Clinical Trials /

Reduced-Dose Intensity-Modulated Radiation Therapy With or Without Cisplatin in Treating Patients With Advanced Oropharyngeal Cancer

NCT02254278

Description:

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.

Related Conditions:
  • Oropharyngeal Squamous Cell Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Reduced-Dose Intensity-Modulated Radiation Therapy With or Without Cisplatin in Treating Patients With Advanced Oropharyngeal Cancer
  • Official Title: A Randomized Phase II Trial for Patients With p16 Positive, Non-Smoking Associated, Locoregionally Advanced Oropharyngeal Cancer

Clinical Trial IDs

  • ORG STUDY ID: NRG-HN002
  • SECONDARY ID: NCI-2014-01279
  • SECONDARY ID: NRG-HN002
  • SECONDARY ID: NRG-HN002
  • SECONDARY ID: U10CA180868
  • NCT ID: NCT02254278

Conditions

  • 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

Interventions

DrugSynonymsArms
CisplatinIMRT 6 weeks + cisplatin

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.

Detailed Description

      PRIMARY OBJECTIVES:

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

      SECONDARY OBJECTIVES:

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

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

        -  To determine late toxicity profiles at 1 and 2 years.

        -  To determine patient-reported swallowing outcomes at 6 months and 1 and 2 years.

        -  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.

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

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

      After completion of study treatment, patients are followed at 1 and 3 months then every 3
      months for 2 years, every 6 months for 3 years, and then annually thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
IMRT 6 weeks + cisplatinExperimentalIMRT 6 weeks with concurrent cisplatin
  • Cisplatin
IMRT 5 weeksExperimentalIMRT 5 weeks

    Eligibility Criteria

            Inclusion Criteria
    
            Step 1: Registration:
    
              1. 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).
    
              2. 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.
    
              3. 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.
    
              4. Clinical stage T1-T2, N1-N2b or T3, N0-N2b (AJCC, 7th 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:
    
                        1. A computed tomography (CT) scan of the neck (with contrast) and a chest CT
                           scan (with or without contrast);
    
                        2. or an MRI of the neck (with contrast) and a chest CT scan (with or without
                           contrast);
    
                        3. or a CT scan of neck (with contrast) and a PET/CT of neck and chest (with or
                           without contrast);
    
                        4. 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 purposes of radiation
                 planning may serve as both staging and planning tools.
    
              5. 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) × 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. While there are reportedly increased risks of head
                 and neck cancer associated with sustained heavy cigar and pipe use (Wyss 2013), such
                 sustained use of non-cigarette products is unusual and does not appear to convey added
                 risk with synchronous cigarette smoking. 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, although
                 this is possibly more concerning given the proximity of the oral cavity and
                 oropharynx. In any case, 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.
    
              6. Zubrod Performance Status of 0-1 within 56 days prior to registration;
    
              7. Age ≥ 18;
    
              8. The trial is open to both genders;
    
              9. Adequate hematologic function within 14 days prior to registration, defined as
                 follows:
    
                   -  Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3;
    
                   -  Platelets ≥ 100,000 cells/mm3;
    
                   -  Hemoglobin (Hgb) ≥ 8.0 g/dl; Note: The use of transfusion or other intervention
                      to achieve Hgb ≥ 8.0 g/dl is acceptable.
    
             10. Adequate renal function within 14 days prior to registration, defined as follows:
    
                 • Serum creatinine (Cr) < 1.5 mg/dl or creatinine clearance (CC) ≥ 50 ml/min
                 determined by 24-hour collection or estimated by Cockcroft-Gault formula:
    
                   -  CC male = [(140 - age) x (wt in kg)] / [(Serum Cr mg/dl) x (72)]
    
                   -  CC female = 0.85 x (CC male)
    
             11. Adequate hepatic function within 14 days prior to registration defined as follows:
    
                   -  Bilirubin < 2 mg/dl;
    
                   -  Aspartate transaminase (AST) or alanine transaminase (ALT) < 3 x the upper limit
                      of normal.
    
             12. Negative serum pregnancy test within 14 days prior to registration for women of
                 childbearing potential;
    
             13. Patients who are HIV positive but have no prior Acquired Immune Deficiency Syndrome
                 (AIDS) -defining illness and have CD4 cells of at least 350/mm3 are eligible.
                 HIV-positive patients must not have multi-drug resistant HIV infection or other
                 concurrent AIDS-defining conditions. Patients must not be sero-positive for Hepatitis
                 B (Hepatitis B surface antigen positive or anti-hepatitis B core antigen positive) or
                 sero-positive 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).
    
             14. The patient must provide study-specific informed consent prior to study entry,
                 including consent for mandatory submission of tissue for required, central p16 review.
    
             15. Patients who speak English (or read one of the languages for which a translation is
                 available (see Section 10.2) 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:
    
             16. p16 positive by immunohistochemistry (defined as greater than 70% strong nuclear or
                 nuclear and cytoplasmic staining of tumor cells), confirmed by central pathology
                 review; (see Section 10.1 for details).
    
            Exclusion Criteria
    
            Step 1: Registration:
    
              1. 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;
    
              2. Carcinoma of the neck of unknown primary site origin (even if p16 positive);
    
              3. Radiographically matted nodes, defined as 3 abutting nodes with loss of the
                 intervening fat plane;
    
              4. Supraclavicular nodes, defined as nodes visualized on the same axial imaging slice as
                 the clavicle;
    
              5. Definitive clinical or radiologic evidence of metastatic disease or adenopathy below
                 the clavicles;
    
              6. 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.
    
              7. Patients with simultaneous primary cancers or separate bilateral primary tumor sites
                 are excluded with the exception of patients with bilateral tonsil cancers;
    
              8. 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);
    
              9. Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a
                 different cancer is allowable;
    
             10. Prior radiotherapy to the region of the study cancer that would result in overlap of
                 radiation therapy fields;
    
             11. 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 in Section 3.2.10.
    
                   -  Acquired Immune Deficiency Syndrome (AIDS) based upon current Centers for Disease
                      Control and Prevention (CDC) definition with immune compromise greater than that
                      noted in Inclusion Criterion 13; note, however, that 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. Protocol-specific requirements may also exclude
                      immuno-compromised patients.
    
             12. Pregnancy; this exclusion is necessary because the treatment involved in this study
                 may be significantly teratogenic.
    
             13. Prior allergic reaction to cisplatin.
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Percentage of Participants Alive Without Progression at Two Years (Progression-free Survival)
    Time Frame:From randomization to 2 years
    Safety Issue:
    Description:Progression is defined as local, regional, or distant disease progression or death due to any cause. Percentage is estimated using the binomial distribution.

    Secondary Outcome Measures

    Measure:Percentage of Participants With Local-regional Failure
    Time Frame:From randomization to 2 years
    Safety Issue:
    Description:Local-regional failure is defined as local or regional progression, salvage surgery of the primary tumor with tumor present/unknown, salvage neck dissection with tumor present/unknown > 20 weeks after the end of radiation therapy, death due to study cancer without documented progression, or death due to unknown causes without documented progression. Distant metastasis and death due to other causes are considered competing risks. Local-regional failure time is defined as time from randomization to the date of first progression/death or last known follow-up (censored). Rates are estimated by the cumulative incidence method.
    Measure:Percentage of Participants With Distant Metastasis
    Time Frame:From randomization to 2 years
    Safety Issue:
    Description:Distant metastasis is defined as distant progression. Local-regional failure and death due to any cause are considered competing risks. Distant metastasis time is defined as time from randomization to the date of progression/death or last known follow-up (censored). Rates are estimated by the cumulative incidence method.
    Measure:Percentage of Participants Alive
    Time Frame:from randomization to 2 years
    Safety Issue:
    Description:Overall survival time is defined as time from randomization to the date of death or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method.
    Measure:Percentage of Participants With Grade 3+ Adverse Events
    Time Frame:End of radiation therapy (RT) (approximately 6 weeks for Arm 1 and 5 weeks for Arm 2), then 1 month, 6 months, 1 year, and two years after end of RT
    Safety Issue:
    Description:Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE.
    Measure:Mean One-year Total MD Anderson Dysphagia Inventory (MDADI) Score (Patient-reported Swallowing Outcome)
    Time Frame:One year post-RT. Radiation therapy (RT) ends at approximately 6 weeks for Arm 1 and 5 weeks for Arm 2
    Safety Issue:
    Description:The MDADI is a 20-item tool with each item scored as Strongly agree; Agree; No opinion; Disagree; or Strongly disagree. There is 1 global item (G1), 6 emotional subscale items (E2-E7), 5 functional subscale items (F1-F5), and 8 physical subscale items (P1-P8). For all items except E7 and F2, Strongly agree corresponds to a score of 1, Agree 2, No opinion 3, Disagree 4, and Strongly disagree 5. For E7 and F2, the scores are reversed; these 2 items are rescored to match the others before calculating summary scores. The composite (total) score is the mean of the 19 items (other than G1) X 20. Composite scores range from 20 to 100 with higher scores indicating less dysphagia.
    Measure:Negative Predictive Value (NPV) of Post-treatment FDG-PET/CT Scan [Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET)/Computed Tomography (CT)] for Progression-free Survival and Local-regional Control at Two Years
    Time Frame:3 months (scan) and two years after the end of RT (approximately 6 weeks for Arm 1 and 5 weeks for Arm 2)
    Safety Issue:
    Description:NPV is the percentage of participants alive and failure-free at 2 years among those with a negative post-treatment scan, as evaluated by central review. Negative scan determined as follows: primary site, right neck, left neck evaluated using a 5-point ordinal scale: 1-Definite complete metabolic response (CMR), 2-Likely CMR, 3-Likely inflammatory, 4-Likely residual metabolic disease (RMD), and 5-Definite RMD. 'Negative'= 1 or 2, 'Indeterminate'=3, 'Positive' = 4 or 5. 'Negative' for all three evaluation sites = overall score of 'Negative.' Progression (failure) is defined as local, regional, or distant disease progression (PR) or any death. Local-regional progression (failure) is defined as local or regional PR, salvage surgery of the primary tumor with tumor present/unknown, salvage neck dissection with tumor present/unknown > 20 weeks post RT, death due to study cancer or unknown causes without documented PR. The protocol specified that both arms would be combined for analysis.
    Measure:Human Papillomavirus (HPV) Deoxyribonucleic Acid (DNA) Detection Rate
    Time Frame:Baseline to up to 2 weeks after the completion of treatment
    Safety Issue:
    Description: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.
    Measure:HPV DNA Rate Decline
    Time Frame:Baseline to up to 2 weeks after the completion of treatment
    Safety Issue:
    Description: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.
    Measure:HPV DNA Copy Number
    Time Frame:Baseline to up to 2 weeks after the completion of treatment
    Safety Issue:
    Description: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.
    Measure:Variance for HPV DNA
    Time Frame:Baseline to up to 2 weeks after the completion of treatment
    Safety Issue:
    Description:Univariable and multivariable cause specific analysis will be performed using the Cox proportional hazards model for rate of relapse.

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Active, not recruiting
    Lead Sponsor:NRG Oncology

    Last Updated

    January 22, 2021