Clinical trial NCT03715946: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Carcinoma, Squamous Cell of Head and Neck
Oropharynx Squamous Cell Carcinoma
Keywords: 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
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
First posted: 2018-10-23
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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 of neck only 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.
* 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. 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.
* 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 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.
* 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.

Primary outcomes:
measure: One-year Progression-free Survival (PFS)
timeFrame: At 1 year post start of treatment
measure: Two-year Progression-free Survival (PFS)
timeFrame: At 2 years post start of treatment
measure: PEG Tube Dependence
timeFrame: At 1-year post-surgery
Secondary outcomes:
measure: Worst Grade of Adverse Events Related to Treatment
timeFrame: Up to 24 months
measure: Local Recurrence-free Survival (RFS) at One Year
timeFrame: At 1-year post-surgery
measure: Local Recurrence-free Survival (RFS) at Two Years
timeFrame: At 2-years post-surgery
measure: Regional Recurrence-free Survival (RFS)
timeFrame: At one year post surgery
measure: Regional Recurrence-free Survival (RFS)
timeFrame: At two years post-surgery
measure: Distant Recurrence-free Survival (RFS) at One Year
timeFrame: At one year post-surgery
measure: Distant Recurrence-free Survival (RFS)
timeFrame: At 2 years post-surgery
measure: Overall Survival (OS) at One Year
timeFrame: At one year
measure: Overall Survival (OS) at Two Years
timeFrame: At two years
measure: MD Anderson Dysphagia Inventory (MDADI)
timeFrame: At baseline
measure: MD Anderson Dysphagia Inventory (MDADI)
timeFrame: At 3 months after start of treatment
measure: MD Anderson Dysphagia Inventory (MDADI)
timeFrame: At 6 months after start of treatment
measure: MD Anderson Dysphagia Inventory (MDADI)
timeFrame: At 9 months after start of treatment
measure: MD Anderson Dysphagia Inventory (MDADI)
timeFrame: At 12 months after start of treatment
measure: MD Anderson Dysphagia Inventory (MDADI)
timeFrame: At 18 months after start of treatment
measure: MD Anderson Dysphagia Inventory (MDADI)
timeFrame: At 21 months after start of treatment
measure: MD Anderson Dysphagia Inventory (MDADI)
timeFrame: At 24 months after start of treatment
measure: MD Anderson Dysphagia Inventory (MDADI)
timeFrame: At 30 months after start of treatment
measure: MD Anderson Dysphagia Inventory (MDADI) (Total - Overall Score)
timeFrame: Up to 30 months after start of treatment
measure: Voice Handicap Index-10 (VHI-10)
timeFrame: At baseline
measure: Voice Handicap Index-10 (VHI-10)
timeFrame: At 3 months after completion of treatment
measure: Voice Handicap Index-10 (VHI-10)
timeFrame: At 6 months after completion of treatment
measure: Voice Handicap Index-10 (VHI-10)
timeFrame: At 9 months after completion of treatment
measure: Voice Handicap Index-10 (VHI-10)
timeFrame: At 12 months after completion of treatment
measure: Voice Handicap Index-10 (VHI-10)
timeFrame: At 18 months after completion of treatment
measure: Voice Handicap Index-10 (VHI-10)
timeFrame: At 21 months after completion of treatment
measure: Voice Handicap Index-10 (VHI-10)
timeFrame: At 24 months after completion of treatment
measure: Voice Handicap Index-10 (VHI-10)
timeFrame: At 30 months after completion of treatment
measure: Voice Handicap Index-10 (VHI-10) (Total)
timeFrame: Calculated at 30 months after completion of treatment
measure: Functional Assessment of Cancer Therapy - Head and Neck Cancer (FACT-H&N) Score
timeFrame: At baseline (prior to treatment)
measure: Functional Assessment of Cancer Therapy - Head and Neck Cancer (FACT-H&N) Score
timeFrame: At 3 months after start of treatment
measure: Functional Assessment of Cancer Therapy - Head and Neck Cancer (FACT-H&N) Score
timeFrame: At 6 months after start of treatment
measure: Functional Assessment of Cancer Therapy - Head and Neck Cancer (FACT-H&N) Score
timeFrame: At 9 months after start of treatment
measure: Functional Assessment of Cancer Therapy - Head and Neck Cancer (FACT-H&N) Score
timeFrame: At 12 months after start of treatment
measure: Functional Assessment of Cancer Therapy - Head and Neck Cancer (FACT-H&N) Score
timeFrame: At 18 months after start of treatment
measure: Functional Assessment of Cancer Therapy - Head and Neck Cancer (FACT-H&N) Score
timeFrame: At 21 months after completion of treatment
measure: Functional Assessment of Cancer Therapy - Head and Neck Cancer (FACT-H&N) Score
timeFrame: At 24 months after start of treatment
measure: Functional Assessment of Cancer Therapy - Head and Neck Cancer (FACT-H&N) Score
timeFrame: At 30 months after start of treatment
measure: Functional Assessment of Cancer Therapy - Head and Neck Cancer (FACT-H&N) Score (Total)
timeFrame: Calculated at 30 months after start of treatment
measure: MD Anderson Symptom Inventory for Head and Neck Cancer (MDASI-HN)
timeFrame: At baseline
measure: MD Anderson Symptom Inventory for Head and Neck Cancer (MDASI-HN)
timeFrame: At 3 months after start of treatment
measure: MD Anderson Symptom Inventory for Head and Neck Cancer (MDASI-HN)
timeFrame: At 6 months after start of treatment
measure: MD Anderson Symptom Inventory for Head and Neck Cancer (MDASI-HN)
timeFrame: At 9 months after start of treatment
measure: MD Anderson Symptom Inventory for Head and Neck Cancer (MDASI-HN)
timeFrame: At 12 months after start of treatment
measure: MD Anderson Symptom Inventory for Head and Neck Cancer (MDASI-HN)
timeFrame: At 18 months
measure: MD Anderson Symptom Inventory for Head and Neck Cancer (MDASI-HN)
timeFrame: At 21 months after start of treatment
measure: MD Anderson Symptom Inventory for Head and Neck Cancer (MDASI-HN)
timeFrame: At 24 months after start of treatment
measure: MD Anderson Symptom Inventory for Head and Neck Cancer (MDASI-HN)
timeFrame: At 30 months after start of treatment
measure: MD Anderson Symptom Inventory for Head and Neck Cancer (MDASI-HN) (Total)
timeFrame: Calculated at 30 months after start of treatment
measure: Modified Barium Swallow (MBS) Rating
timeFrame: At 6 and 24 months after completion of treatment
measure: Performance Status Scale (PSS-HN)
timeFrame: At 3, 6, 12 and 24 months after completion of treatment
measure: EuroQoL-5D Questionnaire
timeFrame: At baseline
measure: EuroQoL-5D Questionnaire
timeFrame: At 3 months after start of treatment
measure: EuroQoL-5D Questionnaire
timeFrame: At 6 months after start of treatment
measure: EuroQoL-5D Questionnaire
timeFrame: At 9 months after start of treatment
measure: EuroQoL-5D Questionnaire
timeFrame: At 12 months after start of treatment
measure: EuroQoL-5D Questionnaire
timeFrame: At 18 months after start of treatment
measure: EuroQoL-5D Questionnaire
timeFrame: At 21 months after start of treatment
measure: EuroQoL-5D Questionnaire
timeFrame: At 24 months after start of treatment
measure: EuroQoL-5D Questionnaire
timeFrame: At 30 months after start of treatment
measure: EuroQoL-5D Questionnaire (Total)
timeFrame: Calculated at 30 months after start of treatment
Other outcomes:
measure: Tumor TP53 Mutation
timeFrame: At baseline prior to treatment; Up to 5 years
measure: Determination of Tumor Genomics
timeFrame: At baseline prior to treatment; Up to 5 years
measure: Presence of Plasma Cytokines
timeFrame: At baseline prior to treatment; Up to 5 years
measure: Antigen-specific Immune Response to Human Papillomavirus (HPV)
timeFrame: At baseline prior to treatment; Up to 5 years
measure: Determination of Oral Human Papillomavirus (HPV) DNA
timeFrame: At baseline prior to treatment
Locations:
city: Atlanta
country: United States
facility: Winship Cancer Institute @ Emory University Hospital Midtown
state: Georgia
city: Portland
country: United States
facility: Providence Cancer Institute
state: Oregon
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center
state: Pennsylvania
Study officials:
affiliation: UPMC Hillman Cancer Center
name: Robert Ferris, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: