Temozolomide With or Without Veliparib in Treating Patients With Relapsed or Refractory Small Cell Lung Cancer

PRIMARY OBJECTIVES:

I. To demonstrate an improvement in progression free survival (PFS) at four months in
patients with relapsed sensitive or refractory small cell lung cancer (SCLC) receiving
ABT-888 (veliparib) and temozolomide compared to placebo and temozolomide.

SECONDARY OBJECTIVES:

I. Determine the objective response rate (ORR) (based on Response Evaluation Criteria in
Solid Tumors [RECIST] 1.1 criteria) in both arms of the study: ABT-888 and temozolomide and
placebo and temozolomide.

II. Determine the overall survival (OS) of patients in both arms of the study. III. Determine
the ORR, PFS and OS of ABT-888 and temozolomide and placebo and temozolomide, in the
following patient groups: sensitive disease vs. refractory disease; second-line treatment vs.
third-line treatment; brain metastases vs. no brain metastases.

IV. Determine the safety and tolerability of ABT-888 and temozolomide in patients with SCLC.

TERTIARY OBJECTIVES:

I. Evaluate available tumor samples for methylated O6-methylguanine-DNA methyltransferase
(MGMT) promoter by the EpiTyper assay, as well as MGMT expression by immunohistochemistry and
determine if these correlate with PFS, ORR, and OS.

II. Evaluate available tumor samples for poly (ADP ribose) polymerase (PARP)-1, breast cancer
1 (BRCA-1) and RAD51 recombinase (RAD51) expression by immunohistochemistry and determine if
they correlate with PFS, ORR, and OS.

III. Evaluate available tumor samples for messenger ribonucleic acid (mRNA) BRCA-1 expression
and determine if it correlates PFS, ORR, and OS.

IV. Evaluate available tumor samples for phosphatase and tensin homolog (PTEN) expression by
immunohistochemistry and determine if it correlates PFS, ORR, and OS.

V. Identify and enumerate circulating tumor cells (CTCs) using the Cell Search System in
these patients with SCLC at baseline and at the time of repeat imaging.

VI. Correlate the number of CTCs with PFS and OS at each time point. VII. Correlate the
change in CTCs with radiographic response. VIII. Correlate the number of CTCs at baseline
with patient characteristics (disease burden, location of metastases, progression at existing
sites or new sites of disease).

IX. Evaluate gamma H2A histone family, member X (H2AX)-positive CTCs using the CellSearch.

X. Assess the percentage increase in DNA fragments during treatment and correlate with
outcome in each of the treatment groups.

XI. Evaluate plasma markers for apoptosis and angiogenesis. XII. Assess changes in plasma
markers for apoptosis and angiogenesis, including caspase-cleaved cytokeratin 18 fragment
(M30), soluble cytokeratin 18 (M65), pro-gastrin-releasing peptide (pro-GRP), soluble
vascular endothelial growth factor (sVEGF), sVEGF receptor 2 (sVEGFR2), and soluble v-kit
Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (sKIT), and correlate these markers
with outcome in the two treatment arms.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive veliparib orally (PO) twice daily (BID) on days 1-7 and temozolomide
PO on days 1-5.

ARM II: Patients receive placebo PO BID on days 1-7 and temozolomide as in Arm I.

In both arms, courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up every 8-12 weeks.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed small cell lung cancer;
confirmation will be done at Memorial Sloan-Kettering Cancer Center (MSKCC) or locally
for participating sites

- Patients' disease has relapsed or progressed after one or two prior chemotherapy
regimens, one of which must have been an etoposide-platinum doublet; eligible patients
will be defined as follows:

- "Sensitive" disease: patients who had one previous line of chemotherapy and
maintained an appropriate response for > 60 days

- "Refractory" disease: those patients with either (a) no response to first-line
chemotherapy or progression =< 60 days after completing treatment, or (b)
"sensitive" or "refractory" disease in need of third-line therapy (i.e. completed
or failed two previous lines of chemotherapy)

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

- Patients with asymptomatic brain metastases that do not require immediate whole brain
radiation therapy and are on stable doses of steroids are allowed

- Patients must have measurable disease, which is defined as at least one lesion that
can be accurately measured in at least one dimension on a computed tomography (CT)
scan as per RECIST version 1.1; brain metastases can be considered measurable disease
if they meet this criterion

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 8.5 g/dL; the use of transfusion to achieve this criterion should be at
the discretion of the investigators

- Total bilirubin =< 1.5 mg/dL x institutional upper limit of normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 3.0 x institutional upper limit of normal

- Creatinine =< 1.5 x institutional upper limit of normal OR creatinine clearance >= 50
mL/min/1.73 m^2 for patients with creatinine levels >= 1.5 x upper limit of
institutional normal

- 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 participating in this study, she should inform her treating physician
immediately

- For women of child-bearing potential, negative pregnancy test within 14 days prior to
starting temozolomide and ABT-888

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

- Able to swallow pills

- Patients will not be excluded based on the diagnosis of acquired immune deficiency
syndrome (AIDS); given the increased risk of infection, these patients should have
cluster of differentiation (CD)4 counts above 200 cells/mm^3; patients with AIDS or
human immunodeficiency virus (HIV) not receiving agents with the potential for
pharmacokinetic interactions with ABT-888 may be eligible

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 3 weeks prior to entering
the study

- Patients who have not recovered from adverse events due to agents administered more
than 3 weeks earlier; toxicities should have resolved to baseline or to within one
grade level of their baseline (not to exceed grade 2)

- Patients who have been administered ABT-888, any other PARP-inhibitor, or temozolomide

- Patients may not be receiving any other investigational agents

- Patients with leptomeningeal involvement

- Patients with active seizures or a history of seizures

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to ABT-888 or temozolomide

- 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; breastfeeding should be discontinued if
the mother is treated with ABT-888; these potential risks also apply to temozolomide

- Patients with either AIDS or HIV on combination antiretroviral therapy are ineligible

- Patients with a synchronous active malignancy requiring treatment