Effect of Pembrolizumab With or Without Carboplatin and Paclitaxel on Immune Response in Patients With Recurrent or Stage IIIB-IV Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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This randomized pilot phase II trial studies the effect of pembrolizumab with or without carboplatin and paclitaxel on immune response in patients with non-small cell lung cancer that has come back or stage IIIB-IV. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. 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. Giving pembrolizumab together with carboplatin and paclitaxel may improve immune responses in patients with non-small cell lung cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the immune effects of single agent pembrolizumab and pembrolizumab combined with low-dose carboplatin and paclitaxel. II. Estimate the treatment response to single agent pembrolizumab and pembrolizumab combined with low-dose carboplatin and paclitaxel. SECONDARY OBJECTIVES: I. Determine the toxicity and tolerability of pembrolizumab and pembrolizumab combined with low-dose carboplatin and paclitaxel. II. Assess quality of life (QOL) in patients receiving single agent pembrolizumab and pembrolizumab combined with carboplatin and paclitaxel. III. Assess the association between immune response and clinical response. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. ARM II: Patients receive pembrolizumab IV over 30 minutes on day 1, paclitaxel IV over 1 hour and carboplatin IV over 1 hour on days 1, 7 and 14. In both arms, courses repeat every 3 weeks for 2 years in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for at least 30 days and then every 8 weeks thereafter.

Official Title
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Immune Response in Patients With Recurrent or Metastatic Non-small Cell Lung Cancer and Performance Status of 2 Treated With a Combination of Pembrolizumab and Low Dose Weekly Carboplatin/Paclitaxel

Conditions
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Recurrent Non-Small Cell Lung Carcinoma, Stage IIIB Non-Small Cell Lung Cancer, Stage IV Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Carboplatin
* Other: Laboratory Biomarker Analysis
* Drug: Paclitaxel
* Biological: Pembrolizumab
* Other: Quality-of-Life Assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically confirmed non-small cell lung cancer (NSCLC) that is advanced/metastatic (stage IIIB/IV) or recurrent (progression after surgery or radiation or chemo-radiation treatment for loco-regional disease). Patients with epidermal growth factor (EGFR) mutation, anaplastic lymphoma kinase (ALK) gene rearrangement or ROS1 translocation must have received an approved EGFR, ALK, or ROS1-directed therapy and have signs of disease progression prior to receiving pembrolizumab. Patients must be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion; newly-obtained is defined as a specimen obtained up to 12 weeks (84 days) prior to date of signing consent. Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen (up to 3 years) only upon agreement from the Sponsor. At least 4 mm of tumor tissue will be needed for PD-L1 staining. Patients who have received zero (0) to two (2) previous lines of systemic chemotherapy and are not currently receiving chemotherapy treatment (within 2 weeks of randomization). At least one measurable lesion as defined by RECIST v1.1 on screening computed tomography (CT) or magnetic resonance imaging (MRI) Age >18 years. ECOG performance status of 2. Patients must have normal organ and marrow function as defined below: white blood cell count > 2,500 cells/mcL absolute neutrophil count >1,500/mcL platelets >100,000/mcL hemoglobin ≥ 9 g/dL total bilirubin ≤ 2.0 x upper limit of normal (ULN) AST(SGOT)/ALT(SGPT) < 2.5 x ULN Or ≤ 5 x ULN in presence of liver metastases creatinine within normal institutional limits OR creatinine clearance > 50 mL/min for patients with creatinine levels above institutional normal potassium ≥ lower limit of normal Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study participation and for 4 weeks after the final administration of study drugs. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Ability to understand and the willingness to sign an IRB-approved informed consent document. Exclusion Criteria Known active (untreated) central nervous system (CNS) metastases that require steroids. Subjects with CNS metastases who have completed a course of therapy would be eligible for the study provided they are clinically stable for at least 2 weeks before study entry, defined as: No evidence of new or enlarging CNS metastasis or new neurological symptoms attributable to CNS metastases. Asymptomatic and receiving either no or stable doses of anticonvulsants and total doses of corticosteroids equivalent to 10 mg of prednisone or less. Current or previous other malignancy within 2 years of study entry, except cured basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in situ of the cervix, or other noninvasive or indolent malignancy without sponsor approval. History of previous exposure to an anti PD1/PD-L1 agent Patients receiving any other investigational agents and or more than two different chemotherapy regimens for treatment of metastatic disease. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. History of allergic reactions attributed to compounds of similar chemical or biologic composition to pembrolizumab, paclitaxel or carboplatin. Current uncontrolled cardiac disease such as angina or myocardial infarction, congestive heart failure including New York Heart Association functional classification of 3, or arrhythmia requiring treatment. History of pneumonitis or active lung infection. Chronic or current active infectious disease requiring systemic antibiotics, antifungals, or antivirals. Patients receiving chronic steroids and or immunosuppression. Known HIV infection, Hepatitis B virus (HBV) or hepatitis C virus (HCV) viremia or at risk for HBV reactivation. HBV DNA and testing for HCV RNA must be undetectable. At risk for HBV reactivation is defined as hepatitis B surface antigen positive or anti-hepatitis B core antibody positive. History of autoimmune disease(s). Psychiatric illness/social situations that would limit compliance with study requirements. Any other condition or circumstance that could interfere with adherence to the study's procedures or requirements, or otherwise compromise the study's objectives such as history of, or any evidence of active, non-infectious pneumonitis. Has an active infection requiring systemic therapy. Pregnant women are excluded from this study because of the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants, breastfeeding should be discontinued prior to study entry.

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (pembrolizumab)<br>Patients receive pembrolizumab IV over 30 minutes on day 1. Courses repeat every 3 weeks for 2 years in the absence of disease progression or unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Biological: Pembrolizumab<br>* Given IV<br>* Other names: SCH 900475;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Experimental: Arm II (pembrolizumab, paclitaxel, carboplatin)<br>Patients receive pembrolizumab IV over 30 minutes on day 1, paclitaxel IV over 1 hour and carboplatin IV over 1 hour on days 1, 7 and 14. Courses repeat every 3 weeks for 2 years in the absence of disease progression or unacceptable toxicity. | Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Biological: Pembrolizumab<br>* Given IV<br>* Other names: SCH 900475;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response | Duration of response will also be assessed in each group and compared using survival analysis methods. | Up to 2 years | 
| Effect of treatment on immune markers | Paired t-tests will be used to analyze the effects of the treatments on immune markers. Two-sample t-tests will compare outcome measures post-randomization and an analysis of covariance compare outcome measures prior to randomization. A longitudinal mixed model will examine the differences between groups over time. | Up to 2 years | 
| Objective response rate (ORR), assessed using RECIST | The Fisher's exact test methods will be used to estimate ORR between groups. The Exact Clopper-Pearson 95% confidence intervals will be calculated for each group. | Up to 2 years | 
| Overall survival | The Kaplan Meier curves will be used to estimate overall survival rates. | Duration of time from randomization to the time of death due to any cause, or the date the subject was last confirmed to be alive, assessed up to 3 years | 
| Progression free survival | The Kaplan Meier curves will be used to estimate progression free survival rates. | Duration of time from randomization to the time of immune-related progressive disease or death, whichever comes first, assessed up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Reported Adverse Events - CTCAE Version 4.0 | Adverse events will be categorized by organ system and severity and summarized as frequency counts and percentages. A treatment will be considered too toxic if ≥6 of 20 patients in a cohort are removed from study because of toxicity. | At baseline, at week 8, week 12, week 20 and up to 30 days after last study drug is administered | 
| Quality of Life - European Organization for Research and Treatment of Cancer (EORTC) QLQ-30 Questionnaire | The QLQ-30 is a 30-item multi-dimensional questionnaire and it contains nine multi-item scales: five functional scales (physical, role, cognitive, emotional, and social); three symptom scales (fatigue, pain, and nausea and vomiting); and a global health and quality-of-life scale, requested by 4-point Likert or visual analogue scales. (1 = not at all to 4 = very much). Summary scores from each instrument will be assessed at each time point and longitudinal comparisons will be made between groups using a repeated measure mixed model approach. Higher scores indicate a greater (worse) effect on quality of life. | At baseline and every 12 weeks during study intervention, up to 2 years | 
| Quality of Life - European Organization for Research and Treatment of Cancer (EORTC) LC-13 Questionnaire | The QLQ-LC13 is a lung cancer-specific module to be used in conjunction with the QLQ-30 and is 13 additional items with scoring on a 4-point Likert or visual analogue scales. (1 = not at all to 4 = very much). Summary scores from each instrument will be assessed at each time point and longitudinal comparisons will be made between groups using a repeated measure mixed model approach. Higher scores indicate a greater (worse) effect on quality of life. | At baseline and then every 12 weeks during study intervention, up to 2 years | 
| Change in Immune Markers with Treatment Response | Treatment response will be grouped into 4 categories as defined earlier in the protocol (complete response, partial response, stable disease, progressive disease). The immune responses for patients within each of these 4 groups will be examined to determine whether there is evidence of an association. For continuous measures of immune response the mean value within each response category will be compared. | At baseline, week 8 and then every 12 weeks until end of treatment visit, up to 2 years |