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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Dose Finding Study Followed by Phase II Randomized, Placebo-Controlled Study of Veliparib (ABT-888) Added to Chemoradiotherapy With Carboplatin and Paclitaxel for Unresectable Stage III Non-small Cell Lung Cancer (NSCLC), (NCI Study Number 8811)

Conditions
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Lung Adenocarcinoma, Lung Adenocarcinoma, Mixed Subtype, Lung Large Cell Carcinoma, Lung Squamous Cell Carcinoma, Minimally Invasive Lung Adenocarcinoma, Stage III Lung Non-Small Cell Cancer AJCC v7, Stage IIIA Lung Non-Small Cell Cancer AJCC v7, Stage IIIB Lung Non-Small Cell Cancer AJCC v7

Intervention / Treatment
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* Radiation: 3-Dimensional Conformal Radiation Therapy
* Drug: Carboplatin
* Other: Laboratory Biomarker Analysis
* Drug: Paclitaxel
* Other: Placebo Administration
* Drug: Veliparib


Participation Criteria
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Eligibility Criteria
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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

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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (RT, veliparib, carboplatin, paclitaxel)<br>Patients undergo 3D-CRT and receive veliparib, carboplatin, and paclitaxel as in Phase I induction and consolidation therapy. | Radiation: 3-Dimensional Conformal Radiation Therapy<br>* Undergo 3D-conformal RT<br>* Other names: Three dimensional external beam radiation therapy (procedure);Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Drug: Veliparib<br>* Given PO<br>* Other names: PARP-1 inhibitor ABT-888;|
| Active Comparator: Arm II (3D-CRT, placebo, carboplatin, paclitaxel)<br>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. | Radiation: 3-Dimensional Conformal Radiation Therapy<br>* Undergo 3D-conformal RT<br>* Other names: Three dimensional external beam radiation therapy (procedure);Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Other: Placebo Administration<br>* Given PO<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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: Radiation esophagitis or dermatitis radiation Grade 3 that lasts > 7 consecutive days or Grade 4 Grade 4 neutropenia for > 7 days or neutropenic fever ( ANC <500 and temperature >= 38.5 oC) Grade 4 thrombocytopenia Grade 4 nausea/vomiting despite appropriate antiemetic therapy Delays in radiotherapy or chemotherapy or ABT-888 due to toxicity of > 3 weeks 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 | 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 | The time from randomization to progression or death due to any cause, assessed up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 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. | Duration of treatment and follow up until death or 5 years post registration |