive for hepatitis B (hepatitis B surface antigen positive or anti-hepatitis B core antigen positive) or seropositive for hepatitis C (anti-hepatitis C antibody positive); however, patients who are immune to hepatitis B (anti-hepatitis B surface antibody positive) are eligible (e.g. patients immunized against hepatitis B)
  • The patient must provide study-specific informed consent prior to study entry, including consent for mandatory submission of tissue for required, central p16 review
  • Patients who speak English (or read one of the languages for which a translation is available must consent to complete the mandatory dysphagia-related patient reported instrument (MDADI); if the patient cannot understand spoken English and reads only languages not available in the MDADI translations, the patient can still participate in the trial, as this has been factored into the trial statistics; for all other patients, the MDADI is mandatory as it is included in the primary endpoint to be studied
  • STEP 2: RANDOMIZATION
  • p16 positive by immunohistochemistry (defined as greater than 70% strong nuclear or nuclear and cytoplasmic staining of tumor cells, confirmed by central pathology review)

Exclusion Criteria:

  • STEP 1 (REGISTRATION)
  • Cancers considered to be from an oral cavity site (oral tongue, floor mouth, alveolar ridge, buccal or lip), or the nasopharynx, hypopharynx, or larynx, even if p16 positive, or histologies of adenosquamous, verrucous, or spindle cell carcinomas
  • Carcinoma of the neck of unknown primary site origin (even if p16 positive)
  • Radiographically matted nodes, defined as 3 abutting nodes with loss of the intervening fat plane
  • Supraclavicular nodes, defined as nodes visualized on the same axial imaging slice as the clavicle
  • Definitive clinical or radiologic evidence of metastatic disease or adenopathy below the clavicles
  • Gross total excision of both primary and nodal disease with curative intent; this includes tonsillectomy, local excision of primary site, and nodal excision that removes all clinically and radiographically evident disease; in other words, to participate in this protocol, the patient must have clinically or radiographically evident gross disease for which disease response can be assessed
  • Patients with simultaneous primary cancers or separate bilateral primary tumor sites are excluded with the exception of patients with bilateral tonsil cancers
  • Prior invasive malignancy (except 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
  • Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
  • Severe, active co-morbidity defined as follows:

    • Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
    • Transmural myocardial infarction within the last 6 months
    • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
    • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days of registration
    • Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for liver function and coagulation parameters are not required for entry into this protocol other than those requested
    • Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that HIV testing is not required for entry into this protocol; protocol-specific requirements may also exclude immuno-compromised patients
  • Pregnancy
  • Prior allergic reaction to cisplatin
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02254278

  Show 184 Study Locations
Sponsors and Collaborators
NRG Oncology
National Cancer Institute (NCI)
Investigators
Principal Investigator: Sue Yom NRG Oncology
  More Information

Responsible Party: NRG Oncology
ClinicalTrials.gov Identifier: NCT02254278     History of Changes
Other Study ID Numbers: NRG-HN002
NCI-2014-01279 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NRG-HN002 ( Other Identifier: NRG Oncology )
NRG-HN002 ( Other Identifier: CTEP )
U10CA180868 ( US NIH Grant/Contract Award Number )
Study First Received: September 29, 2014
Last Updated: March 2, 2017

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Squamous Cell
Oropharyngeal Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Squamous Cell
Pharyngeal Neoplasms
Otorhinolaryngologic Neoplasms
Head and Neck Neoplasms
Neoplasms by Site
Pharyngeal Diseases
Stomatognathic Diseases
Otorhinolaryngologic Diseases
Cisplatin
Succinylcholine
Antineoplastic Agents
Neuromuscular Depolarizing Agents
Neuromuscular Blocking Agents
Neuromuscular Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on April 28, 2017