Clinical Trials /

Adjuvant De-Escalated Radiation + Adjuvant Nivolumab for Intermediate-High Risk P16+ Oropharynx Cancer

NCT03715946

Description:

This clinical trial will evaluate a new combination of treatments for Oropharyngeal Squamous Cell cancers (OPSCC), and compare it to the current standard of care (concurrent, platinum-based chemoradiotherapy). Chemoradiotherapy is efficacious, but also associated with significant toxicities and is only suitable for patients with good performance status and without severe comorbidities. The purpose of this trial is to demonstrate equivalent oncologic outcome with fewer adverse effects and improved quality of life when compared to the standard of care.

Related Conditions:
  • Nasopharyngeal Type Undifferentiated Carcinoma
  • Oropharyngeal Squamous Cell Carcinoma
  • Sinonasal Undifferentiated Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Adjuvant De-Escalated Radiation + Adjuvant Nivolumab for Intermediate-High Risk P16+ Oropharynx Cancer
  • Official Title: Phase II Trial of Adjuvant De-Escalated Radiation + Concurrent and Adjuvant Nivolumab for Intermediate-High Risk P16+ Oropharynx Cancer

Clinical Trial IDs

  • ORG STUDY ID: HCC 18-034
  • NCT ID: NCT03715946

Conditions

  • Carcinoma, Squamous Cell of Head and Neck
  • Oropharynx Squamous Cell Carcinoma

Interventions

DrugSynonymsArms
Nivolumab InjectionBMS-936558Radiotherapy (RT) + Nivolumab Injection

Purpose

This clinical trial will evaluate a new combination of treatments for Oropharyngeal Squamous Cell cancers (OPSCC), and compare it to the current standard of care (concurrent, platinum-based chemoradiotherapy). Chemoradiotherapy is efficacious, but also associated with significant toxicities and is only suitable for patients with good performance status and without severe comorbidities. The purpose of this trial is to demonstrate equivalent oncologic outcome with fewer adverse effects and improved quality of life when compared to the standard of care.

Detailed Description

      This study aims to enroll 135 patients (male and female, age 18+) who are newly diagnosed
      with resectable, squamous cell carcinoma or undifferentiated carcinoma of the oropharynx.
      Survival rate and treatment response of OPSCC varies based on HPV infection status and
      genotype; therefore, in this study, only patients who are HPV seropositive and have HPV type
      16 will be enrolled. All patients will receive the same treatment, i.e. there is no active
      control group.

      In this trial, patients will undergo transoral surgery followed by de-intensified adjuvant
      radiotherapy plus nivolumab. The radiotherapy will consist of 45 or 50 Gy (depending on tumor
      volume) in 25 daily fractions, 6 fractions per week. Nivolumab will be administered at a
      fixed dose of 240 mg over 30 minutes IV every 2 weeks during radiotherapy, and at 480 mg over
      60 minutes IV every 4 weeks for 6 doses after radiotherapy. The first dose will be given
      prior to the first fraction of radiation (Day 1) on Day -3 (+/- 2 days), and continued every
      2 weeks (+/- 2 days). Nivolumab will thus be given in weeks 2 and 4 of radiotherapy. Adjuvant
      nivolumab will then be given for a total of 6 additional doses after the completion of
      radiotherapy every 4 weeks (+/- 7 days), starting in the second or third week after the
      completion of radiotherapy. Doses of nivolumab may be interrupted, delayed, or discontinued
      depending on how well the subject tolerates the treatment. Relevant outcome measures include
      disease free survival (2 year post surgery); percutaneous gastronomy dependence (1-year
      postsurgery); acute and late toxicity; patient-reported Quality of Life measures,
      locoregional control and distant metastatic control.
    

Trial Arms

NameTypeDescriptionInterventions
Radiotherapy (RT) + Nivolumab InjectionExperimentalRT of 45 or 50 Gy in 25 daily fractions, 6 fractions per week. Nivolumab will be administered at 240 mg every 2 weeks during radiotherapy, and at 480 mg every 4 weeks for 6 doses after radiotherapy.
  • Nivolumab Injection

Eligibility Criteria

        Inclusion Criteria:

          -  Age >/= 18 years.

          -  ECOG performance status of 0 or 1.

          -  Patients must have newly diagnosed, histologically or cytologically confirmed squamous
             cell carcinoma or undifferentiated carcinoma of the oropharynx. Patients must have
             been determined to have resectable oropharyngeal disease. Patients with primary tumor
             or nodal metastasis fixed to the carotid artery, skull base or cervical spine are not
             eligible.

          -  Patients must have intermediate risk factors, as described below as determined by
             imaging studies (performed < 45 days prior to registration) and complete neck exam,
             from the skull base to the clavicles. The following imaging is required: CT scan with
             IV contrast or MRI. PET scan of HN and chest with IV contrasted CT correlation is
             encouraged prior to enrollment.

        Intermediate risk features: Tobacco <10 pk-yr: T0-3 plus any one of the following: >N2b (>
        5 LN's +), N2c/N3, +ENE >1 mm, or + margin (if approved by surgical chair) OR Tobacco >10
        pk-yr: T0-3 plus any one of the following: any N2, N3, +ENE >1 mm, or + margin (if approved
        by surgical chair)

          -  Patients must have no evidence of distant metastases (M0)

          -  Patients must have biopsy-proven p16+ oropharynx cancer; the histologic evidence of
             invasive squamous cell carcinoma may have been obtained from the primary tumor or
             metastatic lymph node. It is required that patients have a positive p16 IHC (as
             surrogate for HPV) status from either the primary tumor or metastatic lymph node.

          -  Carcinoma of the oropharynx associated with HPV as determined by p16 protein
             expression using immunohistochemistry (IHC) performed by a CLIA approved laboratory.
             Using p16 antibody obtained from Roche mtm laboratories AG (CINtec, clone E6H4) is
             recommended.

          -  No prior radiation above the clavicles.

          -  Patients with a history of a curatively treated malignancy must be disease-free for at
             least two years except for carcinoma in situ of cervix, differentiated thyroid cancer,
             melanoma in-situ (if fully resected), and/or non-melanomatous skin cancer, or
             clinically negligible in judgement of investigator.

          -  Patients with the following within the last 6 months prior to registration must be
             evaluated by a cardiologist and / or neurologist prior to entry into the study.

               -  Congestive heart failure > NYHA Class II

               -  CVA / TIA

               -  Unstable angina

               -  Myocardial infarction (with or without ST elevation)

          -  Patients must have acceptable renal and hepatic function within 4 weeks prior to
             registration as defined below:

               -  Absolute neutrophil count ≥1,500/mm3

               -  Platelets ≥ 100,000/mm3

               -  Total bilirubin ≤ the upper limit of normal (ULN)

               -  Calculated creatinine clearance must be > 60 ml/min using the Cockcroft-Gault
                  formula: (140-age)*wt(kg)/([Cr]*72). For women the calculation should be
                  multiplied by 0.85

          -  Women must not be pregnant or breast-feeding due to the teratogenicity of therapy. All
             females of childbearing potential must have a blood test or urine study within 2 weeks
             prior to registration to rule out pregnancy. A female of childbearing potential is any
             woman, regardless of sexual orientation or whether they have undergone tubal ligation,
             who meets the following criteria: 1) has not undergone a hysterectomy or bilateral
             oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive
             months (i.e., has had menses at any time in the preceding 24 consecutive months).

          -  Patient without intercurrent illness likely to interfere with protocol therapy.

          -  Patients must not have uncontrolled diabetes, uncontrolled infection despite
             antibiotics or uncontrolled hypertension within 30 days prior to registration.

        Exclusion Criteria:

          -  Any serious or uncontrolled medical disorder that, in the opinion of the investigator,
             may increase the risk associated with study participation or study drug
             administration, impair the ability of the subject to receive protocol therapy, or
             interfere with the interpretation of study results.

          -  Patients with a history of a curatively treated malignancy must be disease-free for at
             least two years except for carcinoma in situ of cervix, melanoma in-situ (if fully
             resected), and/or non-melanomatous skin cancer, superficial bladder cancer, or
             carcinoma in situ of the prostate, cervix, or breast.

          -  Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo,
             type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only
             requiring hormone replacement, psoriasis not requiring systemic treatment, or
             conditions not expected to recur in the absence of an external trigger are permitted
             to enroll.

          -  Subjects with a condition requiring systemic treatment with either corticosteroids (>
             10 mg daily prednisone equivalents) or other immunosuppressive medications within 14
             days of study drug administration. Inhaled or topical steroids and adrenal replacement
             doses > 10 mg daily prednisone equivalents are permitted in the absence of active
             autoimmune disease.

          -  Prior radiation above the clavicles.

          -  Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or
             any other antibody or drug specifically targeting T-cell co-stimulation or immune
             checkpoint pathways.

          -  Treatment with any chemotherapy, radiation therapy, biologics for cancer, or
             investigational therapy within 30 days of first administration of study treatment
             (subjects with prior radiation, cytotoxic or investigational products < 4 weeks prior
             to treatment might be eligible after discussion between investigator and sponsor, if
             toxicities from the prior treatment have been resolved to Grade 1 (NCI CTCAE version
             4).

          -  Known positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C
             virus ribonucleic acid (HCV antibody) indicating acute or chronic infection. Subjects
             who test positive for HCV antibody but negative for HCV ribonucleic acid are permitted
             to enroll.

          -  Known history of testing positive for human immunodeficiency virus (HIV) and CD4 count
             < 200 or known acquired immunodeficiency syndrome (AIDS).

          -  Any Grade 4 laboratory abnormalities.

          -  Patients with the following within the last 6 months prior to registration must be
             evaluated by a cardiologist and / or neurologist prior to entry into the study.

               -  Congestive heart failure > NYHA Class II

               -  CVA / TIA

               -  Unstable angina

               -  Myocardial infarction (with or without ST elevation)

          -  History of allergy to study drug components.

          -  History of severe hypersensitivity reaction to any human monoclonal antibody.

          -  Prisoners or subjects who are involuntarily incarcerated.

          -  Subjects compulsorily detained for treatment of either a psychiatric or physical
             (e.g., infectious disease) illness.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:From beginning of study treatment (post surgery) up to 3-years
Safety Issue:
Description:The length of time (months) from of beginning of study treatment without local, regional or distant disease recurrence until the appearance of new metastatic lesions.

Secondary Outcome Measures

Measure:Functional Assessment of Cancer Therapy - Head and Neck Cancer (FACT-H&N) Score
Time Frame:At 3, 6, 12 and 24 months after completion of treatment
Safety Issue:
Description:The FACT-H&N (version 4)17 consists of a cancer-specific questionnaire, FACT-G, in addition to 12 H&N cancer-specific items (the HN subscale). FACT-G is a 27-item measure that assesses general cancer quality of life. The FACT-G contains 4 subscales: physical, social/family, emotional, and functional well-being. Individuals are asked to indicate how true 27 statements are for them, using the past 7 days as the timeframe. Responses range from not at all (0), to very much (4) on a 5-point scale.
Measure:Locoregional control (LRC)
Time Frame:At 1-year and at 2-year post surgery
Safety Issue:
Description:Identification of disease growth that is present within the area in which it was first located.
Measure:Distant disease recurrence
Time Frame:At 1-year and at 2 year post-surgery
Safety Issue:
Description:Identification of disease that has spread (metastasized) to areas farther away from where it was first located.
Measure:MD Anderson Symptom Inventory for head and neck cancer (MDASI-HN)
Time Frame:At 3, 6, 12 and 24 months after completion of treatment
Safety Issue:
Description:MDASI-HN measures treatment related symptom burden in head and neck cancer patients. The 20-item MDASI measures both severity and burden of symptoms and their effect on patients' daily activities, using a numeric rating scale of 0-10. This instrument includes 13 core symptoms and 9 head and neck specific items. Higher scores indicate superior perception of function.
Measure:MD Anderson Dysphagia Inventory (MDADI)
Time Frame:At 3, 6, 12 and 24 months after completion of treatment
Safety Issue:
Description:The MDADI measures swallowing-related quality of life (QOL) in patients with swallowing dysfunction in a 20 - item written questionnaire. It evaluates the patient's physical (P), emotional (E) and functional (F) perceptions of swallowing dysfunction. This instrument has been psychometrically validated in head and neck cancer patients. Higher scores indicate superior perception of swallowing function.
Measure:Voice Handicap Index-10 (VHI-10)
Time Frame:At 3, 6, 12 and 24 months after completion of treatment
Safety Issue:
Description:The VHI-10 is a patient self-assessment instrument that quantifies patients' perception of their voice handicap. It evaluates patient's physical (P), emotional (E), and functional (F) perceptions of voice and has shown to be highly reliable for internal consistency and test-retest stability. The VHI-10 utilizes a 10-item questionnaire in which the patient circles the response that most accurately reflects his or her own experience on a linear scale (from "never" to "always"). "Always" response is scored 4 points, a "Never" response is scored 0. The remaining options are scored between 1 and 3 points. The tallied number of points for each of the subscales is computed to a total composite score. The patient's values are compared to published norms.
Measure:Performance Status Scale (PSS-HN)
Time Frame:At 3, 6, 12 and 24 months after completion of treatment
Safety Issue:
Description:The Performance Status Scale (PSS-HN) is a clinician-rated instrument consisting of 3 questions: normalcy of diet, public eating/swallowing, and understandability of speech subscales in patients with head and neck cancer. Each subscale is rated from 0 to 100, with higher scores indicating better performance.
Measure:Modified Barium Swallow (MBS) rating
Time Frame:At 6 and 24 months after completion of treatment
Safety Issue:
Description:Three swallowing outcomes will be rated by the SLP conducting the MBS study and reported by research staff: 1) laryngeal penetration (yes, no); 2) aspiration (no, sensate, silent), and 3) pharyngeal residue (no, < 50%, > 50%). These have been selected as universal items generally reported by swallowing clinicians that have been shown to significantly predict pneumonia in patients with oropharyngeal cancers. Prevalence of these dysphagia endpoints will be estimated at each time point.
Measure:Overall Survival
Time Frame:From beginning of study treatment (post surgery) up to 3-years
Safety Issue:
Description:The length of time (in months) from the start of treatment patients remain alive.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Robert Ferris

Trial Keywords

  • Phase II
  • Oropharynx Cancer
  • OPSCC
  • Nivolumab
  • Adjuvant therapy
  • De-Escalated Radiation
  • Squamous cell carcinoma
  • P16+
  • Head and Neck cancer
  • Oropharynx Squamous Cell Carcinoma
  • Carcinoma, Squamous Cell of Head and Neck
  • Transoral surgery
  • Radiotherapy

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