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

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.

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 within 60 days 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 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

- 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 any 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 <
0.60

- 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 < 0.60

- 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

- 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)

- Prior radiotherapy to the region of the study cancer that would result in overlap of
radiation therapy fields

- 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)