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