Birinapant and Intensity Modulated Re-Irradiation Therapy in Treating Patients With Locally Recurrent Head and Neck Squamous Cell Carcinoma

PRIMARY OBJECTIVES:

I. Determine the toxicities and maximum tolerated dose (MTD) of birinapant concurrent with
intensity modulated re-irradiation therapy (IMRRT).

SECONDARY OBJECTIVES:

I. Determine the objective response rate of patients with locoregionally recurrent head and
neck squamous cell carcinoma (HNSCC) treated with re-irradiation and birinapant.

II. Determine the local-regional control, progression free survival (PFS), and overall
survival.

III. Determine if FADD and/or BIRC2/3 copy gain in tumor tissue or in the blood are
associated with improved response, locoregional control (LCR), progression-free survival and
overall survival.

IV. Determine the feasibility of detecting effects of birinapant and re-irradiation on pilot
pharmacodynamic markers in tumor tissue, including microwestern for decrease in drug targets
IAP1/2; increase in apoptosis/necroptosis markers caspase 3 and MLKL.

EXPLORATORY OBJECTIVES:

I. Determine if mutational load detected with whole exome and ribonucleic acid
(RNA)-sequencing of tumor tissue influences objective response rate.

II. Determine if PD-L1, CD8 T-cell tumor infiltration, TNFalpha, and other immune related
biomarkers in tumor tissue are associated with objective response rate.

III. Explore the pharmacokinetics of birinapant in combination with radiotherapy in blood
samples.

OUTLINE: This is a dose-escalation study of birinapant.

Beginning on day 1, patients undergo IMRRT 5 days a week (Monday-Friday). Patients also
receive birinapant intravenously (IV) over 30 minutes on days 2 and 9 of each cycle.
Treatment repeats every 3 weeks for up to 2 cycles in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up at 28 days, and at 3, 6, 12,
and 24 months until confirmation of disease progression.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed locally recurrent HNSCC
for whom re-irradiation for local control is considered standard of care. Patients
with potentially reactive benign nodes will not be excluded

- Patients with human papillomavirus (HPV)-negative or HPV-positive head and neck cancer
are eligible

- Patients who have had prior treatment with immune therapies are eligible

- Patients must have received curative-intent platinum- and/or cetuximab-based
chemoradiotherapy

- Patients must have completed their last treatment dose with chemotherapy or
immunotherapy at least 4 weeks (6 weeks for nitrosoureas or mitomycin C) before
enrolling on study

- Patients must have completed their last treatment dose with radiotherapy at least 6
months before enrolling on study

- Patients who have had major surgery must be fully recovered and require a recovery
period of at least 4 weeks prior to enrolling on study

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Hemoglobin >= 10 g/dL (transfusion permitted)

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 75,000/mcL

- Total bilirubin within 1.5 x the upper limit of normal (ULN) institutional limits

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional upper limit of normal

- Creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above
institutional normal

- Patients must have a corrected QT (QTc) =< 480 msec

- Ability to understand and the willingness to sign a written informed consent document

- Patients must have measurable disease, per Response Evaluation Criteria in Solid
Tumors (RECIST) 1.1

Exclusion Criteria:

- Eligibility for curative-intent surgery

- More than 2 lines of palliative systemic therapy (platinum-, taxane- or
cetuximab-based chemotherapy or immunotherapy)

- Patients who are receiving any other investigational agents

- Patients with known brain metastases should be excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to birinapant

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study because birinapant may have potential for
teratogenic or abortifacient effects. Because there is an unknown but potential risk
for adverse events in nursing infants secondary to treatment of the mother with
birinapant, breastfeeding should be discontinued prior to enrollment

- Human immunodeficiency virus (HIV) positive patients on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions with
birinapant

- Patients requiring the use of anti-tumor necrosis factor (anti TNF) therapies, such as
infliximab, or patients who have received treatment with anti-TNF therapies within 5
half-lives of the drug (48 days for infliximab, 55 days for golimumab, 70 days for
certolizumab and adalimumab, and 16 days for etanercept)

- Patients with previous exposure to birinapant