Combination Chemotherapy With or Without Veliparib in Treating Patients With Stage IV Head and Neck Cancer

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose (MTD), recommended phase II dose, dose limiting
toxicity (DLT), and safety of ABT-888 (veliparib) with carboplatin and paclitaxel induction
chemotherapy in locoregionally advanced head and neck (LAHNC) patients. (Phase I) II. Compare
magnitude of tumor shrinkage (response) following 2 cycles of induction chemotherapy with and
without ABT-888 in LAHNC. (Phase II)

SECONDARY OBJECTIVES:

I. Compare progression-free (PFS), disease-specific (DSS), and overall survival (OS) in
subjects treated with or without ABT-888. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of veliparib followed by a phase II study.

PHASE I: Patients receive veliparib orally (PO) twice daily (BID) on days 1-7, paclitaxel
intravenously (IV) over 60 minutes on days 1, 8, and 15, and carboplatin IV over 30 minutes
on day 1. Treatment repeats every 3 weeks for 2 courses in the absence of disease progression
or unacceptable toxicity. Patients then continue on to concomitant chemoradiotherapy.

PHASE II: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive veliparib, paclitaxel, and carboplatin as in Phase I. Treatment
repeats every 3 weeks for 2 courses in the absence of disease progression or unacceptable
toxicity. Within 10 days from completion of course 2, patients begin concomitant
chemoradiotherapy.

ARM II: Patients receive placebo PO BID on days 1-7. Patients also receive paclitaxel and
carboplatin as in Phase I. Treatment repeats every 3 weeks for 2 courses in the absence of
disease progression or unacceptable toxicity. Within 10 days from completion of course 2,
patients begin concomitant chemoradiotherapy.

CONCOMITANT CHEMORADIOTHERAPY: Patients are assigned to 1 of 2 regimens of concomitant
chemoradiotherapy based on the guidelines of the institution where they are being treated.

OPTION I (CONCOMITANT CHEMORADIATION WITH CISPLATIN): Patients receive cisplatin IV on days 1
and 22 and undergo radiation therapy 5 days per week for 6 weeks. Treatment repeats every 2
weeks for 5 courses.

OPTION II (CONCOMITANT CHEMORADIATION WITH TFHX): Patients receive hydroxyurea PO every 12
hours on days 1-5 for up to 11 doses, fluorouracil IV over 120 hours on days 1-5, paclitaxel
IV on day 1, and undergo radiation therapy BID on days 1-5. Treatment repeats every 2 weeks
for 5 courses.

After completion of study treatment, patients are followed up at 2 weeks, 1, 3, 6, 12, 18,
24, 30, 36, 48, and 60 months. Patients who progress will be followed up every 6 months
through year 5.

Inclusion Criteria:

- PHASE I:

- Patients who are treatment naïve, high risk, stage IVa/IVb (all other sites) and
histologically proven squamous cell carcinoma of the head and neck (SCCHN) with no
definitive evidence of metastatic disease, excluding patients with oropharynx human
papillomavirus (HPV)-positive tumors; in summary, those patients eligible are newly
diagnosed and treatment naive:

- Stage IVa-b squamous cell carcinoma other than oropharyngeal cancer (OPC), or

- Oropharyngeal cancer (OPC) HPV-negative, stage IVa-b

- PHASE II:

- Patients who are treatment naïve, high risk, stage IVa/IVb (all other sites)
histologically proven SCCHN with no definitive evidence of metastatic disease; in
summary, those patients eligible are:

- Stage IVa-b SCCHN other than OPC, or

- OPC, HPV-negative, IVa-b, or

- OPC, HPV positive, with greater than 10 pack-year smoking history and N2b-N3
disease

- PHASE I AND II:

- Patients must have at least one measurable site of disease according to Response
Evaluation Criteria in Solid Tumors (RECIST) criteria; i.e., patients must have
measurable disease, defined as at least one lesion that can be accurately measured in
at least one dimension (longest diameter to be recorded for non-nodal lesions and
short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm
with spiral computed tomography (CT) scan magnetic resonance imaging (MRI), or
calipers by clinical exam

- Eastern Cooperative Oncology Group (ECOG) performance status 0-1

- Patients must be able to swallow the drug

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

- Leukocytes >= 3,000/mm^3

- Absolute neutrophil count >= 1,500/mm^3

- Platelets >= 100,000/mm^3

- Total bilirubin =< 1.5 institutional upper limit of normal (ULN)

- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and
serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 x
institutional ULN as calculated by Cockcroft-Gault

- Creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above
ULN as calculated by Cockcroft-Gault

- Patients who are receiving any other investigational agents are not eligible

- Patients with active seizure or a history of seizure are not eligible

- Patients with a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to ABT-888 or other agents used in study, including
Cremophor, carboplatin, paclitaxel, cisplatin, 5-fluorouracil, hydroxyurea, or any
compounds of similar chemical or biologic composition are not eligible

- Patients with impairment of gastrointestinal function or gastrointestinal disease that
may significantly alter the absorption of ABT-888 (e.g., ulcerative disease,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel
resection) are not eligible to participate in this study

- Patients with 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 are not eligible to participate in the study

- Pregnant women are not eligible to participate in this study; NOTE: women of child
bearing potential must have a negative serum or urine pregnancy test within 7 days
prior to treatment

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry
and for the duration of study participation; should a woman become pregnant or
suspect she is pregnant while she or her partner is participating in this study,
she should inform her treating physician immediately;

- Breastfeeding should be discontinued if the mother is treated with ABT-888

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are not eligible

- Patients receiving chronic, systemic treatment with corticosteroids or another
immunosuppressive agent are not eligible to participate in this study; topical or
inhaled corticosteroids are allowed

- Patients with other malignancies within the past 2 years, except for adequately
treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin or
surgically treated early stage solid tumors are ineligible to participate in this
study