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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)

Description

Background:Combined modality therapy with chemotherapy and radiation has become the standard of care for the treatment of patients with locally advanced NSCLC.The Cancer and Leukemia Group B (CALGB) conducted a randomized Phase II study of two cycles of induction chemotherapy followed by two additional cycles of the same drugs with concomitant radiotherapy for patients with locally advanced NSCLC. The results of this trial demonstrated similar survival rates between the 2 arms.We propose to use a backbone of standard chemoradiotherapy with carboplatin and paclitaxel to investigate the addition of oral ABT-888. ABT-888 potentiates the anti-cancer effects of various cytotoxic agents including carboplatin in preclinical studies.Objectives:To establish the MTD and the recommended Phase II dose of ABT-888 when given concurrently with standard carboplatin/paclitaxel and radiotherapy in patients with unresectable Stage III non-small cell lung cancer (NSCLC).Study Population: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). Patients age is 18 years and over.Primary Endpoints: a. Measurable disease: 1. Lesions that can be accurately measured in at least one dimension 2. Malignant lymph nodes b. Non-measurable disease: 1. All other lesions (or sites of disease), including small lesionsDescription of Study Arms:Phase I portion:First Registration: Chemoradiation Phase 6 weeks of external beam radiation + paclitaxel + carboplatin + ABT-888 at assigned dose level. Re-evaluation and Second RegistrationConsolidation Phase (ABT-888 + carboplatin + paclitaxel) (Two 21-day cycles)Phase II portion:First Registration/Randomization: Chemoradiation Phase 6 weeks of external beam radiation + paclitaxel + carboplatin + ABT-888/placebo at assigned dose level.Re-evaluation and Second Registration:ABT-888 Carboplatin Paclitaxel (2 cycles) OR Placebo Carboplatin Paclitaxel (2 cycles) Only Arm 2 will be done at USC.Intervention:Emergency unblinding will proceed in the event of an emergency or severe adverse reaction necessitating identification of the medication for the welfare of the patient.Toxicities attributable to the study regimen will undergo dose limiting. (DLT) Patient will be removed from the study for progression of disease or symptomatic deterioration, grade 3 or worse infusion reactions and unacceptable toxicity.Follow-up:All patients will be followed until death or 5 years after registration, whichever occurs first.Statistics/Analysis:This study will initially be open in limited institutions, with an expected accrual of 10-30 patients in the Phase I portion of the trial. The estimated accrual rate for this part of the study is 2-3 patients/ month. The Phase II portion of the trial will be open Group-wide. Based on data from previous studies in similar patient populations the estimated accrual rate is 8-9 patients/month for the phase II portion of the study.Primary analyses will be performed on an intent-to-treat basis. A stratified log-rank test at the 10% level will be used to test the primary hypothesis. The final analysis will take place upon the observation of 68 progression events.

Phase

Phase 2 - takes the treatment one step further, assessing the activity of a particular therapy in a disease, often building upon leads from the Phase I trial. While patients are generally required to be previously untreated, participation in a Phase II trial doesn't usually preclude the patient from getting the standard treatment after they've received the investigational agent. At best they are allowed to get a new drug they wouldn't be able to get otherwise that may turn out to be better for their disease.

Inclusion and Exclusion Criteria

  • 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

Sites

  • California

    • City of Hope Medical Center, Duarte, California, 91010
    • City of Hope Comprehensive Cancer Center, Duarte, California, 91010
    • University of California Davis Comprehensive Cancer Center, Sacramento, California, 95817
    • University of California at Davis Cancer Center, Sacramento, California, 95817
  • Arizona

    • Arizona Cancer Center at University Medical Center North, Tucson, Arizona, 85719
    • University of Arizona Health Sciences Center, Tucson, Arizona, 85724
  • Colorado

    • University of Colorado Cancer Center - Anschutz Cancer Pavilion, Aurora, Colorado, 80045
  • Texas

    • University of Texas Health Science Center at San Antonio, San Antonio, Texas, 78229
    • Cancer Therapy and Research Center at The UT Health Science Center at San Antonio, San Antonio, Texas, 78229
    • University Hospital, San Antonio, Texas, 78229
    • Audie L Murphy Veterans Affairs Hospital, San Antonio, Texas, 78209
    • M D Anderson Cancer Center, Houston, Texas, 77030
  • Illinois

    • Central Illinois Hematology Oncology Center, Springfield, Illinois, 62702
    • Illinois CancerCare-Peoria, Peoria, Illinois, 61615
    • Loyola University Medical Center, Maywood, Illinois, 60153
  • Indiana

    • Fort Wayne Medical Oncology and Hematology Inc-Parkview, Fort Wayne, Indiana, 46845
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