This phase I/II partially randomized trial studies the side effects and best dose of veliparib when given together with radiation therapy, carboplatin, and paclitaxel and to see how well it works in treating patients with stage III non-small cell lung cancer that cannot be removed by surgery. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether radiation therapy, carboplatin, and paclitaxel are more effective with or without veliparib in treating non-small cell lung cancer.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
53
Undergo 3D-conformal RT
Given IV
Correlative studies
Given IV
Given PO
Given PO
Anchorage Associates in Radiation Medicine
Anchorage, Alaska, United States
Alaska Breast Care and Surgery LLC
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Alaska Oncology and Hematology LLC
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Alaska Women's Cancer Care
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Anchorage Oncology Centre
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Maximum Tolerated Dose of Veliparib When Given Concurrently With Standard Carboplatin/Paclitaxel and Radiotherapy, Determined According to Incidence of Dose Limiting Toxicity (DLT) (Phase I)
DLTs will be graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. DLTs must be attributable (probably, possibly, definitely related) to the study regimen and only occur during RT or 2 weeks after completing RT. DLTs are defined as: 1. Radiation esophagitis or dermatitis radiation Grade 3 that lasts \> 7 consecutive days or Grade 4 2. Grade 4 neutropenia for \> 7 days or neutropenic fever ( ANC \<500 and temperature \>= 38.5 oC) 3. Grade 4 thrombocytopenia 4. Grade 4 nausea/vomiting despite appropriate antiemetic therapy 5. Delays in radiotherapy or chemotherapy or ABT-888 due to toxicity of \> 3 weeks 6. All other non-hematologic toxicities \>= Grade 3, except * anorexia * fatigue * infection without neutropenia * Grade 3 AST/ALT elevations \<= 7 days, infusion reactions * Grade 3 or 4 lymphopenia * Grade 3 or 4 electrolyte abnormalities that are corrected to \<=Grade 2 in \< 48 hours * Grade 3 dehydration lasting \< 7 days
Time frame: 9 weeks
Progression-free Survival of Patients Treated With Chemoradiotherapy Plus Veliparib (Phase II)
Time from date of registration to date of first documentation of progression or symptomatic deterioration or death due to any cause. Participants last known to be alive are censored at date of last contact. Assessed by Response Evaluation Criteria in Solid Tumors, RECIST 1.1
Time frame: The time from randomization to progression or death due to any cause, assessed up to 5 years
Overall Survival (Phase II)
From date of registration to date of death due to any cause. Participants last known to be alive are censored at date of last contact.
Time frame: Up to 5 years
Objective Response Rate (Phase II)
ORR is defined as the percentage of participants with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1
Time frame: Up to 5 years
Incidence of Serious (>= Grade 3) Adverse Events as Measured by National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (Phase II)
Adverse Events (AEs) are reported by CTCAE Version 4.0. Only adverse events that are possibly, probably or definitely related to study drug are reported.
Time frame: Duration of treatment and follow up until death or 5 years post registration
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