Birinapant and Intensity Modulated Re-Irradiation Therapy for Local-Regionally Recurrent Head and Neck Squamous Cell Carcinoma

Background:

- Head and neck squamous cell carcinomas (HNSCC) affect 52,000 new patients and cause
approximately 11,000 deaths in the U.S. annually.

- The Cancer Genome Atlas recently uncovered amplifications of chromosome 11q13/22 in
approximately 30% of HNSCC.

- The 11q13/22 loci harbor genes Fas Associated Death Domain (FADD) and Baculovirus
Inhibitor of apoptosis Repeat Containing (BIRC2/cIAP1). A mutually exclusive subset
harboring mutation of caspase 8 (CASP8) affects an additional 10% of HPV- cases.
Further, deletions in Tumor Necrosis Factor Associated Factor 3 and overexpression of
BIRC3 (cIAP2) are detected in 20% of HPV+ HNSCC.

- These genes encode proteins that form critical components of the Tumor Necrosis Factor
Receptor/Death Domain Receptor signaling complex, which is deregulated and implicated in
cell survival and therapeutic resistance in cancer.

- Based on pre-clinical studies, birinapant plus radiation demonstrates anti-tumor
activity and improved survival, but the dose, schedule and tolerability in human studies
needs to be determined.

Objectives:

-The primary objective is to determine the toxicities and maximum tolerated dose (MTD) of
birinapant concurrent with IMRRT

Eligibility:

-Patients must have histologically or cytologically confirmed locally recurrent HNSCC for
whom re-irradiation for local control is considered standard of care.

Design:

-Birinapant dose levels include 5.6, 11, 17 and 24mg/m2 IV on days 2 and 9 of each cycle. The
primary endpoints are acute toxicities and the MTD for 2/3 week and weekly administration
schedule of birinapant plus re-IMRT. Secondary clinical endpoints include overall response by
PET- CT and RECIST criteria at 2 months post treatment, delayed toxicities, duration of local
and regional control, progression free survival (PFS), Overall Survival (OS), and Whole
ExomeSequencing of tumor biopsies. Exploratory endpoints are FADD and BIRC2 copy number.

- 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 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.

- Age greater than or equal to 18 years.

- ECOG performance status less than or equal to 2 (see Appendix A).

- Patients must have normal organ and marrow function as defined below:

- Hemoglobin greater than or equal to 10 g/dL (transfusion permitted)

- Absolute neutrophil count greater than or equal to 1,500/mcL

- Platelets greater than or equal to 75,000/mcL

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

- AST(SGOT)/ALT(SGPT) less than or equal to 2.5 (SqrRoot) institutional upper limit
of normal

- Creatinine clearance greater than or equal to 60 mL/min/1.73 m squared for
patients with creatinine levels above institutional normal.

- Patients must have a QTc less than or equal to 480 msec.

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

- Patients must have measurable disease.

EXCLUSION CRITERIA:

- Eligibility for curative-intent surgery.

- More than 2 lines of palliative systemic therapy (platinum-, taxane- or cetuximabbased
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.

- 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, and16 days for etanercept).

- Patients with previous exposure to birinapant.