Cisplatin and Etoposide With or Without Veliparib in Treating Patients With Extensive Stage Small Cell Lung Cancer

Study Overview
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Brief Summary
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This randomized phase I/II trial studies the side effects and best dose of veliparib when given together with or without cisplatin and etoposide and to see how well they work in treating patients with extensive stage small cell lung cancer or large cell neuroendocrine non-small cell lung cancer that has spread to other parts of the body. Drugs used in chemotherapy, such as cisplatin and etoposide, 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. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving cisplatin and etoposide with or without veliparib may work better in treating patients with extensive stage small cell lung cancer or metastatic large cell neuroendocrine non-small cell lung cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the recommended phase II dose (RP2D) of veliparib to use in combination with cisplatin and etoposide (CE). (Phase I) II. To determine whether the addition of ABT-888 (veliparib) to cisplatin etoposide (CE) results in improved progression free survival (PFS) over CE with placebo in the frontline therapy of newly diagnosed extensive stage small cell lung cancer. (Phase II) SECONDARY OBJECTIVES: I. To determine the overall survival (OS) associated with the combination of CE plus ABT-888. (Phase II) II. To assess the overall response rate (ORR) as well as complete response rate (CRR) associated with the combination of CE plus ABT-888. (Phase II) III. To determine the toxicity profile of the combination of ABT-888 and CE chemotherapy in this patient population. (Phase II) OTHER PRE-SPECIFIED OBJECTIVES: I. To conduct exploratory correlative analysis of the impact of the select biomarkers. (Phase II) II. To compare the overall toxicity profile and specifically the incidence and severity of chemotherapy-induced peripheral neuropathy with the addition of ABT-888 to CE. (Phase II) OUTLINE: This is a phase I, dose-escalation study of veliparib followed by a phase II study. Phase I: Patients receive veliparib orally (PO) twice daily (BID) on days 1-7, etoposide intravenously (IV) over 60-120 minutes on days 1-3, and cisplatin IV over 60-120 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Phase II: Patients are randomized to 1 of 2 treatment arms. ARM D: Patients receive veliparib PO BID on days 1-7, etoposide IV over 60-120 minutes on days 1-3, and cisplatin IV over 60-120 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. ARM E: Patients receive placebo PO BID on days 1-7, etoposide IV over 60-120 minutes on days 1-3, and cisplatin IV over 60-120 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 1 year.

Official Title
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Phase I and Randomized Phase II Double Blind Clinical Trial of Cisplatin and Etoposide in Combination With Veliparib (ABT-888) or Placebo as Frontline Therapy for Extensive Stage Small Cell Lung Cancer

Conditions
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Extensive Stage Small Cell Lung Carcinoma, Large Cell Lung Carcinoma, Neuroendocrine Carcinoma, Small Cell Carcinoma, Stage IV Non-Small Cell Lung Cancer AJCC v7

Intervention / Treatment
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* Drug: Cisplatin
* Drug: Etoposide
* Drug: Veliparib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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PHASE I Inclusion Criteria (phase I): Women must not be pregnant or breastfeeding; breastfeeding must be discontinued or the subject is not eligible for the study All females of childbearing potential must have a blood test within 2 weeks prior to randomization to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception Patients must have histologically or cytologically confirmed: Extensive stage small cell lung cancer (SCLC) or Stage IV (M1a or M1b according to American Joint Committee on Cancer [AJCC] Staging Manual, 7th edition) large cell neuroendocrine non-small cell lung cancer (NSCLC) or Small cell carcinoma of unknown primary or extrapulmonary origin and must be a candidate for systemic therapy NOTE: The extensive disease SCLC classification for this protocol includes all patients with disease sites not defined as limited stage; limited stage disease category includes patients with disease restricted to one hemithorax with regional lymph node metastases, including hilar, ipsilateral and contralateral mediastinal, and/or ipsilateral supraclavicular nodes; extensive disease patients are defined as those patients with extrathoracic metastatic disease, malignant pleural effusion, bilateral or contralateral supraclavicular adenopathy Patients must have measurable or non-measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; baseline measurements and evaluations of all sites of disease must be obtained =< 4 weeks prior to registration (Phase I) Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Absolute neutrophil count >= 1,500/mm^3 Platelets >= 100,000/mm^3 Leukocytes >= 3,000/mm^3 Hemoglobin >= 9 g/dL Total bilirubin =< 1.5 times institutional upper limit of normal (ULN) Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase[SGPT]) =< 3 times institutional ULN (=< 5 times if liver function test [LFT] elevations due to known liver metastases) Creatinine =< 1.5 X ULN OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels > 1.5 x ULN Patients with central nervous system (CNS) metastases or a history of CNS metastases are ineligible Patients cannot have had prior chemotherapy or biologic therapy for SCLC or large cell neuroendocrine NSCLC, or small cell carcinoma of unknown primary or extrapulmonary origin; patients receiving prior radiation cannot register within 7 days after completion of radiation, and must have resolved adverse events attributed to radiation to =< grade 1; no previous irradiation to the only site of measurable or evaluable disease, unless that site had subsequent evidence of progression Patients receiving prior radiation cannot register within 7 days after completion of radiation, and must have resolved adverse events attributed to radiation to =< grade 1; no previous irradiation to the only site of measurable or evaluable disease, unless that site had subsequent evidence of progression Patients must NOT have uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible Patient must be able to swallow pills Exclusion Criteria (phase I): Patients have active seizure(s) or history of seizure(s) Patients have history of allergic reactions attributed to compounds of similar chemical or biologic composition to veliparib or other agents used in the study PHASE II Inclusion Criteria (phase II): Women must not be pregnant or breastfeeding; breastfeeding must be discontinued or the subject is not eligible for the study All females of childbearing potential must have a blood test within 2 weeks prior to randomization to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) with the current month counted as month 1 Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception Patients must have extensive stage, histologically or cytologically confirmed small cell lung cancer; NOTE: the extensive disease classification for this protocol includes all patients with disease sites not defined as limited stage; limited stage disease category includes patients with disease restricted to one hemithorax with regional lymph node metastases, including hilar, ipsilateral and contralateral mediastinal, and/or ipsilateral supraclavicular nodes; extensive disease patients are defined as those patients with extrathoracic metastatic disease, malignant pleural effusion, bilateral or contralateral supraclavicular adenopathy Patients must have measurable disease based on RECIST 1.1; baseline measurements and evaluations of all sites of disease must be obtained =< 4 weeks prior to registration ECOG performance status 0 or 1 Absolute neutrophil count >= 1,500/mm^3 Platelets >= 100,000/mm^3 Leukocytes >= 3,000/mm^3 Hemoglobin >= 9 g/dL Total bilirubin =< 1.5 times institutional upper limit of normal (ULN) AST (SGOT) and ALT (SGPT) =< 3 times institutional ULN (=< 5 times if LFT elevations due to known liver metastases) Creatinine =< 1.5 X ULN OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels > 1.5 x ULN Patients cannot have had prior chemotherapy or biologic therapy for small cell lung cancer; patients receiving prior radiation cannot register within 7 days after completion of radiation, and must have resolved adverse events attributed to radiation to =< grade 1; no previous irradiation to the only site of measurable or evaluable disease, unless that site had subsequent evidence of progression Patient must be able to swallow pills Patients may not be receiving any other investigational agents while on study Exclusion Criteria (phase II): Patients with CNS metastases or a history of CNS metastases are ineligible Patients have history of allergic reactions attributed to compounds of similar chemical or biologic composition to veliparib or other agents used in the study Patients have active seizure(s) or history of seizure(s) Patients must NOT have uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with veliparib; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated

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 A (veliparib)<br>Patients receive veliparib PO BID on days 1-7, etoposide IV over 60-120 minutes on days 1-3, and cisplatin IV over 60-120 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. | Drug: Cisplatin<br>* Given IV<br>* Other names: NSC 119875;Drug: Etoposide<br>* Given IV<br>* Other names: VP-16;Drug: Veliparib<br>* Given PO<br>* Other names: A-861695.0;|
| Active Comparator: Arm B (placebo)<br>Patients receive placebo PO BID on days 1-7, etoposide IV over 60-120 minutes on days 1-3, and cisplatin IV over 60-120 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. | Drug: Cisplatin<br>* Given IV<br>* Other names: NSC 119875;Drug: Etoposide<br>* Given IV<br>* Other names: VP-16;Drug: Placebo<br>* placebo of Veliparib<br>* Other names: placebo therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Phase II Dose (Phase I) | dose of veliparib which was deemed to be the recommended phase II dose to be administered in the combination with CE for the phase II clinical trial | assessed for a maximum of cycle 1 | 
| Progression Free Survival (Phase II) | Profession free survival (PFS) is defined as time from randomization to date of disease progression or death from any cause, whichever occurred first. Patients who had not experienced an event of interest by the time of analysis were censored at the date they were last known to be alive and progression-free. Tumor response was evaluated via Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria, and progression was defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study, or appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Median PFS was estimated using the Kaplan-Meier method. | Assessed every 3 months for patients < 2 years from registration and every 6 months if patient is 2- 3 years from registration until the date of first documented progression or death. No specific requirements if patient is > 3 years from registration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival (OS) is defined as time from randomization to death from any cause. Median OS was estimated using the Kaplan-Meier method. | Assessed every 3 months for patients < 2 years from registration and every 6 months if patient is 2- 3 years from registration until the date of death. No specific requirements if patient is > 3 years from registration | 
| Overall Response Rate (ORR) | Tumor response was evaluated using Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. Complete response (CR) was defined as disappearance of all target lesions. Partial response (PR) was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Overall response rate= (CR+PR)/all eligible and treated patients | assessed every 6 weeks while on study, then every 3 months for patients < 2 years from registration and every 6 months if patient is 2- 3 years from registration. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Veliparib, Small cell lung cancer