The purpose of this study is to investigate other drugs that may be combined with radiation
to treat cancer. The study focuses on determining whether a combination of durvalumab with
radiation can both improve cure rate and at the same time have less serious side effects.
Throughout this document, this investigational drug will be referred to as the "study drug",
or named individually (durvalumab). The study drug in this research is referred to as
investigational because the U.S. Food and Drug Administration (FDA) has not yet approved
itfor the treatment of head and neck cancer. Durvalumab was FDA approved in 2017 for the
treatment of certain types of bladder cancer, but has not been approved for use in Head and
Neck cancer patients.
Durvalumab is an experimental drug that uses the body's immune system to fight the cancer.
This study drug is being used in other ongoing clinical trials for other types of cancers.
The doctor feels that a patient may experience fewer side effects using this study drug with
radiation rather than using cisplatin. The doctor is also investigating whether using this
drug can increase the effectiveness of treatment.
Primary Objective -To estimate median 3-year disease free survival (DFS) in patients with
intermediate-risk HNSCC treated with adjuvant durvalumab with radiotherapy.
- To characterize safety by evaluating Grade 3-4 acute toxicities of adjuvant durvalumab
with radiotherapy in intermediate-risk HNSCC patients
- To characterize the Grade 3-4 chronic toxicities of adjuvant durvalumab with
radiotherapy in intermediate-risk HNSCC patients.
- To characterize any-grade chronic toxicities of adjuvant durvalumab with radiotherapy in
intermediate-risk HNSCC patients.
- To estimate median OS in patients with intermediate-risk HNSCC treated with adjuvant
durvalumab with radiotherapy.
- To correlate PD-L1 expression with disease free survival
- To analyze disease free survival by HPV status
- To determine how treatment with adjuvant durvalumab and radiotherapy changes markers of
tumor infiltrating lymphocytes (TIL)
-3-year DFS will be estimated via the Kaplan-Meier method. DFS is defined as the time from D1
of treatment to time of disease recurrence or death
- Grade 3-5 acute toxicity will be evaluated according to guidelines from NCI CTCAE, v5.0
and include toxicity from the first day of treatment with immunotherapy until 30 days
after completion of concurrent immunotherapy and radiation. Toxicity will include all
toxicity attributed to the total study regimen (inclusive of radiation) not just to
- Grade chronic 3-5 toxicity will be evaluated according to guidelines from NCI CTCAE,
v5.0 and include toxicity continuing or occurring 30 days after completion of concurrent
immunotherapy and radiation, and will be followed for up to 6 months.
- OS will be estimated via the Kaplan-Meier method. OS is defined as the time from D1 of
treatment to death from any cause.
- Measure PD-LI expression by immunohistochemistry. Pre-treatment PD-L1 expression will be
correlated with disease free survival following treatment of adjuvant durvalumab with
- Measure HPV status. HPV status will be correlated with disease free survival following
treatment of adjuvant durvalumab with radiotherapy
- Measure tumor infiltrating lymphocytes (TIL) by flow cytometry at baseline
(post-surgical, pre-treatment tissue) and at disease progression (post-treatment
tissue). Changes in TIL levels will be compared between these two time points.
Treatment Dosage This Phase II trial will evaluate the combination of durvalumab with
radiation therapy as post-operative therapy in intermediate risk patients with HNSCC. All
patients will receive durvalumab and radiation therapy during cycles 1-3. Radiation therapy
is administered per standard radiation oncology regimens, on a daily basis and/or as
scheduled during a Monday-Friday working week. Radiation therapy is given concurrently with
durvalumab during Cycles 1-3. Durvalumab treatment (1500 mg Q3W) Cycles 1-3 are 3-weeks long
cycles (total of 9 weeks). Radiation therapy will be delivered at a dose of 2 Gy over 30
fractions totalling a final dose of 60 Gy. Radiation treatment will take 6 weeks (Mon-Fri) or
30 days and will occur for 6 of 9 weeks that define Cycles 1-3. However, due to delays or
missed appointments, completion of those 30 fractions may take longer than the allotted 6
weeks and this is allowed. Radiation therapy must be scheduled and completed within Cycles
1-3 and should not extend into Cycle 4. Please refer to Section 6.2 for additional details
During Cycle 4-6, only durvalumab 1500mg Q4W will be given.
Duration of Follow Up All patients will be followed for up to 5 years, or until death,
whichever occurs first after removal from study treatment for determination of study
endpoints. Patients removed from study treatment for unacceptable adverse event (AE)s will be
followed for resolution or stabilization of the adverse event(s). All patients (including
those withdrawn for AEs) should be followed after removal from study treatment as stipulated
in the protocol.
- Written informed consent obtained to participate in the study and HIPAA authorization
for release of personal health information. Consent for the use of any residual
material from biopsy (archival tissue) and serial blood draws will be required for
- Age ≥ 18 years of age on day of signing informed consent
- ECOG Performance Status of 0 or 1 (See Appendix 12.4: ECOG Performance Status)
- Histologically confirmed squamous cell carcinoma of the head and neck, including the
following subtypes: oral cavity, oropharynx, hypopharynx, larynx
- Must have undergone gross total resection of the primary tumor with curative intent
within the past 8 weeks with surgical pathology demonstrating ≥ 1 of the following
criteria for "intermediate" risk of recurrence:
- perineural invasion
- lymphovascular invasion
- single lymph node > 3 cm or at least 2 nodes without evidence of extracapsular
- close margins defined as < 5 mm but not frankly positive (in the case of
ambiguous, controversial, or superseded margins, final clinical assessment
regarding margin status will prevail)
- pathologically confirmed T3 or T4 primary tumor
- No prior therapy to primary tumor prior to surgical resection (no induction therapy or
- Demonstrated adequate organ function as defined in the protocol
- Women of childbearing potential (WOCBP) must have a negative serum pregnancy test
within 7 days prior to treatment. NOTE: Females are considered of child bearing
potential unless they are surgically sterile (have undergone a hysterectomy, bilateral
tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at
least 12 consecutive months. Documentation of postmenopausal status must be provided.
- WOCBP must be willing to abstain from heterosexual activity or to use at least 1
highly effective method of contraception from the time of informed consent until 90
days after durvalumab monotherapy treatment is discontinued (whichever is longer). See
section 5.6 of the protocol for additional details on contraception requirements for
WOCBP and male participants in this trial.
- Male patients with female partners must have had a prior vasectomy or agree to use an
adequate method of contraception (i.e., double barrier method: condom plus spermicidal
agent) starting with the first dose of study therapy through 90 days after durvalumab
monotherapy is discontinued.
- Subjects must be willing and able to comply with study procedures based on the
judgment of the investigator or protocol designee.
Subjects meeting any of the following exclusion criteria will not be able to participate in
- Is currently participating in or has participated in a study of an investigational
agent or an investigational device within 4 weeks of the first dose of treatment.
- Concurrent enrollment in another clinical study, unless it is an observational
(non-interventional) clinical study or during the follow-up period of an
- Has evidence of metastatic disease at time of diagnosis
- Is receiving concurrent chemotherapy, investigational drug, biologic, or hormonal
therapy for cancer treatment. Concurrent use of hormonal therapy for
non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
- Treatment with any investigational drug within 28 days or 5 half-lives of Day 1 of
treatment on this study, whichever is shortest.
- Has not received any antibiotics <7 days prior to 1st dose of durvalumab. If the
patient receives either IV antibiotics or >5 day treatment course (oral or IV), then
the 1st durvalumab dose should not be given until 14 days of last antibiotic dose.
During eligibility screening, subjects who receive any antibiotics within 30 days
prior to the proposed initial infusion of durvalumab should be flagged and reviewed by
the site's Principle Investigator to determine if the subject is a good candidate to
- Known allergy or hypersensitivity to durvalumab or any of the study drug excipients.
- Prior randomization or treatment in a previous durvalumab clinical study regardless of
treatment arm assignment.
- Current or prior use of immunosuppressive medication within 14 days before the first
dose of durvalumab. The following are exceptions to this criterion:
- Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or its equivalent
- Steroids as premedication for hypersensitivity reactions (e.g., CT scan
- Has received systemic steroid therapy or any other form of immunosuppressive therapy
within 7 days prior to the first dose of trial treatment.
- Active infection requiring systemic therapy including tuberculosis (clinical
evaluation that includes clinical history, physical examination and radiographic
findings, and TB testing in line with local practice), hepatitis B (known positive HBV
surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus
(positive HIV 1/2 antibodies).
- 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 (HCV) antibody are eligible only if polymerase
chain reaction is negative for HCV RNA.
- Has a known contraindication to radiation therapy, including inherited syndromes
associated with hypersensitivity to ionizing radiation such as Ataxia-Telangiectasia
and Nijmegen Breakage Syndrome
- Has a history of uncontrolled liver disease (including but not limited to cirrhosis).
- Subjects with baseline weight ≤ 40kg (88 lbs).
- Female patients who are pregnant or breastfeeding (NOTE: breast milk cannot be stored
for future use while the mother is being treated on study) or male or female patients
of reproductive potential who are not willing to employ effective birth control from
screening to 90 days after the last dose of durvalumab monotherapy.
- History of another primary malignancy except for.
- Malignancy treated with curative intent and with no known active disease ≥5 years
before the first dose of IP and of low potential risk for recurrence
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
- Adequately treated carcinoma in situ without evidence of disease
- History of leptomeningeal carcinomatosis.
- Has an active autoimmune disease (or inflammatory disorders) requiring systemic
treatment within the past 3 months or a documented history of clinically severe
autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive
agents. Subjects with 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:
- Subjects with vitiligo or alopecia or resolved childhood asthma/atopy
- Subjects who require intermittent use of bronchodilators or local steroid injections
would not be excluded from the study.
- Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone
replacement or with Sjorgen's syndrome will not be excluded from the study
- Any chronic skin condition that does not require systemic therapy
- Subjects without active HNSCC disease in the last 5 years may be included but only
after consultation with the study physician
- Subjects with celiac disease controlled by diet alone
- Has a history of non-infectious pneumonitis that required steroids or evidence of
interstitial lung disease or current active, non-infectious pneumonitis.
- Major surgical procedure (as defined by the Investigator) within 21 days prior to
the first dose of investigational product (IP). Note: Local surgery of isolated
lesions for palliative intent is acceptable.
- Uncontrolled intercurrent illness, including but not limited to, ongoing or
active infection, symptomatic congestive heart failure, uncontrolled
hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung
disease, serious chronic gastrointestinal conditions associated with diarrhea, or
psychiatric illness/social situations that would limit compliance with study
requirement, substantially increase risk of incurring AEs or compromise the
ability of the patient to give written informed consent.
- Receipt of live attenuated vaccine within 30 days prior to the first dose of
study drug. Note: Patients, if enrolled, should not receive live vaccine whilst
receiving study treatment and up to 30 days after the last dose of study