Neoplasms

All Conditions

Respiratory Tract (Lung and Bronchial) Diseases

Rare Diseases

Carcinoma

Adenocarcinoma

Carcinoma, Non-Small-Cell Lung

Carcinoma, Squamous Cell

Lung Neoplasms

Adenocarcinoma of Lung

Carcinoma, Large Cell

Adenocarcinoma, Bronchiolo-Alveolar

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Adenocarcinoma

Antineoplastic Agents

All Drugs and Chemicals

Paclitaxel

Albumin-Bound Paclitaxel

Carboplatin

Veliparib

Tubulin Modulators

Antimitotic Agents

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

Patients undergo 3D-CRT and receive veliparib, carboplatin, and paclitaxel as in Phase I induction and consolidation therapy.

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.

3-Dimensional Conformal Radiation Therapy

Laboratory Biomarker Analysis

Placebo Administration

Athanassios (Ethan) Argiris

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.

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

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)

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 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

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.

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

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.

National Cancer Institute (NCI)

Adverse Events (AEs) are reported by CTCAE Version 4.0.

21 participants in phase I and 31 participants in phase II who were eligible and received protocol therapy were assessed for AEs. 1 participant in phase II arm 1 did not receive protocol therapy so was not assessed for AEs. All cause modality analysis will include all eligible participants as participants at risk.

Participants undergo 3D-CRT and receive 40 mg veliparib, carboplatin, and paclitaxel during concurrent radiotherapy

Phase I 40 mg Veliparib Cohort

Participants undergo 3D-CRT and receive 80 mg veliparib, carboplatin, and paclitaxel during concurrent radiotherapy

Phase I 80 mg Veliparib Cohort

Participants undergo 3D-CRT and receive 120 mg veliparib, carboplatin, and paclitaxel during concurrent radiotherapy

Phase I 120 mg Veliparib Cohort

Phase II Arm I (Veliparib, 3D-CRT, Carboplatin, Paclitaxel)

Participants undergo 3D-CRT and receive placebo, carboplatin, and paclitaxel during concurrent radiotherapy

Phase II Arm II (Placebo, 3D-CRT, Carboplatin, Paclitaxel)

Participants receive 80 mg veliparib (PO twice daily, Days 1-7, Days 22-28), carboplatin, and paclitaxel for 2 cycles.

Phase I Consolidation 40mg Cohort

Phase I Consolidation 80mg Cohort

Phase I Consolidation 120mg Cohort

Phase II Arm I Consolidation

Participants receive 80 mg placebo (PO twice daily, Days 1-7, Days 22-28), carboplatin, and paclitaxel for 2 cycles.

Phase II Arm II Consolidation

Participants undergo 3D-CRT and receive 40 mg veliparib, carboplatin, and paclitaxel during RT 3-Dimensional Conformal Radiation Therapy: Undergo 3D-conformal RT Carboplatin: Given IV Laboratory Biomarker Analysis: Correlative studies Paclitaxel: Given IV Veliparib: Given PO

Phase I 40mg Veliparib Cohort

Participants undergo 3D-CRT and receive 80 mg veliparib, carboplatin, and paclitaxel during RT 3-Dimensional Conformal Radiation Therapy: Undergo 3D-conformal RT Carboplatin: Given IV Laboratory Biomarker Analysis: Correlative studies Paclitaxel: Given IV Veliparib: Given PO

Phase I 80mg Veliparib Cohort

Participants undergo 3D-CRT and receive 120 mg veliparib, carboplatin, and paclitaxel during RT 3-Dimensional Conformal Radiation Therapy: Undergo 3D-conformal RT Carboplatin: Given IV Laboratory Biomarker Analysis: Correlative studies Paclitaxel: Given IV Veliparib: Given PO

Phase I 120mg Veliparib Cohort

Patients undergo 3D-CRT and receive veliparib, carboplatin, and paclitaxel as in Phase I induction and consolidation therapy.

3-Dimensional Conformal Radiation Therapy: Undergo 3D-conformal RT

Carboplatin: Given IV

Laboratory Biomarker Analysis: Correlative studies

Paclitaxel: Given IV

Veliparib: Given PO

Arm I (RT, Veliparib, Carboplatin, Paclitaxel)

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.

3-Dimensional Conformal Radiation Therapy: Undergo 3D-conformal RT

Carboplatin: Given IV

Laboratory Biomarker Analysis: Correlative studies

Paclitaxel: Given IV

Placebo Administration: Given PO

Arm II (3D-CRT, Placebo, Carboplatin, Paclitaxel)

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

0 - Fully active, able to carry on all pre-disease performance without restriction.

1 - Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work.

Zubrod Performance Status

Tumors are staged per AJCC Cancer Staging Manual, 7th edition

IIIA - T4 N0-1 M0 T3 N1 M0 T1-3 N2 M0

IIIB - T4 N2 M0 T1-4 N3 M0

Stage

Histology

Baseline LDH

Smoking Status

Weight loss past 6 months

Lung Committee Statistician

During induction, participants undergo 3D-CRT and receive 40 mg veliparib (PO twice daily), carboplatin, and paclitaxel for 6 weeks.

During consolidation, participants receive 40 mg veliparib (PO twice daily, Days 1-7, Days 22-28), carboplatin, and paclitaxel for 2 cycles.

Phase I 40mg Veliparib

During induction, participants undergo 3D-CRT and receive 80mg veliparib (PO twice daily), carboplatin, and paclitaxel for 6 weeks.

During consolidation, participants receive 80 mg veliparib (PO twice daily, Days 1-7, Days 22-28), carboplatin, and paclitaxel for 2 cycles.

Phase I 80mg Veliparib

During induction, participants undergo 3D-CRT and receive 120mg veliparib (PO twice daily), carboplatin, and paclitaxel for 6 weeks.

During consolidation, participants receive 120 mg veliparib (PO twice daily, Days 1-7, Days 22-28), carboplatin, and paclitaxel for 2 cycles.

Phase I 120mg Veliparib

Eligible participants evaluable for dose limiting toxicity assessment

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)

Progression-free Survival of Patients Treated With Chemoradiotherapy Plus Veliparib (Phase II)

Overall Survival (Phase II)

Objective Response Rate (Phase II)

Anemia

Anorexia

Dehydration

Diarrhea

Dysphagia

Esophageal pain

Esophagitis

Fatigue

Hyperglycemia

Hypocalcemia

Hypoglycemia

Hypokalemia

Hypomagnesemia

Hyponatremia

Hypotension

Lung infection

Lymphocyte count decreased

Mucositis oral

Nausea

Neutrophil count decreased

Platelet count decreased

Pneumonitis

Upper gastrointestinal hemorrhage

Vomiting

Weight loss

White blood cell decreased

Participants undergo 3D-CRT and receive veliparib, carboplatin, and paclitaxel as in Phase I induction and consolidation therapy.

3-Dimensional Conformal Radiation Therapy: Undergo 3D-conformal RT Carboplatin: Given IV Laboratory Biomarker Analysis: Correlative studies Paclitaxel: Given IV Veliparib: Given PO

Arm I Concurrent Chemoradiation (Veliparib, 3D-CRT, Carboplati

Participants 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, participants receive placebo on days 1-7 and carboplatin and paclitaxel as in Phase I.

3-Dimensional Conformal Radiation Therapy: Undergo 3D-conformal RT Carboplatin: Given IV Laboratory Biomarker Analysis: Correlative studies Paclitaxel: Given IV Placebo Administration: Given PO

Arm II Concurrent Chemoradiation (Placebo, 3D-CRT, Carboplatin

Arm I Consolidation (Veliparib, Carboplatin, Paclitaxel)

Participants receive 80mg placebo (PO twice daily, Days 1-7, Days 22-28), carboplatin, and paclitaxel for 2 cycles.

Arm II Consolidation (Placebo, Carboplatin, Paclitaxel)

Up to 4 weeks after completion of consolidation therapy

Incidence of Serious (>= Grade 3) Adverse Events as Measured by National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (Phase II)

Participants undergo 3D-CRT and receive 40 mg veliparib, carboplatin, and paclitaxel during RT

Participants receive 80 mg veliparib (PO twice daily, Days 1-7, Days 22-28), carboplatin, and paclitaxel for 2 cycles

Participants undergo 3D-CRT and receive 80 mg veliparib, carboplatin, and paclitaxel during RT

Participants undergo 3D-CRT and receive 120 mg veliparib, carboplatin, and paclitaxel during RT.

Participants undergo 3D-CRT and receive 120mg veliparib, carboplatin, and paclitaxel

During consolidation, participants receive 80 mg veliparib (PO twice daily, Days 1-7, Days 22-28), carboplatin, and paclitaxel for 2 cycles.

Phase II Arm I (RT, Veliparib, Carboplatin, Paclitaxel)

Participants undergo 3D-CRT and receive placebo PO BID, carboplatin and paclitaxel.

During consolidation, participants receive 80 mg placebo (PO twice daily, Days 1-7, Days 22-28), carboplatin, and paclitaxel for 2 cycles.

Spots Global Cancer Trial Database for lung adenocarcinoma, mixed subtype