Naloxegol in Treating Patients With Stage IIIB-IV Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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This randomized pilot clinical trial studies the side effects and best dose of naloxegol and to see how well it works in treating patients with stage IIIB-IV non-small cell lung cancer. Naloxegol may relieve some of the side effects of opioid pain medication and fight off future growth in the cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine feasibility and safety of long-term administration of two doses of a peripheral opioid receptor antagonist in patients with advanced non-small cell lung cancer (NSCLC) receiving first-line systemic therapy. SECONDARY OBJECTIVES: I. To explore whether patients randomized to one or both of the two study drug arms have less decline in health-related quality of life (HRQoL) than patients randomized to placebo. II. To estimate the difference in the pain levels and opioid/non-opioid analgesic requirements between patients receiving naloxegol or placebo. III. To estimate the difference in the adverse peripheral effects of opioids (e.g. constipation, nausea/emesis, dry mouth and urinary retention) between patients receiving naloxegol or placebo. IV. To explore whether there is a signal that naloxegol may be associated with longer progression-free survival (PFS) and overall survival (OS). V. To evaluate the difference in discontinuation rate of systemic therapy due to adverse events (AEs) and deaths attributable to systemic therapy. After completion of study treatment, patients are followed up every 3 months.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled Pilot Study of an Oral, Selective Peripheral Opioid Receptor Antagonist in Advanced Non-Small Cell Lung Cancer

Conditions
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Stage IIIB Non-Small Cell Lung Cancer, Stage IV Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: Naloxegol
* Other: Placebo
* Other: Laboratory Biomarker Analysis
* Other: Quality-of-Life Assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Advanced (stage IIIB or IV) non-small cell lung cancer diagnosed by biopsy of the primary or metastatic site (American Joint Committee on Cancer 7.0) No known presence of known EGFR or EML4-ALK driver mutations in the tumor Started first-line systemic therapy of the investigator's choice within 12 weeks prior to registration, or planning to initiate first-line systemic therapy of the investigator's choice within 4 weeks after registration; no planned initiation of definitive (potentially curative) concurrent chemo-radiation No prior systemic therapy for advanced NSCLC, including chemotherapy, targeted therapy or immunotherapy (other than current treatment); prior palliative radiation permitted; prior adjuvant systemic therapy /radiation is permitted No more than 7 days of prior use of mixed opioid agonist/opioid antagonists or other opioid antagonists within 4 weeks before registration; patients should not receive such medications after registration and for the entire duration of study treatment No methadone within 4 weeks prior to registration Patients must have used opioid medication(s) for pain at some time in the 4 weeks prior to registration; current use of opioids (at the time of registration) and/or later during the course of the study is permitted but not required Expected survival > 3 months No concurrently active second invasive malignancies except non-melanoma skin cancer No history of gastrointestinal obstruction, or conditions that increase the risk of gastrointestinal obstruction, perforation, bleeding or impairment of the gastrointestinal wall; no abdominal surgery within 60 days of registration No acute gastrointestinal conditions, such as: obstruction, fecal impaction, obstipation, acute surgical abdomen, ongoing need for manual maneuvers to induce bowel movements (such as digital evacuation) No conditions that may compromise blood-brain barrier permeability (e.g., multiple sclerosis, recent brain trauma, Alzheimer's disease, or uncontrolled seizures) No symptomatic and untreated brain metastases; patients will be eligible for study if radiation therapy for brain metastases was completed at least 7 days prior to registration Patients having received stereotactic radiation will be eligible if the radiation was completed at least 7 days prior to registration Patients having undergone surgical resection of brain metastases will be eligible after they have healed and recovered from the surgical intervention sufficiently to start systemic treatment for NSCLC, as determined by a neurosurgeon No known leptomeningeal carcinomatosis No history of myocardial infarction =< 6 months prior to registration; no current symptomatic congestive heart failure, uncontrolled angina, or uncontrolled cardiac arrhythmias No severe hepatic impairment (Child-Pugh class C) or acute liver disease No known serious or severe hypersensitivity reaction to naloxegol or any of its excipients No concurrent use of moderate/strong CYP3A4 inhibitors, or strong CYP3A4 inducers Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown; therefore, for women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is required; a female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months) Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Absolute neutrophil count (ANC) >= 1,500/mm^3 Platelet count >= 100,000/mm^3 Calculated (calc.) creatinine clearance >= 60 mL/min calculated using the Cockcroft-Gault formula Total bilirubin =< 1.2 x upper limit of normal (ULN) unless due to Gilbert's disease Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)

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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group I (lower dose naloxegol, placebo)<br>Patients receive lower dose naloxegol PO QD and placebo PO QD. Courses repeat every 3 weeks in year 1 and then every 3 months in year 2 in the absence of unacceptable toxicity. | Drug: Naloxegol<br>* Given PO<br>Other: Placebo<br>* Given PO<br>Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>|
| Active Comparator: Group II (placebo, higher dose naloxegol)<br>Patients receive placebo PO QD and higher dose naloxegol PO QD. Courses repeat every 3 weeks in year 1 and then every 3 months in year 2 in the absence of unacceptable toxicity. | Drug: Naloxegol<br>* Given PO<br>Other: Placebo<br>* Given PO<br>Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>|
| Placebo Comparator: Group III (placebo)<br>Patients receive placebo PO QD. Courses repeat every 3 weeks in year 1 and then every 3 months in year 2 in the absence of unacceptable toxicity. | Other: Placebo<br>* Given PO<br>Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Observed Accrual Rate Defined as Rate of Accrual Remaining >= 80% of the Expected | Calculated as the total number of patients accrued to the study over two years divided by 184, the total expected accrual of patients evaluable for the primary endpoint. | Up to 2 years | 
| Proportion of Patients Alive Who Continue Study Drug and Complete the Health-related Quality of Life and Other Forms | The proportion of patients alive at 6 months who continue study drug and complete the health-related quality of life and other forms for at least 6 months will be calculated by arm. | Up to 6 months | 
| Incidence of Adverse Events as Described and Graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 | The frequency of adverse events will be summarized by arm and compared between each treatment arm vs the placebo arm using Fisher's exact test. <3 is better and 3+ is worse. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Trial Outcome Index | Health-related quality of life scores at each timepoint and changes in scores between 6 months and baseline will be summarized by mean standard deviation, median (inter-quartile range). Scores will be plotted to explore the pattern over time and to examine differences between treatment arms. Differences in health-related quality of life between the treatment arms and the placebo arm will be conducted through linear mixed models and growth curve models to account for repeated assessments. Trial outcome index score is 0-92 with 0 being the worst and 92 being the best. | Baseline to 6 months | 
| Change in Function Subscales | Health-related quality of life scores at each timepoint and changes in scores between 6 months and baseline will be summarized by mean standard deviation, median (inter-quartile range). Scores will be plotted to explore the pattern over time and to examine differences between treatment arms. Differences in health-related quality of life between the treatment arms and the placebo arm will be conducted through linear mixed models and growth curve models to account for repeated assessments. Function subscales score is 0-28 with 0 being the worst and 28 being the best. | Baseline to 6 months | 
| Change in Lung Cancer Subscale of the Functional Assessment of Cancer Therapy-Lung | Health-related quality of life scores at each timepoint and changes in scores between 6 months and baseline will be summarized by mean standard deviation, median (inter-quartile range). Scores will be plotted to explore the pattern over time and to examine differences between treatment arms. Differences in health-related quality of life between the treatment arms and the placebo arm will be conducted through linear mixed models and growth curve models to account for repeated assessments. Lung cancer subscale score is 0-36 with 0 being the worst and 36 being the best. | Baseline to 6 months | 
| Patient-reported Outcome Assessed by Patient-Reported Outcome-Common Terminology Criteria for Adverse Events | Patient-Reported Outcome-Common Terminology Criteria for Adverse Events items will be summarized by arm. Patient-Reported Outcome-Common Terminology Criteria for Adverse Events response will be compared between the treatment arms vs. placebo arm using a chi-square test or Fisher's exact test as appropriate. Chosen PRO-CTCAE question is In the last 7 days, what was the SEVERITY of your PAIN IN THE ABDOMEN (BELLY AREA) at its WORST? | Up to 2 years | 
| Patient-reported Outcome Assessed by a Urinary Retention Linear Analogue Self-Assessment | Linear Analogue Self-Assessment items will be summarized by arm. Linear Analogue Self-Assessment scores will be compared between treatment arms versus placebo arm using Wilcoxon test. Linear Analogue Self-Assessment score is 0-10, with 0 being no trouble with ability to urinate easily and 10 being worst trouble with ability to urinate easily. | Baseline to 6 months | 
| Opioid-induced Constipation Rating Scale | Opioid-induced constipation rating scale will be summarized by arm. Scores will be compared between treatment arms vs. placebo arm using Wilcoxon test. Question from Bowel Function Diary is In the past 24 hours, how much pain did you feel in your abdomen because of constipation?. Opioid-induced constipation rating scale is from 0-6, with 0 being none and 6 being very severe. | Baseline to 6 months | 
| Level of Pain | Pain scores will be summarized by arm. Pain scores will be compared between treatment arms vs. placebo using Wilcoxon test. Pain score scale is 0-10, with 10 being worst pain imaginable | Baseline to 6 months | 
| Analgesic Use | The protocol-defined analysis for this secondary endpoint was not performed due to not specifying analgesic use in the questionnaire. Analgesic use will be summarized by arm. Frequencies of analgesic used will be compared using chi-square test or Fisher's exact test, as appropriate. | Up to 2 years | 
| Unexpected Clinical Outcomes With Chemotherapy | A Fisher's exact test was not performed due to low sample size. Frequency of discontinuation of chemotherapy will be summarized by arm and compared between each treatment arm vs the placebo arm using Fisher's exact test. | Up to 2 years | 
| Progression-free Survival Assessed by Using the Standard Response Evaluation Criteria in Solid Tumors 1.1 Criteria | Progression-free survival probabilities will be estimated by arm using the Kaplan-Meier estimator. In an exploratory manner, a Cox proportional hazards model will be used to determine the effect of naloxegol on progression-free survival. | From randomization to disease progression/relapse, death, or loss to follow-up, whichever occurs first, assessed up to 2 years | 
| Overall Survival | Overall survival probabilities will be estimated by arm using the Kaplan-Meier estimator. In an exploratory manner, a Cox proportional hazards model will be used to determine the effect of naloxegol on overall survival. | From randomization to death or loss to follow-up, whichever occurs first, assessed up to 2 years | 
| Prognostic Effect of MOR Expression/Interaction on Health-related Quality of Life | The protocol-defined analysis for this secondary endpoint was not performed due to being a correlative endpoint and not being collected in the data. MOR expression and activation will be included as a covariate in the linear mixed model, an interaction between MOR expression/activation and treatment will be evaluated. | Up to 2 years |