Veliparib With or Without Radiation Therapy, Carboplatin, and Paclitaxel in Patients With Stage III Non-small Cell Lung Cancer That Cannot Be Removed by Surgery

PRIMARY OBJECTIVES:

I. To establish the maximum tolerated dose (MTD) and the recommended phase II dose of ABT-888
(veliparib) when given concurrently with standard carboplatin/paclitaxel and radiotherapy in
patients with unresectable stage III non-small cell lung cancer (NSCLC). (Phase I) II. To
assess whether carboplatin/paclitaxel plus ABT-888 compared with carboplatin/paclitaxel plus
placebo improves progression-free survival (PFS) in patients with unresectable stage III
NSCLC. (Phase II) III. To compare overall survival (OS) in patients treated with
carboplatin/paclitaxel and radiotherapy plus ABT-888 to those treated with carboplatin,
paclitaxel and radiotherapy plus placebo. (Phase II) IV. To assess the response rate
(confirmed and unconfirmed, complete and partial responses) and disease control rate in the
subset of patients with measurable disease by Response Evaluation Criteria in Solid Tumors
(RECIST) criteria. (Phase II) V. To assess the safety and toxicity profile of the regimen.
(Phase II)

SECONDARY OBJECTIVES:

I. To collect tumor tissue from pretreatment biopsies (archival samples) for biomarker
studies, including poly (ADP-ribose) polymerase 1 (PARP) activity by measuring the levels of
poly-ADP-ribose, gamma-H2A histone family, member X (gamma-H2AX), and messenger ribonucleic
acid (mRNA) expression levels of deoxyribonucleic acid (DNA) repair enzymes such as excision
repair cross-complementing rodent repair deficiency, complementation group 1 (ERCC1)/x-ray
repair complementing defective repair in Chinese hamster cells 1 (XRCC1).

II. To collect blood samples for evaluation of gamma-H2AX (circulating tumor cells) and other
relevant future studies.

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

PHASE I:

INDUCTION THERAPY: Patients undergo 3-dimensional conformal radiation therapy (3D-CRT) once
daily (QD), 5 days a week, for 6 weeks. Patients also receive veliparib orally (PO) twice
daily (BID) on days 1-43 and carboplatin intravenously (IV) over 30 minutes and paclitaxel IV
over 1 hour on days 1, 8, 15, 22, 36, and 43 in the absence of disease progression or
unacceptable toxicity. Patients without disease progression after completion of
chemoradiotherapy undergo consolidation therapy.

CONSOLIDATION THERAPY: Beginning within 4-6 weeks of chemotherapy and radiation therapy,
patients receive veliparib PO BID on days 1-7 (course 1) and 22-28 (course 2) and carboplatin
IV over 30 minutes and paclitaxel IV over 3 hours on day 1 and on day 22 of course 2.
Treatment repeats every 21 days for 2 courses in the absence of disease progression or
unacceptable toxicity.

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

ARM I: Patients undergo 3D-CRT and receive veliparib, carboplatin, and paclitaxel as in Phase
I induction and consolidation therapy.

ARM II: Patients undergo 3D-CRT as in arm I. Patients also receive placebo PO BID on days
1-43 and carboplatin and paclitaxel as in Phase I. Within 4-6 weeks after completion of
chemotherapy and radiation therapy, patients receive placebo on days 1-7 and carboplatin and
paclitaxel as in Phase I.

After completion of study treatment, patients are followed up every 4 months for first 2
years and then every 6 months until 5 years.

Inclusion Criteria:

- Patients must have histologically or cytologically-proven new diagnosis of
unresectable stage IIIA/IIIB*, non-small cell lung cancer (adenocarcinoma,
bronchioloalveolar cell carcinoma, large cell carcinoma, squamous cell carcinoma, or
mixed)

- Per the American Joint Committee on Cancer (AJCC) 7th edition, pleural and
pericardial are now considered stage M1a disease; when pleural fluid is visible
on the computed tomography (CT) scan or on a chest x-ray, a thoracentesis is
required to confirm that the pleural fluid is cytologically negative; patients
with exudative pleural effusions are excluded, regardless of cytology; patients
with effusions that are minimal (i.e. not visible on chest x-ray) that are too
small to safely tap are eligible; a small effusion that has positive
fludeoxyglucose F 18 (FDG) uptake on positron emission tomography (PET) has to be
proven to be malignant per standard of care diagnostic procedures for the patient
to be excluded

- Patients must have measurable or non-measurable disease documented by CT, magnetic
resonance imaging (MRI) or PET/CT; the CT from a combined PET/CT may be used to
document only non-measurable disease unless the scan is of diagnostic quality;
measurable disease must be assessed by CT within 28 days prior to registration;
pleural effusions, ascites and laboratory parameters are not acceptable as the only
evidence of disease; non-measurable disease must be assessed within 42 days prior to
registration; all disease must be assessed and documented on the Baseline Tumor
Assessment Form

- Patients with brain metastases are ineligible; all patients must have a pretreatment
CT or MRI scan of the brain to evaluate for central nervous system (CNS) disease
within 42 days prior to registration

- Patients must not have received any prior systemic therapy (chemotherapy or other
biologic therapy) for lung cancer

- Patients must not have received prior chest radiation therapy for NSCLC

- Patients must not have had a previous surgical resection; however, patients may have
undergone exploratory thoracotomy, mediastinoscopy, excisional biopsy or similar
surgery for the purpose of determining the diagnosis, stage or potential resectability
of newly diagnosed lung tumor; at least 28 days must have elapsed since thoracic
surgery (excluding mediastinoscopy or other minor surgeries) and patients should have
recovered from all associated toxicities at the time of registration; patients must
not be planning to undergo a minor surgical procedure while on this study

- Patients must have Zubrod performance status 0-1

- Patients must have tumor tissue available for submission to assess gene expression of
ERCC1 and XRCC1; patients must also be offered participation in banking for future use
of specimens

- Absolute neutrophil count >= 1,500/mcl

- Platelets >= 100,000/mcl

- Hemoglobin >= 9.0 g/dl

- Total bilirubin within institutional upper limit of normal (IULN)

- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or
serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 x
IULN

- Patients must not be pregnant or nursing; women/men of reproductive potential must
have agreed to use an effective contraceptive method; a woman is considered to be of
"reproductive potential" if she has had menses at any time in the preceding 12
consecutive months; in addition to routine contraceptive methods, "effective
contraception" also includes heterosexual celibacy and surgery intended to prevent
pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy,
bilateral oophorectomy or bilateral tubal ligation; however, if at any point a
previously celibate patient chooses to become heterosexually active during the time
period for use of contraceptive measures outlined in the protocol, he/she is
responsible for beginning contraceptive measures

- Patients must have a serum creatinine =< the IULN AND measured or calculated
creatinine clearance >= 60 cc/min using the Cockroft-Gault formula

- Patients must have pulmonary function tests (PFTs) including forced expiratory volume
in 1 second (FEV1) within 84 days prior to registration; for FEV1, the best value
obtained pre- or post-bronchodilator must be >= 1.2 liters/second and/or >= 50%
predicted

- Patients may not be planning to receive any other investigational agents

- Patients must not have more than 10% weight loss in the past 6 months

- Patients must not have a history of allergic reactions attributed to compounds of
similar chemical or biologic composition to ABT-888, carboplatin, paclitaxel or other
agents used in study

- No other prior malignancy is allowed except for the following: adequately treated
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated
stage I or II cancer from which the patient is currently in complete remission, or any
other cancer from which the patient has been disease free for five years

- Patient must not have any 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

- Patients must not currently have a > grade 1 symptomatic neuropathy-sensory (National
Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version
4.0)

- Patients must not have a history of seizures

- Patients must not have any known immune deficiencies; patients with immune deficiency
are at increased risk of lethal infections when treated with marrow-suppressive
therapy; therefore, known human immunodeficiency virus (HIV) positive patients
receiving combination anti-retroviral therapy are excluded from the study

- Patients must be able to swallow whole capsules

- Prestudy history and physical must be obtained within 28 days prior to registration

- All patients must be informed of the investigational nature of this study and must
sign and give written informed consent in accordance with institutional and federal
guidelines

- As a part of the Oncology Patient Enrollment Network (OPEN) registration process the
treating institution's identity is provided in order to ensure that the current
(within 365 days) date of institutional review board approval for this study has been
entered in the system

- REGISTRATION #2 - PRIOR TO CONSOLIDATION CHEMOTHERAPY:

- REGISTRATION #2 - PRIOR TO CONSOLIDATION CHEMOTHERAPY: Patients must have completed
chemoradiotherapy per protocol and at least four weeks but no more than six weeks must
have elapsed from the last day of induction therapy (the last day of radiation)

- REGISTRATION #2 - PRIOR TO CONSOLIDATION CHEMOTHERAPY: Patients must have undergone
restaging tests according to the study calendar and determined to have no evidence of
disease progression

- REGISTRATION #2 - PRIOR TO CONSOLIDATION CHEMOTHERAPY: Patients must have a serum
creatinine =< (IULN) AND measured of calculated creatinine clearance >= 60 cc/min
using the Cockroft-Gault formula

- REGISTRATION #2 - PRIOR TO CONSOLIDATION CHEMOTHERAPY: Absolute neutrophil count >=
1,500 mcl

- REGISTRATION #2 - PRIOR TO CONSOLIDATION CHEMOTHERAPY: Platelets >= 100,000/mcl

- REGISTRATION #2 - PRIOR TO CONSOLIDATION CHEMOTHERAPY: Hemoglobin >= 9.0 g/dl

- REGISTRATION #2 - PRIOR TO CONSOLIDATION CHEMOTHERAPY: Total bilirubin =< IULN

- REGISTRATION #2 - PRIOR TO CONSOLIDATION CHEMOTHERAPY: SGOT (AST) or SGPT (ALT) =< 2.5
x IULN

- REGISTRATION #2 - PRIOR TO CONSOLIDATION CHEMOTHERAPY: Patients must have Zubrod
performance status 0-1