Durvalumab and Tremelimumab With Radiotherapy for Adjuvant Treatment of Intermediate Risk SCCHN

Primary Objectives

- To determine a safe adjuvant immunotherapy regimen that includes durvalumab with or
without tremelimumab to combine with radiotherapy in intermediate-risk HNSCC patients
based on dose limiting toxicities.

- To characterize safety by evaluating Grade 3-5 acute toxicities of adjuvant durvalumab
and tremelimumab with radiotherapy in intermediate-risk HNSCC patients.

Secondary Objectives

- To characterize the Grade 3-4 chronic toxicities of adjuvant durvalumab and tremelimumab
with radiotherapy in intermediate-risk HNSCC patients.

- To characterize any-grade chronic toxicities of adjuvant durvalumab and tremelimumab
with radiotherapy in intermediate-risk HNSCC patients.

- To estimate median disease free survival (DFS) in patients with intermediate-risk HNSCC
treated with adjuvant durvalumab and tremelimumab with radiotherapy.

- To estimate median overall survival (OS) in patients with intermediate-risk HNSCC
treated with adjuvant durvalumab and tremelimumab with radiotherapy.

- To correlate PD-L1 expression with disease free survival.

Exploratory Objectives

- To correlate CTLA-4 expression with disease free survival

- To analyze disease free survival by Human papilloma virus (HPV) status

- To determine how treatment with adjuvant durvalumab, tremelimumab, and radiotherapy
changes markers of tumor infiltrating lymphocytes (TIL)

Primary Endpoints

- A safe immunotherapy regimen with radiation will be determined based on pre-defined dose
limiting toxicities following standard 3+3 regimen de-escalation rules outlined in the
study schema in section 5.1.

- 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 the
immunotherapy alone.

Secondary Endpoints

- 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.

- 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.

- 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 Programmed cell death ligand 1 (PD-LI) expression by immunohistochemistry.
Pre-treatment PD-L1 expression will be correlated with disease free survival following
treatment of adjuvant durvalumab and tremelimumab with radiotherapy

Exploratory Endpoints

- Measure Cytotoxic T lymphocyte associated antigen 4 (CTLA-4) expression by
immunohistochemistry. Pre-treatment CTLA-4 expression will be correlated with disease
free survival following treatment of adjuvant durvalumab and tremelimumab with
radiotherapy

- Measure HPV status. HPV status will be correlated with disease free survival following
treatment of adjuvant durvalumab and tremelimumab 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 I trial includes a traditional 3 + 3 dose regimen de-escalation
rules to evaluate the combination of durvalumab + tremelimumab with radiation therapy based
on three possible combination regimens (Table 1). In regimen cohort 1, three patients will
receive durvalumab (1500mg Q3W) with tremelimumab (75 mg IV Q3W) for four total cycles. They
will receive radiation therapy (60Gy over 30 fractions) during cycles 2-4. During Cycle 5 and
6, only durvalumab 1500mg Q3W will be given. Patients will be assessed for dose limiting
toxicity (DLT) during cycles 1-4. If ≤1 patient experiences a DLT in cohort 1 on this regimen
per the 3+3 rules outlined above, then the study will continue to enroll subjects on this
regimen in the dose expansion cohort. If ≥2 patients experience DLTs on this regimen in
cohort 1, it will be deemed intolerable and cohort -1 will be opened for enrolment. Three
patients will be enrolled to receive durvalumab (1500mg Q3W) with tremelimumab (75 mg IV Q6W)
in regimen cohort -1. Similarly, if ≤1 patient experiences a DLT at regimen level -1, then
the study will continue to enroll patients in the dose expansion cohort. If ≥2 patients
experience DLTs at regimen level -1, then regimen level -2 will be opened for enrolment and
three patients will receive durvalumab (1500mg Q3W) alone with radiotherapy in this cohort.
If ≤ 1 patient experiences a DLT at regimen level -2, then this cohort will be expanded and
subjects treated on this combination regimen. If ≥2 patients experience DLTs at regimen level
-2, then the study will be discontinued.

The acceptable regimen will be defined as the immunotherapy and radiotherapy combination at
which ≤1 out of 6 patients have experienced a dose limiting toxicity (DLT). As noted in the
schema above, expanded enrollment of subjects on the combination regimen selected will accrue
24 subjects.

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.

Inclusion Criteria:

- 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
enrollment.

- Age ≥ 18 years of age on day of signing informed consent

- Eastern Cooperative Oncology Group (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 > 3cm or at least 2 nodes without evidence of extracapsular
extension

- 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
recurrent disease).

- Demonstrate adequate organ function as defined in the table below; all screening labs
to be obtained within 14 days prior to initiating study treatment

- Women of childbearing potential (WOCBP) must have a negative serum pregnancy test
within 24 days prior to registration. 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 180
days after durvalumab and tremelimumab combination therapy is stopped; or 90 days
after durvalumab monotherapy treatment is discontinued (whichever is longer).

- 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 6 months (180 days) after
the last dose of durvalumab and tremelimumab combination therapy; or 90 days after
durvalumab monotherapy is discontinued (whichever is longer).

- Subjects are willing and able to comply with study procedures based on the judgment of
the investigator or protocol designee.

Exclusion Criteria:

Subjects meeting any of the following exclusion criteria will not be able to participate in
this study:

- 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
interventional study.

- 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.

- Known allergy or hypersensitivity to any of the study drugs or any of the study drug
excipients.

- Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical
study regardless of treatment arm assignment.

- Current or prior use of immunosuppressive medication within 14 days before the first
dose of durvalumab or tremelimumab. The following are exceptions to this criterion:

- Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
articular injection)

- 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 premedication)

- 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 (TB) (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 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 or 180 days after the last dose of durvalumab +
tremelimumab combination therapy.

- 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 investigational product (IP) and of low potential risk for
recurrence

- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of
disease

- 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 that require intermittent use of bronchodilators or local steroid injections
would not be excluded from the study.

- Subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will
not be excluded from the study

- Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone
replacement

- Any chronic skin condition that does not require systemic therapy

- Subjects without active 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 28 days prior to the
first dose of 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 treatment.