Radiation Therapy With Durvalumab or Cetuximab in Treating Patients With Locoregionally Advanced Head and Neck Cancer Who Cannot Take Cisplatin

Phase 2

Active, not recruiting

Conditions: Oropharyngeal Squamous Cell Carcinoma
Stage III Lip and Oral Cavity Cancer AJCC v8
Stage IVA Laryngeal Cancer AJCC v8
Stage IVB Hypopharyngeal Carcinoma AJCC v8
Head and Neck Squamous Cell Carcinoma
Squamous Cell Carcinoma of Unknown Primary
Stage IVA Hypopharyngeal Carcinoma AJCC v8
Pathologic Stage III HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8
Stage III Hypopharyngeal Carcinoma AJCC v8
Stage IVA Lip and Oral Cavity Cancer AJCC v8

Interventions: Biological: Cetuximab
Biological: Durvalumab
Radiation: Intensity-Modulated Radiation Therapy
Other: Laboratory Biomarker Analysis
Other: Quality-of-Life Assessment
Other: Questionnaire Administration

Registration Number: NCT03258554

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This phase II/III trial studies how well radiation therapy works with durvalumab or cetuximab in treating patients with head and neck cancer that has spread to a local and/or regional area of the body who cannot take cisplatin. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Cetuximab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. It is not known if radiation therapy with durvalumab will work better than the usual therapy of radiation therapy with cetuximab in treating patients with head and neck cancer.

Detailed Description: PRIMARY OBJECTIVES:

I. To determine the safety of radiotherapy (RT) with concurrent and adjuvant anti-PD-L1 therapy (MEDI4736 \[durvalumab\]) is safe in patients with locoregionally advanced head and neck cancer (HNC) who have a contraindication to cisplatin. (Lead-in) II. To test the hypothesis that concurrent RT and anti-PD-L1 therapy improves progression free survival (PFS) compared to standard therapy (RT with concurrent cetuximab) in patients with locoregionally advanced HNC who have a contraindication to cisplatin. (Phase II) III. To test the hypothesis that concurrent RT and anti-PD-L1 therapy improves overall survival compared to standard therapy (RT with concurrent cetuximab) in patients with locoregionally advanced HNC who have a contraindication to cisplatin. (Phase III)

SECONDARY OBJECTIVES:

I. To compare toxicity using Common Terminology Criteria for Adverse Events (CTCAE) and Patient Reported Outcomes (PRO)-CTCAE between patients treated with RT + anti-PD-L1 therapy versus RT/cetuximab.

II. To test the effect of anti-PD-L1 therapy in the subpopulation of patients with tumors that overexpress PD-L1.

III. To compare overall survival, response (at 4-month fludeoxyglucose F-18 \[FDG\]-positron emission tomography \[PET\]-computed tomography \[CT\]), locoregional failure, distant metastasis, and competing mortality in the two arms by known risk factors, including p16 status and omega score.

IV. To test the hypothesis that MEDI4736 (durvalumab) therapy arm will have less decline in the physical function domain of European Organization for Research and Treatment of Cancer Core Questionnaire (EORTC QLQ-C30 version 3.0) based on the change in score from baseline to 12 months from end of RT, compared to the cetuximab-RT arm in patients with locoregionally advanced HNC who have a contraindication to cisplatin.

V. To test the hypothesis that MEDI4736 (durvalumab) therapy arm at 1 year (from end of RT) will have less decline in swallowing related quality of life (QOL) using the M. D. Anderson Dysphagia Inventory (MDADI) total composite score, based on the change in score from baseline to 12 months from end of RT, compared to the cetuximab-RT arm in patients who are medically unfit for cisplatin.

VI. To compare swallowing related performance and function short and long term using the Performance Status Scale for Head \& Neck Cancer Patients (PSS-HN).

VII. To evaluate gastrostomy tube retention rates between arms.

EXPLORATORY OBJECTIVES:

I. To test the hypothesis that radiation combined with MEDI4736 (durvalumab) enhances the adaptive immune response using three types of immunophenotyping compared to radiation combined with cetuximab.

II. To compare overall QOL short term (end RT-8 months) and long term (12-24 months from end of RT) between arms using the EORTC QLQ-C30 version 3.0/HN35.

III. To evaluate swallowing related QOL short term (end RT-8 months) and long term (12-24 months from end of RT) using the EORTC Head and Neck (HN)35 swallowing domain and MDADI (subscales) between arms in patients with locoregionally advanced HNC who have a contraindication to cisplatin.

IV. To evaluate patient reported fatigue using the fatigue items in the EORTC QLQ and PRO-CTCAE.

V. To compare clinician and patient reported toxicity using CTCAE and PRO CTCAE.

VI. To explore health utilities between cetuximab and MEDI4736 (durvalumab) RT using the European Quality of Life 5 Dimensional-5 Level (EQ5D-5L).

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive cetuximab intravenously (IV) weekly over 60-120 minutes. Treatment repeats every week for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Beginning 5-7 days after first cetuximab dose, patients undergo intensity modulated radiation therapy (IMRT) 5 fractions per week for up to 7 weeks.

ARM II: Patients receive durvalumab IV over 60 minutes every 4 weeks. Treatment repeats every 4 weeks for up to 7 cycles in the absence of disease progression or unacceptable toxicity. Beginning week 2, patients undergo IMRT 5 fractions per week for up to 7 weeks.

After completion of study treatment, patients are followed up at 1 month, every 4 months for 1 year, every 6 months for 2 years, then annually thereafter.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 196

Inclusion Criteria

PRIOR TO STEP 1 REGISTRATION INCLUSION CRITERIA
Patients must have pathologically confirmed, previously untreated, unresected squamous cell carcinoma of the larynx, hypopharynx, oropharynx, oral cavity, or carcinoma of unknown head/neck primary prior to step 1 registration; submission of hematoxylin and eosin (H&E) stained slides and formalin-fixed and paraffin-embedded (FFPE) tissue block (or punch biopsy of FFPE block) to the biospecimen bank at University of California, San Francisco (UCSF) for central review for oropharyngeal and unknown primaries and for p16 analysis for all other non-oropharyngeal primaries is mandatory for all patients; investigators should check with their pathology department regarding release of biospecimens before approaching patients about participation in the trial; for oropharyngeal and unknown primaries, submission of H&E and p16 stained slides (with the required block for PD-L1) to the biospecimen bank at UCSF for central review is also required prior to step 2 registration
- Note: fine needle aspirates (FNA) samples are not acceptable since they do not provide enough material for PD-L1 and p16 testing; however, if a cell block derived from the FNA is available, it is allowable if there are sufficient cells present in the block for PD-L1 testing; Dr. Jordan will determine this upon receipt; for sites submitting FNA cell blocks for ALL patients they must do so within 7-10 business days from registering the patient; sites must confirm with their cytology/pathology labs to make sure they can provide the required material as the bank must be able to retain these samples for the mandatory testing
Patients must have locoregionally advanced head and neck squamous cell carcinoma (HNSCC)
- For p16-positive oropharyngeal/unknown primaries, American Joint Committee on Cancer [AJCC] 8th edition stage III and selected stage I-II based on smoking status in pack-years
- For laryngeal, hypopharyngeal, and oral cavity primaries and p16-negative oropharyngeal/unknown primaries, AJCC 8th edition stage III-IVB
- Based on the following minimum diagnostic workup within 60 days prior to step 1 registration:
  - General history and physical examination by a radiation oncologist or medical oncologist or ear, nose and throat (ENT) or head & neck surgeon
  - For larynx, hypopharynx, and base of tongue primaries, a laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) is required, unless the patient cannot tolerate or refuses
- Imaging of the head and neck with a neck CT or magnetic resonance imaging (MRI) (with contrast, unless contraindicated) or PET/CT; note that the CT portion of the PET/CT must be of diagnostic quality, including contrast administration unless contraindicated. If the CT portion of the PET/CT study is low-dose (non-diagnostic), then an additional CT or MRI study with contrast (unless contraindicated) is required
- Chest imaging: chest CT with and without contrast (unless contraindicated) or PET/CT
Patients must have a contraindication to cisplatin as defined in the following bullet points; sites must complete the online tool at comogram.org prior to step 1 registration to determine if the patient is eligible; the scores must be recorded on a case report form (CRF)
- Age >= 70 with moderate to severe comorbidity or vulnerability to cisplatin, defined as having one or more of the following conditions within 30 days prior to step 1 registration:
  - Modified Charlson Comorbidity Index >= 1
  - Adult Comorbidity Evaluation (ACE)-27 Index >= 1
  - Generalized Competing Event Model for Cancer Risk (GCE) omega PFS score < 0.80
  - Geriatric screening (G-8) score =< 14
  - Cancer and Aging Research Group (CARG) toxicity score >= 30%
  - Cumulative Illness Rating scale for Geriatrics (CIRS-G) score >= 4 OR
- Age < 70 with severe comorbidity or vulnerability to cisplatin, defined as having two or more of the following conditions within 30 days prior to step 1 registration
  - Modified Charlson Comorbidity Index >= 1
  - ACE-27 Index >= 1
  - GCE omega PFS-score < 0.80
  - G-8 score =< 14
  - CARG Toxicity score >= 30%
  - CIRS-G score >= 4 OR
- Age >= 18 with an absolute or relative contraindication to cisplatin, defined as one or more of the following within 30 days prior to step 1 registration:
  - Creatinine clearance (CC) > 30 and < 60 cc/min; for this calculation, use the Cockcroft-Gault formula
  - Zubrod performance status 2 prior to step 1 registration
  - Pre-existing peripheral neuropathy grade >= 1
  - History of hearing loss, defined as either:
    - Existing need of a hearing aid OR
    - >= 25 decibel shift over 2 contiguous frequencies on a pretreatment hearing test as clinically indicated
Absolute neutrophil count (ANC) >= 1,000 cells/mm^3 (within 14 days prior to step 1 registration)
Platelets >= 100,000 cells/mm^3 (within 14 days prior to step 1 registration)
Hemoglobin >= 9.0 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 9.0 g/dl is acceptable) (within 14 days prior to step 1 registration)
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 2.5 times institutional upper limit of normal (within 14 days prior to step 1 registration)
Serum bilirubin =< 1.5 x institutional upper limit of normal (within 14 days prior to step 1 registration)
Measured creatinine clearance (CL) > 30 mL/min or calculated creatinine CL > 30 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance (within 14 days prior to step 1 registration)
For women of childbearing potential, a negative serum or urine pregnancy test within 14 days prior to step 1 registration; Note: women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause; the following age-specific requirements apply:
- Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy)
- Women >= 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)
The patient or a legally authorized representative must provide study-specific informed consent prior to step 1 registration
PRIOR TO STEP 2 REGISTRATION INCLUSION CRITERIA
For patients with oropharyngeal or unknown primaries: p16 determination by immunohistochemistry (defined as greater than 70% strong nuclear or nuclear and cytoplasmic staining of tumor cells), confirmed by central pathology review
- Note: for patients with oral cavity, laryngeal, and hypopharyngeal primaries, analysis of p16 status prior to step 2 registration/randomization is not required (p16 status will be analyzed centrally post-hoc); step 2 registration for these patients can be completed after step 1 registration

Exclusion Criteria

PRIOR TO STEP 1 REGISTRATION EXCLUSION CRITERIA
Prior invasive malignancy within the past 3 years (except for non-melanomatous skin cancer, and early stage treated prostate cancer); synchronous head and neck primaries are ineligible
Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
- Note: Prior external beam radiotherapy is excluded, but iodine 131 is allowed
Prior immunotherapy
Prior systemic therapy, including cytotoxic chemotherapy, biologic/targeted therapy, or immune therapy for the study cancer
Major surgery within 28 days prior to step 1 registration
Proven evidence of distant metastases
If both of the following conditions are present, the patient is ineligible:
- =< 10 pack-year smoking history
- p16-positive carcinoma of the oropharynx or unknown primary that are T0-3, N0-1 (AJCC 8th Edition)
  - Note: in the event that a registered patient with =< 10 pack-years has a p16-positive result on central review with the tumor and nodal stage T0-3, N0-1 (AJCC 8th Edition), then the site will be notified that the patient is ineligible
Zubrod performance status >= 3
Body weight =< 30 kg
Patients with oral cavity cancer are excluded from participation if the patient is medically operable and resection of the primary tumor is considered technically feasible by an oral or head and neck cancers surgical subspecialist;(please consult the surgical oncology co-principal investigator [PI], Steven Chang, Doctor of Medicine [MD], if clarification is needed on an individual case)
Sodium < 130 mmol/L or > 155 mmol/L (within 14 days of step 1 registration, unless corrected prior to step 1 registration)
Potassium < 3.5 mmol/L or > 6 mmol/L (within 14 days of step 1 registration, unless corrected prior to step 1 registration)
Fasting glucose < 40 mg/dl or > 400 mg/dl (within 14 days of step 1 registration, unless corrected prior to step 1 registration)
Serum calcium (ionized or adjusted for albumin) < 7 mg/dl or > 12.5 mg/dl (within 14 days of step 1 registration, unless corrected prior to step 1 registration)
Magnesium < 0.9 mg/dl or > 3 mg/dl (within 14 days of step 1 registration, unless corrected prior to step 1 registration)
Unstable angina and/or congestive heart failure requiring hospitalization within 3 months prior to step 1 registration
Transmural myocardial infarction within 3 months prior to step 1 registration
Respiratory illness requiring hospitalization at the time of step 1 registration
- Note: if the respiratory illness is resolved and the patient meets the eligibility status above, then the patient can be considered for the trial
Idiopathic pulmonary fibrosis or other severe interstitial lung disease that requires oxygen therapy or is thought to require oxygen therapy within 1 year prior to step 1 registration
History of (non-infectious) pneumonitis that required steroids or current pneumonitis
Clinically apparent jaundice and/or known coagulation defects
Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis], Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.)
- The following are exceptions to this criterion:
  - Patients with vitiligo or alopecia;
  - Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement;
  - Any chronic skin condition that does not require systemic therapy;
  - Patients without active disease in the last 5 years may be included but only after consultation with the medical oncology study chair;
  - Patients with celiac disease controlled by diet alone
History of active primary immunodeficiency including, but not limited to acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; Note: human immunodeficiency virus (HIV) testing is not required for entry into this protocol; the need to exclude patients with AIDS from this protocol is necessary because the treatment involved in this protocol may be immunosuppressive; patients with known HIV, CD4 counts >= 200/uL, and undetectable viral loads who are stable on an antiretroviral regimen may be included
Current or prior use of immunosuppressive medication within 14 days before step 1 registration, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid
Receipt of live attenuated vaccination within 30 days prior to step 1 registration
Medical or psychiatric illness which would compromise the patient's ability to tolerate treatment or limit compliance with study requirements
Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception during treatment and for 6 months after the last dose of cetuximab or MEDI14736 (durvalumab); this exclusion is necessary because the treatment involved in this study may be significantly teratogenic; women who are breastfeeding are also excluded
Prior allergic reaction or hypersensitivity to cetuximab or MEDI4736 (durvalumab) or any of study drug excipients
History of allogenic organ transplantation
Uncontrolled hypertension
Uncontrolled cardiac arrhythmia
Uncontrolled serious chronic gastrointestinal condition associated with diarrhea
Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis [TB] testing in line with local practice), hepatitis B (known positive hepatitis B virus [HBV] surface antigen [HBsAg] result), hepatitis C; patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible; patients positive for hepatitis C (hepatitis C virus [HCV]) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (cetuximab, radiation therapy)	Laboratory Biomarker Analysis	Patients receive cetuximab IV weekly over 60-120 minutes. Treatment repeats every week for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Beginning 5-7 days after first cetuximab dose, patients undergo IMRT 5 fractions per week for up to 7 weeks.
Arm II (durvalumab, radiation therapy)	Intensity-Modulated Radiation Therapy	Patients receive durvalumab IV over 60 minutes every 4 weeks. Treatment repeats every 4 weeks for up to 7 cycles in the absence of disease progression or unacceptable toxicity. Beginning week 2, patients undergo IMRT 5 fractions per week for up to 7 weeks.
Arm II (durvalumab, radiation therapy)	Quality-of-Life Assessment	Patients receive durvalumab IV over 60 minutes every 4 weeks. Treatment repeats every 4 weeks for up to 7 cycles in the absence of disease progression or unacceptable toxicity. Beginning week 2, patients undergo IMRT 5 fractions per week for up to 7 weeks.
Arm II (durvalumab, radiation therapy)	Questionnaire Administration	Patients receive durvalumab IV over 60 minutes every 4 weeks. Treatment repeats every 4 weeks for up to 7 cycles in the absence of disease progression or unacceptable toxicity. Beginning week 2, patients undergo IMRT 5 fractions per week for up to 7 weeks.
Arm I (cetuximab, radiation therapy)	Cetuximab	Patients receive cetuximab IV weekly over 60-120 minutes. Treatment repeats every week for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Beginning 5-7 days after first cetuximab dose, patients undergo IMRT 5 fractions per week for up to 7 weeks.
Arm II (durvalumab, radiation therapy)	Durvalumab	Patients receive durvalumab IV over 60 minutes every 4 weeks. Treatment repeats every 4 weeks for up to 7 cycles in the absence of disease progression or unacceptable toxicity. Beginning week 2, patients undergo IMRT 5 fractions per week for up to 7 weeks.
Arm II (durvalumab, radiation therapy)	Laboratory Biomarker Analysis	Patients receive durvalumab IV over 60 minutes every 4 weeks. Treatment repeats every 4 weeks for up to 7 cycles in the absence of disease progression or unacceptable toxicity. Beginning week 2, patients undergo IMRT 5 fractions per week for up to 7 weeks.
Arm I (cetuximab, radiation therapy)	Intensity-Modulated Radiation Therapy	Patients receive cetuximab IV weekly over 60-120 minutes. Treatment repeats every week for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Beginning 5-7 days after first cetuximab dose, patients undergo IMRT 5 fractions per week for up to 7 weeks.
Arm I (cetuximab, radiation therapy)	Quality-of-Life Assessment	Patients receive cetuximab IV weekly over 60-120 minutes. Treatment repeats every week for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Beginning 5-7 days after first cetuximab dose, patients undergo IMRT 5 fractions per week for up to 7 weeks.
Arm I (cetuximab, radiation therapy)	Questionnaire Administration	Patients receive cetuximab IV weekly over 60-120 minutes. Treatment repeats every week for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Beginning 5-7 days after first cetuximab dose, patients undergo IMRT 5 fractions per week for up to 7 weeks.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Dose-limiting Toxicity (DLT) [Lead-in Phase]	From start of durvalumab to 4 weeks after radiation therapy, approximately 13 weeks. Weekly during RT, at RT end, prior to adjuvant durvalumab, one month after end of RT.	DLTs were collected to verify the safety of durvalumab with RT in this population. Safety was determined if ≤ 2 of 8 participants in the cohort had any DLT, in which case the study would proceed to phase II with that dose schedule (DS). The probability for the DS to be deemed too toxic, given a true toxicity rate ≥ 45%, is at least 78%. With a true toxicity rate ≤ 20%, the probability for the DS do be deemed safe is 80%. The full DLT definition does not fit here, but includes all grade 5 AEs, grade 3 or 4 AEs definitely or probably related to durvalumab (DPRD) except for specified AEs and situations, and incomplete or \> 2-week delay completing RT due to immune toxicity DPRD. AEs were graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, which grade severity from 1=mild to 5=death. Two alternate DSs with a delayed 2nd dose (to reduce/avoid doses concurrent with RT) would be tried if the initial DS was too toxic.
Progression-free Survival (Percentage of Participants Alive Without Progression) [Phase II Primary]	From randomization to last follow-up: weekly during RT, after end of RT: every 4 months for 1 year, every 6 months for 2 years, then annually. Additionally, every 4 weeks during adjuvant durvalumab. Maximum follow-up at time of analysis was 4.2 years.	Progression (failure) is defined as local, regional, or distant disease progression, or death from any cause. Progression was assessed by imaging, clinical assessment, or biopsy. Failure time is defined as time from randomization to failure or last follow-up (censored). Failure rates are estimated using the Kaplan-Meier method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Two-year estimates are provided. Analysis was planned to occur after 69 failure events had been reported.
Overall Survival (Percentage of Participants Alive) [Originally Phase III Primary / Now Phase II Secondary]	From randomization to last follow-up: weekly during RT, after end of RT: every 4 months for 1 year, every 6 months for 2 years, then annually. Additionally, every 4 weeks during adjuvant durvalumab. Maximum follow-up at time of analysis was 4.2 years.	Overall survival (OS) time is defined as time from randomization to the date of death from any cause or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Two-year estimates are provided.

Secondary Outcome Measures

Name	Time	Method
Locoregional Failure (Percentage of Participants With Locoregional Failure)	From randomization to last follow-up: weekly during RT, after end of RT: every 4 months for 1 year, every 6 months for 2 years, then annually. Additionally, every 4 weeks during adjuvant durvalumab. Maximum follow-up at time of analysis was 4.2 years.	Locoregional progression is defined as local or regional progression or recurrence, death due to study cancer or unknown causes without documented progression. Progression was assessed by imaging, clinical assessment, or biopsy. Failure time is defined as time from randomization to failure, distant metastasis (competing risk), deaths from other causes (competing risk), or last follow-up (censored). Failure rates are estimated using the cumulative incidence method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Two-year estimates are provided.
Distant Metastasis (Percentage of Participants With Distant Metastasis)	From randomization to last follow-up: weekly during RT, after end of RT: every 4 months for 1 year, every 6 months for 2 years, then annually. Additionally, every 4 weeks during adjuvant durvalumab. Maximum follow-up at time of analysis was 4.2 years.	Failure is defined as the occurrence of distant metastasis. Failure time is defined as time from randomization to first occurrence of distant metastasis, local or regional progression or recurrence (competing risk), death (competing risk), or last follow-up (censored). Failure rates are estimated using the cumulative incidence method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Two-year estimates are provided.
Competing Mortality (Percentage of Participants Who Died Due to Causes Other Than Study Cancer)	From randomization to last follow-up: weekly during RT, after end of RT: every 4 months for 1 year, every 6 months for 2 years, then annually. Additionally, every 4 weeks during adjuvant durvalumab. Maximum follow-up at time of analysis was 4.2 years.	Failure is defined as Death from second primary, protocol treatment, or "other cause". Failure time is defined as time from randomization to first occurrence of failure, death due to study cancer or unknown cause (competing risk), or last follow-up (censored). Failure rates are estimated using the cumulative incidence method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Two-year estimates are provided.
Percentage of Participants With Complete or Partial Response at 4-month Scan Determined by Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1	Baseline and 4 months after end of RT (approximately 6.5 months)	Fludeoxyglucose F-18 positron emission tomography/computed tomography (FDG-PET/CT) scans at baseline and four months after the end of radiation therapy are compared. Per RECIST 1.1: * Complete response: * Disappearance of all lesions and pathologic lymph nodes * Partial response: * ≥ 30% decrease sum of the longest diameters * No new lesions * No progression of non-target lesions
Number of Participants by Highest Grade Adverse Event Reported	From randomization to last follow-up: weekly during RT, RT end, from end of RT: months 1, (Cetuximab: 2, 3,) 4, 8, 12, 18, 24, 30, 36, then annually. Additionally, prior to each adjuvant durvalumab cycle. Maximum follow-up at time of analysis= 4.2 yr.	Common Terminology Criteria for Adverse Events (version 5.0) grades adverse event severity from 1=mild to 5=death. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data.
Change in Quality of Life (QOL) Analysis	Baseline up to 12 months	Assessed using European Organization for Research and Treatment of Cancer Core Questionnaire (EORTC QLQ)/Head-and-Neck module (H\&N35), EuroQol- 5 Dimension (EQ5D), M. D. Anderson Dysphagia Inventory (MDADI), patient reported outcomes (PRO)-CTCAE, geriatric screening (G8). The mean summary score of the EORTC QLQ/H\&N35, EQ5D, MDADI, PRO-CTCAE, G8, CCI, and the subscales will be determined. The mean change from baseline at each time point will be summarized using mean and standard deviations for each arm. Mean change from baseline will be compared between the arms using a two sample t test. If data normality assumptions are not met, the Wilcoxon rank sum test will be used to test the hypothesis. Mean change from baseline will be tested using an omnibus F test followed by individual comparisons of change scores at different time points within each treatment group. The same analysis will be conducted for between group comparisons at each time point.
Change in Swallowing QOL Using Total Composite M. D. Anderson Dysphagia Inventory (MDADI) Score	Baseline up to 1 year	The mean change from baseline at each time point will be summarized using mean and standard deviations for each arm. Mean change from baseline will be compared between the arms using a two sample t test. If data normality assumptions are not met, the Wilcoxon rank sum test will be used to test the hypothesis.
Progression-free Survival (Percentage of Participants Alive Without Progression) by Baseline PD-L1 (Programmed Cell Death Ligand 1) Expression	From randomization to date of progression or last follow-up, whichever occurs first. Maximum follow-up at time of analysis was 4.2 years. Two-year PFS estimates are reported.	Failure for progression-free survival is defined as local, regional, or distant disease progression, or death from any cause. Progression was assessed by imaging, clinical assessment, or biopsy. Failure time is defined as time from randomization to failure or last follow-up (censored). PD-L1 expression is defined by a combined positive score (CPS) ≥ 1, assessed by masked central analysis of baseline tissue specimens. CPS = \[(number of tumor cells positive for PD-L1) / (number of tumor cells positive for PD-L1 + number of tumor cells negative for PD-L1)\] multiplied by 100, yielding a possible score of 0 to 100. Treatment effect hazard ratios within PD-L1 subgroup were estimated by Cox proportional hazards model and progression-free survival estimates were estimated by Kaplan-Meier method. Analysis was planned to occur after 69 failure events had been reported and tissue specimen analysis was complete.
Progression-free Survival (Percentage of Participants Alive Without Progression) by Baseline p16 Status	From randomization to date of progression or last follow-up, whichever occurs first. Maximum follow-up at time of analysis was 4.2 years. Two-year PFS estimates are reported.	Failure for progression-free survival is defined as local, regional, or distant disease progression, or death from any cause. Progression was assessed by imaging, clinical assessment, or biopsy. Failure time is defined as time from randomization to failure or last follow-up (censored). Positive p16 status was defined as more than 70% strong nuclear or nuclear and cytoplasmic staining of tumor cells, confirmed by central pathology review. Treatment effect hazard ratios within p16 subgroup were estimated by Cox proportional hazards model and progression-free survival estimates were estimated by Kaplan-Meier method. Analysis was planned to occur after 69 failure events had been reported and tissue specimen analysis was complete.

Trial Locations

Locations (256): Springfield Memorial Hospital
🇺🇸
Springfield, Illinois, United States
Logan Health Medical Center
🇺🇸
Kalispell, Montana, United States
University of Alabama at Birmingham Cancer Center
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Birmingham, Alabama, United States
University of South Alabama Mitchell Cancer Institute
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Mobile, Alabama, United States
Banner MD Anderson Cancer Center
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Gilbert, Arizona, United States
CTCA at Western Regional Medical Center
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Goodyear, Arizona, United States
Banner University Medical Center - Tucson
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Tucson, Arizona, United States
University of Arizona Cancer Center-North Campus
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Tucson, Arizona, United States
Kaiser Permanente-Deer Valley Medical Center
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Antioch, California, United States
Sutter Cancer Centers Radiation Oncology Services-Auburn
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Auburn, California, United States
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Springfield Memorial Hospital
🇺🇸Springfield, Illinois, United States