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

Study Overview
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Brief Summary
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This randomized phase II trial studies how well temozolomide with or without veliparib works in treating patients with small cell lung cancer that has returned or does not respond to treatment. Temozolomide works by damaging molecules inside the cancer cells, such as deoxyribonucleic acid (DNA), that are needed for cancer survival and growth. Veliparib may stop the growth of tumor cells by blocking proteins that are needed for repairing the damaged DNA and it may also help temozolomide to kill more cancer cells. It is not yet know whether temozolomide is more effective with or without veliparib in treating patients with relapsed or refractory small cell lung cancer.

Detailed Description
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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.

Official Title
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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

Conditions
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Recurrent Small Cell Lung Carcinoma

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Other: Placebo
* Drug: Temozolomide
* Drug: Veliparib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (veliparib and temozolomide)<br>Patients receive veliparib PO BID on days 1-7 and temozolomide PO on days 1-5. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Temozolomide<br>* Given PO<br>* Other names: Temomedac;Drug: Veliparib<br>* Given PO<br>* Other names: PARP-1 inhibitor ABT-888;|
| Active Comparator: Arm II (placebo and temozolomide)<br>Patients receive placebo PO BID on days 1-7 and temozolomide as in Arm I. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Placebo<br>* Given PO<br>* Other names: sham therapy;Drug: Temozolomide<br>* Given PO<br>* Other names: Temomedac;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response (ORR) by RECIST 1.1 Criteria | Corresponding exact two-sided 95% confidence intervals will be calculated and reported in both arms of the study. Comparisons between treatment arms will be performed using Fisher-exact test. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 4 months | 
| Overall Survival | Estimated in each treatment group using Kaplan-Meier method. Group comparisons will be performed using log-rank test. | From randomization to time of death | 
| Number of Participants With Adverse Events | Tabulated According to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0. Summary level. | From the start of treatment until 30 days from coming off treatment |