A Multi-Center, Randomized, Double-Blind Phase II Study Comparing ABT-888, a PARP Inhibitor, Versus Placebo With Temozolomide in Patients With Relapsed Sensitive or Refractory Small Cell Lung Cancer
I. To demonstrate an improvement in progression free survival (PFS) at four months in
patients with relapsed sensitive or refractory SCLC receiving ABT-888 and temozolomide
compared to placebo and temozolomide.
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.
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 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 H2AX-positive CTCs using the CellSearch. X. Assess the percentage
increase in DNA fragments during treatment and correlate with outcome in each of the
XI. In a subset of patients, identify and enumerate CTCs using the CTC-Chip. XII. Compare
the predictive ability of CTC number measured by Veridex CellSearch System and CTC-Chip,
with respect to PFS, ORR and OS.
XIII. Evaluate plasma markers for apoptosis and angiogenesis. XIV. Assess changes in plasma
markers for apoptosis and angiogenesis, including M30, M65, pro-gastrin-releasing peptide
(pro-GRP), soluble vascular endothelial growth factor (sVEGF), sVEGF receptor 2 (sVEGFR2),
and 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
After completion of study treatment, patients are followed up every 8-12 weeks.
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment
Progression-free survival, calculated as the proportion of patients alive and without evidence of disease
Compared across the two arms using a Fisher exact test.
From randomization to time of progression or death, whichever occurs first, assessed at 4 months
Memorial Sloan-Kettering Cancer Center
United States: Food and Drug Administration
|Memorial Sloan-Kettering Cancer Center||New York, New York 10021|
|Case Western Reserve University||Cleveland, Ohio 44106|
|M D Anderson Cancer Center||Houston, Texas 77030|
|Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital||Baltimore, Maryland 21231|