Neoplasms

All Conditions

Respiratory Tract (Lung and Bronchial) Diseases

Rare Diseases

Carcinoma

Small Cell Lung Carcinoma

Carcinoma, Neuroendocrine

Carcinoma, Non-Small-Cell Lung

Carcinoma, Small Cell

Lung Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Adenocarcinoma

Neoplasms, Nerve Tissue

Small Cell Lung Cancer

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Dermatologic Agents

Etoposide

Cisplatin

Etoposide phosphate

Podophyllotoxin

Veliparib

Enzyme Inhibitors

Keratolytic Agents

Tubulin Modulators

Antimitotic Agents

Poly(ADP-ribose) Polymerase Inhibitors

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.

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.

Placebo

Taofeek Owonikoko

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.

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

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

Neurotoxicity total score was measured by the 11 items in the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) questionnaire. Each item was scored from 0-4. The severity of neurotoxicity was measured by the total score of the 11 items, ranged from 0 to 44. Lower values of the FACT/GOG-Ntx neurotoxicity total score indicate higher neurotoxicity.

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

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.

Overall survival (OS) is defined as time from randomization to death from any cause. Median OS was estimated using the Kaplan-Meier method.

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

National Cancer Institute (NCI)

The phase I portion of the study was designed to determine the recommended dose for veliparib for the phase II portion of the trial. A total of 9 patients were treated on the phase I study. A total of 3 dose levels of veliparib were planned: 60mg (level 1), 100gm (level 2) and 40mg (level -1). 1 cycle=3 weeks, maximum of 4 cycles.

Phase I: Arm A (Dose Level 1)

Phase I: Arm B (Dose Level 2)

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.

Cisplatin: Given IV Etoposide: Given IV Veliparib: Given PO

Phase II: Arm D (Veliparib)

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.

Cisplatin: Given IV Etoposide: Given IV Placebo: placebo of Veliparib

Phase II: Arm E (Placebo)

Phase I

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.

Cisplatin: Given IV

Etoposide: Given IV

Veliparib: Given PO

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.

Cisplatin: Given IV

Etoposide: Given IV

Placebo: placebo of Veliparib

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Study Statistician

Recommended Phase II Dose (Phase I)

The significance test reported here was for treatment arms comparison in patients within the male/abnormal LDH stratum

The significance test reported here was for treatment arms comparison in patients not in the male/abnormal LDH stratum.

If there was a significant treatment-by-stratification factor interaction, the results would be reported separately for each stratum. Significance was defined as the p value was less than 0.05.

Overall sample

Patients within the male/abnormal LDH stratum

Patients not within the male/abnormal LDH stratum

Progression Free Survival (Phase II)

Overall Survival (OS)

Overall Response Rate (ORR)

eligible and treated patients who had neurotoxicity data at both baseline and 3 months assessments

Neurotoxicity Total Score Change Between Baseline and 3 Months After Treatment Start

Phase I: Arm B (Dose Level II)

Overall Study

Carboplatin

Pembrolizumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Patients receive pembrolizumab IV over 30 minutes on day 1 and undergo radiation therapy BID 5 days a week for 3 weeks. Patients also receive cisplatin IV over 2 hours or carboplatin IV over 30 minutes and etoposide IV over 4 hours on days 1, 2, and 3. Treatment repeats every 3 weeks for 16 courses (1 course for radiation therapy, 4 courses for chemotherapy) in the absence of disease progression or unacceptable toxicity. Patients who achieve systemic disease control and do not exhibit severe (grade \> 3) pembrolizumab related toxicity during/after completion of 16 courses may receive 16 additional courses of pembrolizumab in the absence of disease progression or unacceptable toxicity.

Beginning after the completion of chemotherapy, patients receive pembrolizumab IV over 30 minutes on day 1 and undergo radiation therapy BID 5 days a week for 3 weeks. Treatment repeats every 3 weeks for 16 courses (1 course for radiation therapy) in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis

Radiation Therapy

James Welsh

This phase I trial studies the side effects and best dose of pembrolizumab when given together with chemoradiotherapy or radiation therapy in treating patients with small cell lung cancer. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays to kill cancer cells and shrink tumors. Giving chemotherapy with radiation therapy may kill more cancer cells. Giving pembrolizumab with chemoradiotherapy or radiation therapy may be a better treatment for small cell lung cancer.

PRIMARY OBJECTIVES:

I. Safety of pembrolizumab (MK 3475) plus chemotherapy (chemo)/radiation for limited-stage small-cell lung cancer (LS-SCLC).

II. Safety of MK-3475 plus radiation for extensive-stage small-cell lung cancer (ES-SCLC).

SECONDARY OBJECTIVES:

I. MK-3475 will improve progression free survival (PFS) compared to historical controls for LS-SCLC and ES-SCLC.

OUTLINE: This is a dose-escalation study of pembrolizumab. Patients are assigned to either Part A or Part B based on diagnosis.

PART A (LS-SCLC): Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and undergo radiation therapy twice daily (BID) 5 days a week for 3 weeks. Patients also receive cisplatin IV over 2 hours or carboplatin IV over 30 minutes and etoposide IV over 4 hours on days 1, 2, and 3. Treatment repeats every 3 weeks for 16 courses (1 course for radiation therapy, 4 courses for chemotherapy) in the absence of disease progression or unacceptable toxicity. Patients who achieve systemic disease control and do not exhibit severe (grade \> 3) pembrolizumab related toxicity during/after completion of 16 courses may receive 16 additional courses of pembrolizumab in the absence of disease progression or unacceptable toxicity.

PART B (ES-SCLC): Beginning after the completion of chemotherapy, patients receive pembrolizumab IV over 30 minutes on day 1 and undergo radiation therapy BID 5 days a week for 3 weeks. Treatment repeats every 3 weeks for 16 courses (1 course for radiation therapy) in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, all patients are followed up at 30 days and then every 12 weeks.

Pembrolizumab and Concurrent Chemoradiotherapy or Radiation Therapy in Treating Patients With Small Cell Lung Cancer

Phase I Trial of MK-3475 and Concurrent Chemo/Radiation for the Elimination of Small Cell Lung Cancer

Frequency of adverse events will be tabulated by grade, type, and dose/cohort. Relative frequencies and confidence intervals will also be constructed.

Will be performed using Global Immune Related Response Criteria that factors all indexed and non-indexed lesions, In-Field Immune Related Response Criteria in which only non-radiation therapy-treated lesions and non-index lesions arising outside the radiation therapy planning target volume will be considered, and Out-Field Immune Related Response Criteria in which only non-radiation therapy-treated lesions and non-index lesions arising outside the radiation therapy planning target volume will be considered.

Time to event distributions for progression free survival will be estimated via Kaplan-Meier analysis.

Time to event distributions for overall response will be estimated via Kaplan-Meier analysis.

Descriptive analysis will include a global assessment of patient outcomes for parts A and B separately.

M.D. Anderson Cancer Center

Symptoms and General Pathology

Neoplasm Metastasis

LY2510924: 20 milligram (mg) administered once daily as a subcutaneous(SC) injection on days 1 to 7 of the 21 day cycle; repeat every 21 days for 6 cycles. Carboplatin: 5 milligram/millimeter/per minute (mg/mL/min) area under the curve (AUC) administered intravenously on day 1 of the 21 day cycle; repeat every 21 days for 6 cycles.

Etoposide: 100 milligram square meter (mg/m\^2) administered intravenously on days 1 to 3 of the 21 day cycle; repeat every 21 days for 6 cycles.

Carboplatin: 5 mg/mL/min area under the curve administered intravenously on day 1 of the 21 day cycle; repeat every 21 days for 6 cycles.

Etoposide: 100 milligram square meter (mg/m\^2) administered on days 1 to 3 of the 21 day cycle; repeat every 21 days for 6 cycles.

LY2510924

Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)

The purpose of this trial is to compare the progression free survival of LY2510924 + carboplatin + etoposide therapy versus carboplatin + etoposide therapy in participants with extensive-stage disease small cell lung cancer (SCLC)

A Study of LY2510924 in Participants With Extensive-Stage Small Cell Lung Carcinoma

A Randomized Phase 2 Study of LY2510924 and Carboplatin/Etoposide Versus Carboplatin/Etoposide in Extensive-Stage Small Cell Lung Carcinoma

Lilly provides access to the individual patient data from studies on approved medicines and indications as defined by the sponsor specific information on ClinicalStudyDataRequest.com.

This access is provided in a timely fashion after the primary publication is accepted. Researchers need to have an approved research proposal submitted through ClinicalStudyDataRequest.com. Access to the data will be provided in a secure data sharing environment after signing a data sharing agreement.

PFS is defined as the time from the date of randomization to the first date of objectively determined progressive disease (PD) or death from any cause. For participants who are still alive at the time of analysis and without evidence of tumor progression, PFS will be censored at the date of the most recent objective progression-free observation. For participants who receive subsequent anticancer therapy (except PCI) prior to objective disease progression or death, PFS will be censored at the date of the last objective progression-free observation prior to the date of subsequent therapy.

ORR is defined as the number of participants with a best response of CR and PR defined using Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) criteria. CR is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm.Tumor marker results must have normalized. PR is defined as at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD)is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (including the baseline sum if that is the smallest). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.The appearance of one or more new lesions is also considered progression.

Overall survival (OS) is defined as the time from the randomization to the date of death from any cause. For participants who are still alive as of the data cutoff date, OS time will be censored on the date of the participant's last contact (last contact for participants in postdiscontinuation is last known alive date in mortality status).

DOR was defined as the time from first objective status assessment of CR or PR to the first time of progression or death as a result of any cause. Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) criteria. CR is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Tumor marker results must have normalized. PR is defined as at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD)is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (including the baseline sum if that is the smallest). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.

Eli Lilly and Company

All participants who received at least one dose of study drug.

LY2510924: 20 milligram (mg) administered once daily as a subcutaneous injection on days 1 to 7 of the 21 day cycle; repeat every 21 days for 6 cycles. Carboplatin: 5 milligram/millimeter/per minute (mg/mL/min) area under the curve (AUC) administered intravenously on day 1 of the 21 day cycle; repeat every 21 days for 6 cycles. Etoposide: 100 milligram square meter (mg/m\^2) administered intravenously on days 1 to 3 of the 21 day cycle; repeat every 21 days for 6 cycles.

LY2510924 + Carboplatin + Etoposide

Carboplatin: 5 mg/mL/min area under the curve administered intravenously on day 1 of the 21 day cycle; repeat every 21 days for 6 cycles. Etoposide: 100 milligram square meter (mg/m\^2) administered on days 1 to 3 of the 21 day cycle; repeat every 21 days for 6 cycles.

Carboplatin + Etoposide

Ethnicity (NIH/OMB)

United States

Region of Enrollment

All participants who received at least one dose of study.

Chief Medical Officer

All participants who received at least one dose of study drug. One participant was excluded from analysis due to protocol violation.The number of participants censored were LY2510924 + Carboplatin + Etoposide=13 and Carboplatin + Etoposide=7.

Progression Free Survival (PFS)

All participants who received at least one dose of study drug. One participant was excluded from analysis due to protocol violation.

Number of Participants Achieving Complete Response (CR) or Partial Response (PR) (Overall Response Rate[ORR])

All participants who received at least one dose of study drug. One participant was excluded from analysis due to protocol violation. The numbers of participants censored were LY2510924 + Carboplatin + Etoposide= 4 and Carboplatin + Etoposide=3.

All participants who received at least one dose of study drug. One participant was excluded from analysis due to protocol violation. The number of participants censored were LY2510924 + Carboplatin + Etoposide=47 and Carboplatin + Etoposide=42.

Duration of Overall Response (DOR)

Patients receive pembrolizumab IV over 30 minutes on day 1. Courses repeat every 21 days for up to 12 months in the absence of disease progression or unacceptable toxicity.

Ammar Sukari

This phase II trial studies how well pembrolizumab works in treating patients with extensive stage small cell lung cancer after completion of combination chemotherapy. Pembrolizumab may be effective in controlling small cell lung cancer for a longer period of time in patients with responsive or stable disease after completion of combination chemotherapy.

PRIMARY OBJECTIVES:

I. To assess Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 defined progression-free survival (PFS) in extensive stage small cell lung cancer (SCLC) patients, who have complete response (CR), partial response (PR) or stable disease following minimum of 4 cycles of platinum (cisplatin or carboplatin) and etoposide.

SECONDARY OBJECTIVES:

I. To assess modified PFS in all patients enrolled. II. To assess overall survival of patients enrolled on the trial. III. To assess programmed cell death 1 ligand 1 (PD-L1) expression in archival tumor tissues and in circulating tumor cells (CTCs) and correlate the expression to RECIST defined PFS.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Courses repeat every 21 days for up to 24 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then every 12 weeks.

MK-3475 as Maintenance Therapy in Extensive Stage SCLC

Phase II Study of MK-3475 as Maintenance Therapy in Extensive Stage Small Cell Lung Cancer (SCLC) Patients

Progression is defined using RECIST 1.1. PFS will be estimated with the standard Kaplan-Meier method, from which summary statistics of interest (median, 1-year rate, etc.) will be derived. Both point and 95% confidence interval estimates of PFS will be calculated.

Progression is defined using RECIST 1.1. Estimated using standard Kaplan-Meier methods, from which the median and a 90% confidence interval will be calculated.

Estimated using standard Kaplan-Meier methods, from which the median and a 95% confidence interval will be calculated.

Barbara Ann Karmanos Cancer Institute

Principal Investigator

Patients receive pembrolizumab IV over 30 minutes on day 1. Courses repeat every 21 days for up to 12 months in the absence of disease progression or unacceptable toxicity.

Pembrolizumab: Given IV

Laboratory Biomarker Analysis: Correlative studies

Treatment (Pembrolizumab)

Age, Categorical

Race/Ethnicity, Customized

Dr. Ammar Sukari

PFS Using RECIST 1.1

Modified PFS Defined by RECIST as Progression That is Confirmed by a Second Scan at Least 4 Weeks Apart

Overall Survival

Amino Acids

Antibodies

Immunoglobulins

Immunoglobulin G

Immunoglobulins, Intravenous

Immunologic Factors

Proline

Patients receive pembrolizumab IV on day 1 and epacadostat PO BID on days 1-21. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. Patients benefiting from treatment may continue for an additional 17 courses.

Epacadostat

Ravi Salgia, MD

Jacob Sands, MD

This phase II trial studies how well pembrolizumab and epacadostat work in combination treating patients with extensive stage small cell lung cancer. Monoclonal antibodies, such as pembrolizumab, may assist the immune system in recognizing cancer cells leading to elimination of those cells. Epacadostat may prevent down-regulation of T-cells, which means it can boost the immune system. Giving pembrolizumab and epacadostat together may work better than either drug alone in treating extensive stage small cell lung cancer.

PRIMARY OBJECTIVES:

I. To assess the objective response rate (ORR) as measured by a modified Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 in subjects with extensive stage small cell lung cancer undergoing treatment with combination pembrolizumab and epacadostat.

SECONDARY OBJECTIVES:

I. To assess the progression free survival (PFS) as measured by a modified RECIST v1.1 in subjects with extensive stage small cell lung cancer undergoing treatment with combination pembrolizumab and epacadostat.

II. To assess the overall survival in subjects with extensive stage small cell lung cancer undergoing treatment with combination pembrolizumab and epacadostat.

III. To assess the \>= grade 3 drug related adverse event profile of combination pembrolizumab and epacadostat in subjects with extensive stage small cell lung cancer.

TERTIARY OBJECTIVES:

I. To assess tumor genomics, T-cell, myeloid-derived suppressor cells, and receptors (including PD-L1, IDO1, etc) in relation to response rates.

II. To assess cell free deoxyribonucleic acid (DNA) (cfDNA), cell free ribonucleic acid (RNA) (cfRNA), micro RNA (miRNA), and exosomes as predictors for outcomes to treatment with pembrolizumab and epacadostat in subjects with extensive stage small cell lung cancer and to evaluate plasma for predictive markers for outcomes to therapy.

III. Blood samples will be also be stored for future evaluation.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) on day 1 and epacadostat orally (PO) twice daily (BID) on days 1-21. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. Patients benefiting from treatment may continue for an additional 17 courses.

After completion of study treatment, patients are followed up at 30 days, then every 12 weeks thereafter.

ALCMI-005: Pembrolizumab and Epacadostat in Treating Patients With Extensive Stage Small Cell Lung Cancer

ALCMI-005: Phase II Study of Pembrolizumab and Epacadostat for Small Cell Lung Cancer After Previous Treatment With Platinum-Based Therapy

Proportions and associated confidence intervals will be estimated.

The method of Kaplan-Meier will be used to estimate progression free survival. The Brookmeyer-Crowley method will be used to estimate confidence intervals about median survival times.

The method of Kaplan-Meier will be used to estimate overall survival. The Brookmeyer-Crowley method will be used to estimate confidence intervals about median survival times.

Binary proportions such as toxicity rates can be estimated to within 15% with 95% confidence.

Addario Lung Cancer Medical Institute

City of Hope Medical Center

Patients undergo PCI using 3DCRT daily for 2 weeks.

Patients undergo PCI with HA using IMRT daily for 2 weeks.

3-Dimensional Conformal Radiation Therapy

Cognitive Assessment

Intensity-Modulated Radiation Therapy

Quality-of-Life Assessment

Vinai Gondi

This randomized phase II/III trial studies how well whole-brain radiation therapy works and compares it with or without hippocampal avoidance in treating patients with small cell lung cancer that is found in one lung, the tissues between the lungs, and nearby lymph nodes only (limited stage) or has spread outside of the lung in which it began or to other parts of the body (extensive stage). Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. The hippocampus is part of the brain that is important for memory. Avoiding the hippocampus during whole-brain radiation could decrease the chance of side effects on memory and thinking. It is not yet known whether giving whole-brain radiation therapy is more effective with or without hippocampal avoidance in treating patients with small cell lung cancer.

PRIMARY OBJECTIVES:

I. Determine whether the 12-month intracranial relapse rate following hippocampal avoidance (HA)-prophylactic cranial irradiation (PCI) is non-inferior compared to the rate following PCI for patients with small cell lung cancer (SCLC). (Randomized Phase II Component \[Non-Inferiority\]) II. Determine whether HA-PCI reduces the likelihood of 6-month deterioration from baseline in Hopkins Verbal Learning Test (HVLT)-Revised (R) delayed recall compared to PCI for patients with SCLC. (Phase III Component \[Efficacy\])

SECONDARY OBJECTIVES:

I. Compare time to cognitive failure, as measured by a battery of tests (HVLT-R, Controlled Oral Word Association \[COWA\] test, and Trail Making Test \[TMT\] parts A and B), after PCI versus HA-PCI in SCLC.

II. Compare time to cognitive failure as separately measured by each test (HVLT-R for Total Recall and Delayed Recognition, COWA test, and TMT parts A and B), after PCI versus HA-PCI for SCLC.

III. Compare patient-reported cognitive functioning and other quality of life domains (assessed by the European Organization for Research and Treatment of Cancer \[EORTC\] Quality of Life Questionnaire \[QLQ\]-Core \[C\]30 and BN20) between PCI versus HA-PCI for patients with SCLC.

IV. Compare overall survival after PCI versus HA-PCI for patients with SCLC. V. Compare 12-month intracranial relapse rate (at completion of phase III) and time to intracranial relapse after PCI versus HA-PCI for patients with SCLC.

VI. Evaluate adverse events according to Common Terminology Criteria for Adverse Events (CTCAE) criteria.

VII. Correlate changes in health-related quality of life (HRQOL) domains with changes in cognitive testing outcomes following PCI versus HA-PCI for patients with SCLC.

VIII. Assess cost-effectiveness of HA-PCI (intensity modulated radiation therapy \[IMRT\]) and PCI (3-dimensional conformal radiation therapy \[3DCRT\]) using the EuroQual (EQ)-5-Dimensions (5D)-5L.

IX. Correlate miRNA signatures with cognitive failure in SCLC patients who received PCI and HA-PCI.

X. Evaluate APOE genotyping as potential predictor of neurocognitive decline, hippocampal atrophy after brain irradiation and/or differential benefit from hippocampal avoidance.

XI. Evaluate baseline MR imaging biomarkers of white matter injury and hippocampal volumetry as potential predictors of cognitive decline and differential benefit from HA-PCI as compared to PCI.

TERTIARY OBJECTIVES:

I. Collect serum, whole blood, and urine for future translational research analyses.

II. Evaluate baseline magnetic resonance (MR) imaging biomarkers of white matter injury and hippocampal volumetry as potential predictors of cognitive decline and differential benefit from HAPCI as compared to PCI.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients undergo PCI using 3DCRT daily for 2 weeks.

ARM II: Patients undergo PCI with HA using IMRT daily for 2 weeks.

After completion of study treatment, patients are followed every 3 months for 1 year, then every 6 months until 3 years and then annually until death.

Whole-Brain Radiation Therapy With or Without Hippocampal Avoidance in Treating Patients With Limited Stage or Extensive Stage Small Cell Lung Cancer

Randomized Phase II/III Trial of Prophylactic Cranial Irradiation With or Without Hippocampal Avoidance for Small Cell Lung Cancer

The change from baseline to 6 months will be compared between arms using the t-test (or Wilcoxon test if not normally distributed) in the total score and the two subscale scores (agency and pathway). These scores will be correlated with the EORTC- QLQ-C30 total score using a Pearson correlation coefficient. A general linear model will be used to assess hopefulness, performed separately for the AHS total score and subscale scores, between treatment arms while adjusting for depression.

Compared using Fisher's exact test at a significance level of 0.05.

It will be compared between arms using a binomial test of difference in proportions at a significance level of 0.1. If the rate of relapse in the HA-PCI arm is significantly greater than that of the PCI only arm, this study will not continue to the phase III portion.

Quality-adjusted life years (QALY's) will be assessed as the area under the preference-weighted survival curve. Cost will be assessed using a societal perspective. The primary cost-effectiveness outcome will be the pooled incremental cost-per QALY ratio for HA-PCI versus standard PCI. The incremental cost per QALY ratio will be calculated as the total cost of the HA-PCI minus total cost of standard PCI which will be divided by the quality adjusted survival of the patients treated with HA-PCI minus the quality adjusted survival of patients receiving standard PCI.

Counts of all AEs by grade will be provided by treatment arm. Counts and frequencies will be provided for the worst grade AE experienced by the patient by treatment arm.

The occurrence of intracranial relapse will be defined as appearance of brain metastasis in brain. Cumulative incidence approach will be used to estimate the median time to intracranial relapse to account for the competing risk of death. Gray's test will be used to test for statistically significant difference in the distribution of intracranial relapse times. Cause-specific Cox proportional hazards regression model will be used to evaluate effect of stratification variables (age, stage, and planned concurrent memantine use) and other baseline characteristics, on time to intracranial relapse.

Estimated using the Kaplan-Meier method and differences between treatment arms will be tested using the log rank test. The Cox proportional hazard model will be performed with the stratification variables and other baseline characteristics as fixed variables to assess the treatment effect while adjusting for patient-specific risk factors.

Correlation of changes in HRQOL domains measured by the EORTC QLQ-C30 and BN20 with changes in cognitive function will be assessed. Additionally cognitive function decline at 3, 6, 12, 18 and 24 months will also be assessed and compared using Fisher's exact test. Decline from baseline to each time point (3, 6, 12, 18, and 24 months from the start of treatment) in the following subscales will also be assessed and compared using Fisher's exact test: global QOL, physical functioning, role functioning, emotional functioning, and social functioning domains along with fatigue and pain items.

Standardized scores that adjust for age, education, and gender when necessary will be analyzed. For discrete time point analyses, the change from baseline to each follow-up time point (3, 6, 12, 18, and 24 months from the start of treatment) will be calculated and compared between treatment arms using a t-test or Wilcoxon-Mann- Whitney test, depending on the normality of the data. Neurocognitive decline using the RCI for the HVLT-R, COWA, and TMT also will be compared between treatment arms at each follow-up time point using Fisher's exact test.

The cumulative incidence approach will be used to estimate the median time to neurocognitive failure to account for the competing risk of death. Gray's test will be used to test for statistically significant difference in the distribution of neurocognitive failure times. The cause-specific Cox proportional hazards regression model will be used to evaluate the effect of stratification variables (age, stage, and planned concurrent memantine use) and other baseline characteristics, on time to neurocognitive decline.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Cisplatin and Etoposide With or Without Veliparib in Treating Patients With Extensive Stage Small Cell Lung Cancer	NCT01642251	Extensive Stage... Large Cell Lung... Neuroendocrine ... Small Cell Carc... Stage IV Non-Sm...	Cisplatin Etoposide Veliparib Placebo	18 Years -	National Cancer Institute (NCI)
Pembrolizumab and Concurrent Chemoradiotherapy or Radiation Therapy in Treating Patients With Small Cell Lung Cancer	NCT02402920	Extensive Stage... Limited Stage S... Neuroendocrine ...	Carboplatin Cisplatin Etoposide Laboratory Biom... Pembrolizumab Radiation Thera...	18 Years -	M.D. Anderson Cancer Center
A Study of LY2510924 in Participants With Extensive-Stage Small Cell Lung Carcinoma	NCT01439568	Extensive Stage...	LY2510924 Carboplatin Etoposide	18 Years -	Eli Lilly and Company
MK-3475 as Maintenance Therapy in Extensive Stage SCLC	NCT02359019	Extensive Stage...	Pembrolizumab Laboratory Biom...	18 Years -	Barbara Ann Karmanos Cancer Institute
ALCMI-005: Pembrolizumab and Epacadostat in Treating Patients With Extensive Stage Small Cell Lung Cancer	NCT03402880	Extensive Stage...	Pembrolizumab Epacadostat Laboratory Biom...	18 Years -	City of Hope Medical Center
Whole-Brain Radiation Therapy With or Without Hippocampal Avoidance in Treating Patients With Limited Stage or Extensive Stage Small Cell Lung Cancer	NCT02635009	Extensive Stage... Limited Stage S...	3-Dimensional C... Cognitive Asses... Intensity-Modul... Laboratory Biom... Quality-of-Life...	18 Years -	NRG Oncology
Tumor-Treating Fields Therapy in Preventing Brain Tumors in Participants With Extensive-Stage Small Cell Lung Cancer	NCT03607682	Extensive Stage...	Tumor Treating ... NovoTTF-200A De... Quality-of-Life...	22 Years -	Vanderbilt-Ingram Cancer Center
A Randomized Phase II Study of Cisplatin and Etoposide in Combination With Either Hedgehog Inhibitor GDC-0449 or IGF-1R MOAB IMC-A12 for Patients With Extensive Stage	NCT00887159	Extensive Stage... Recurrent Small...	Cisplatin Cixutumumab Etoposide Laboratory Biom... Vismodegib	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for extensive stage small cell lung carcinoma