Stage IIIB Non-Small Cell Lung Cancer, Stage IV Non-small Cell Lung Cancer
Conditions
Brief summary
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
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.
Interventions
DRUGNaloxegol
Given PO
OTHERPlacebo
Given PO
OTHERLaboratory Biomarker Analysis
Correlative studies
OTHERQuality-of-Life Assessment
Ancillary studies
Sponsors
National Cancer Institute (NCI)
Alliance for Clinical Trials in Oncology
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events as Described and Graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 | Up to 2 years | 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. |
| Observed Accrual Rate Defined as Rate of Accrual Remaining >= 80% of the Expected | Up to 2 years | 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. |
| Proportion of Patients Alive Who Continue Study Drug and Complete the Health-related Quality of Life and Other Forms | Up to 6 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Lung Cancer Subscale of the Functional Assessment of Cancer Therapy-Lung | Baseline to 6 months | 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. |
| Patient-reported Outcome Assessed by Patient-Reported Outcome-Common Terminology Criteria for Adverse Events | Up to 2 years | 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? |
| Patient-reported Outcome Assessed by a Urinary Retention Linear Analogue Self-Assessment | Baseline to 6 months | 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. |
| Opioid-induced Constipation Rating Scale | Baseline to 6 months | 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. |
| Analgesic Use | Up to 2 years | 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. |
| Unexpected Clinical Outcomes With Chemotherapy | Up to 2 years | 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. |
| Progression-free Survival Assessed by Using the Standard Response Evaluation Criteria in Solid Tumors 1.1 Criteria | From randomization to disease progression/relapse, death, or loss to follow-up, whichever occurs first, assessed up to 2 years | 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. |
| Overall Survival | From randomization to death or loss to follow-up, whichever occurs first, assessed up to 2 years | 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. |
| Level of Pain | Baseline to 6 months | 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 |
| Change in Trial Outcome Index | Baseline to 6 months | 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. |
| Change in Function Subscales | Baseline to 6 months | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Prognostic Effect of MOR Expression/Interaction on Health-related Quality of Life | Up to 2 years | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group I (Lower Dose Naloxegol, Placebo) 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.\>\> \>\> Naloxegol: Given PO\>\>
\>\> Placebo: Given PO\>\>
\>\> Laboratory Biomarker Analysis: Correlative studies\>\>
\>\> Quality-of-Life Assessment: Ancillary studies | 15 |
| Group II (Placebo, Higher Dose Naloxegol) 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.\>\> \>\> Naloxegol: Given PO\>\>
\>\> Placebo: Given PO\>\>
\>\> Laboratory Biomarker Analysis: Correlative studies\>\>
\>\> Quality-of-Life Assessment: Ancillary studies | 15 |
| Group III (Placebo) 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.\>\>
\>\> Placebo: Given PO\>\>
\>\> Laboratory Biomarker Analysis: Correlative studies\>\>
\>\> Quality-of-Life Assessment: Ancillary studies | 13 |
| Total | 43 |
Baseline characteristics
| Characteristic | Group I (Lower Dose Naloxegol, Placebo) | Group II (Placebo, Higher Dose Naloxegol) | Group III (Placebo) | Total |
|---|---|---|---|---|
| Age, Continuous | 64.0 years | 67.0 years | 62.0 years | 66.0 years |
| ECOG Performance Score 0-1 | 10 Participants | 12 Participants | 11 Participants | 33 Participants |
| ECOG Performance Score 2 | 5 Participants | 3 Participants | 2 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 14 Participants | 12 Participants | 41 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Pathologic T Stage T0 | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Pathologic T Stage T1a | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Pathologic T Stage T1b | 2 Participants | 1 Participants | 2 Participants | 5 Participants |
| Pathologic T Stage T2a | 2 Participants | 2 Participants | 1 Participants | 5 Participants |
| Pathologic T Stage T2b | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
| Pathologic T Stage T3a | 2 Participants | 2 Participants | 2 Participants | 6 Participants |
| Pathologic T Stage T3b | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Pathologic T Stage T4 | 5 Participants | 0 Participants | 5 Participants | 10 Participants |
| Pathologic T Stage Tx | 3 Participants | 4 Participants | 2 Participants | 9 Participants |
| Planned use of Bevacizumab No | 14 Participants | 14 Participants | 13 Participants | 41 Participants |
| Planned use of Bevacizumab Yes | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 12 Participants | 11 Participants | 12 Participants | 35 Participants |
| Sex: Female, Male Female | 9 Participants | 3 Participants | 4 Participants | 16 Participants |
| Sex: Female, Male Male | 6 Participants | 12 Participants | 9 Participants | 27 Participants |
| Smoking Status Current smoker | 6 Participants | 4 Participants | 8 Participants | 18 Participants |
| Smoking Status Former smoker (no smoking for one year or more) | 8 Participants | 11 Participants | 4 Participants | 23 Participants |
| Smoking Status Never smoked (less than 100 cigarettes in lifetime) | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 17 | 10 / 16 | 8 / 17 |
| other Total, other adverse events | 13 / 14 | 11 / 16 | 15 / 15 |
| serious Total, serious adverse events | 7 / 14 | 9 / 16 | 9 / 15 |
Outcome results
Primary
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.
Time frame: Up to 2 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Expected Accrued Patients | Incidence of Adverse Events as Described and Graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 | Non-Hematologic Adverse Events (regardless of attribution) : <3 | 6 Participants |
| Expected Accrued Patients | Incidence of Adverse Events as Described and Graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 | Hematologic Adverse Events (regardless of attribution) : 3+ | 4 Participants |
| Expected Accrued Patients | Incidence of Adverse Events as Described and Graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 | Hematologic Adverse Events (regardless of attribution) : <3 | 11 Participants |
| Expected Accrued Patients | Incidence of Adverse Events as Described and Graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 | Non-Hematologic Adverse Events (regardless of attribution) : 3+ | 9 Participants |
| Expected Accrued Patients | Incidence of Adverse Events as Described and Graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 | Hematologic Adverse Events (at least possibly related to study) : 3+ | 1 Participants |
| Expected Accrued Patients | Incidence of Adverse Events as Described and Graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 | Hematologic Adverse Events (at least possibly related to study) : <3 | 14 Participants |
| Expected Accrued Patients | Incidence of Adverse Events as Described and Graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 | Non-Hematologic Adverse Events (at least possibly related to study) : 3+ | 1 Participants |
| Expected Accrued Patients | Incidence of Adverse Events as Described and Graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 | Non-Hematologic Adverse Events (at least possibly related to study) : <3 | 14 Participants |
| Group II (Placebo, Higher Dose Naloxegol) | Incidence of Adverse Events as Described and Graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 | Non-Hematologic Adverse Events (at least possibly related to study) : 3+ | 3 Participants |
| Group II (Placebo, Higher Dose Naloxegol) | Incidence of Adverse Events as Described and Graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 | Non-Hematologic Adverse Events (regardless of attribution) : <3 | 6 Participants |
| Group II (Placebo, Higher Dose Naloxegol) | Incidence of Adverse Events as Described and Graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 | Hematologic Adverse Events (at least possibly related to study) : 3+ | 0 Participants |
| Group II (Placebo, Higher Dose Naloxegol) | Incidence of Adverse Events as Described and Graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 | Hematologic Adverse Events (at least possibly related to study) : <3 | 15 Participants |
| Group II (Placebo, Higher Dose Naloxegol) | Incidence of Adverse Events as Described and Graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 | Hematologic Adverse Events (regardless of attribution) : 3+ | 3 Participants |
| Group II (Placebo, Higher Dose Naloxegol) | Incidence of Adverse Events as Described and Graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 | Non-Hematologic Adverse Events (at least possibly related to study) : <3 | 12 Participants |
| Group II (Placebo, Higher Dose Naloxegol) | Incidence of Adverse Events as Described and Graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 | Hematologic Adverse Events (regardless of attribution) : <3 | 12 Participants |
| Group II (Placebo, Higher Dose Naloxegol) | Incidence of Adverse Events as Described and Graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 | Non-Hematologic Adverse Events (regardless of attribution) : 3+ | 9 Participants |
| Group III (Placebo) | Incidence of Adverse Events as Described and Graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 | Hematologic Adverse Events (regardless of attribution) : 3+ | 2 Participants |
| Group III (Placebo) | Incidence of Adverse Events as Described and Graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 | Non-Hematologic Adverse Events (regardless of attribution) : 3+ | 6 Participants |
| Group III (Placebo) | Incidence of Adverse Events as Described and Graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 | Hematologic Adverse Events (at least possibly related to study) : <3 | 13 Participants |
| Group III (Placebo) | Incidence of Adverse Events as Described and Graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 | Non-Hematologic Adverse Events (regardless of attribution) : <3 | 7 Participants |
| Group III (Placebo) | Incidence of Adverse Events as Described and Graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 | Non-Hematologic Adverse Events (at least possibly related to study) : 3+ | 0 Participants |
| Group III (Placebo) | Incidence of Adverse Events as Described and Graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 | Hematologic Adverse Events (regardless of attribution) : <3 | 11 Participants |
| Group III (Placebo) | Incidence of Adverse Events as Described and Graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 | Hematologic Adverse Events (at least possibly related to study) : 3+ | 0 Participants |
| Group III (Placebo) | Incidence of Adverse Events as Described and Graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 | Non-Hematologic Adverse Events (at least possibly related to study) : <3 | 13 Participants |
Comparison: Comparison of Hematologic 3+ vs Hematologic \<3p-value: <1Fisher Exact
Comparison: Comparison of Non-Hematologic 3+ vs Non-Hematologic \<3p-value: <0.7051Fisher Exact
Comparison: Comparison of Hematologic 3+ vs Hematologic \<3p-value: <0.6546Fisher Exact
Comparison: Comparison of Non-Hematologic 3+ vs Non-Hematologic \<3p-value: <0.7051Fisher Exact
Comparison: Comparison of Non-Hematologic 3+ vs Non-Hematologic \<3p-value: <0.2262Fisher Exact
Comparison: Comparison of Hematologic 3+ vs Hematologic \<3p-value: <1Fisher Exact
Comparison: Comparison of Non-Hematologic 3+ vs Non-Hematologic \<3p-value: <1Fisher Exact
Primary
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.
Time frame: Up to 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Expected Accrued Patients | Observed Accrual Rate Defined as Rate of Accrual Remaining >= 80% of the Expected | 0.272 proportion of participants |
Primary
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.
Time frame: Up to 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Expected Accrued Patients | Proportion of Patients Alive Who Continue Study Drug and Complete the Health-related Quality of Life and Other Forms | 0.4667 Ratio of patients evaluable for endpoint |
| Group II (Placebo, Higher Dose Naloxegol) | Proportion of Patients Alive Who Continue Study Drug and Complete the Health-related Quality of Life and Other Forms | 0.4667 Ratio of patients evaluable for endpoint |
| Group III (Placebo) | Proportion of Patients Alive Who Continue Study Drug and Complete the Health-related Quality of Life and Other Forms | 0.3846 Ratio of patients evaluable for endpoint |
Secondary
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.
Time frame: Up to 2 years
Population: Only 19 patients completed the primary endpoint of staying on treatment and completing QOL booklets for 6 months.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Expected Accrued Patients | Analgesic Use | Analgesic use at Baseline? | Yes | 13 Participants |
| Expected Accrued Patients | Analgesic Use | Analgesic use at Baseline? | No | 2 Participants |
| Expected Accrued Patients | Analgesic Use | Analgesic use at Baseline? | Missing | 0 Participants |
| Expected Accrued Patients | Analgesic Use | Analgesic Use at 6 Months? | Yes | 3 Participants |
| Expected Accrued Patients | Analgesic Use | Analgesic Use at 6 Months? | No | 4 Participants |
| Expected Accrued Patients | Analgesic Use | Analgesic Use at 6 Months? | Missing | 0 Participants |
| Group II (Placebo, Higher Dose Naloxegol) | Analgesic Use | Analgesic Use at 6 Months? | Missing | 0 Participants |
| Group II (Placebo, Higher Dose Naloxegol) | Analgesic Use | Analgesic use at Baseline? | Yes | 10 Participants |
| Group II (Placebo, Higher Dose Naloxegol) | Analgesic Use | Analgesic Use at 6 Months? | Yes | 5 Participants |
| Group II (Placebo, Higher Dose Naloxegol) | Analgesic Use | Analgesic Use at 6 Months? | No | 2 Participants |
| Group II (Placebo, Higher Dose Naloxegol) | Analgesic Use | Analgesic use at Baseline? | No | 3 Participants |
| Group II (Placebo, Higher Dose Naloxegol) | Analgesic Use | Analgesic use at Baseline? | Missing | 0 Participants |
| Group III (Placebo) | Analgesic Use | Analgesic use at Baseline? | No | 1 Participants |
| Group III (Placebo) | Analgesic Use | Analgesic use at Baseline? | Missing | 0 Participants |
| Group III (Placebo) | Analgesic Use | Analgesic Use at 6 Months? | Missing | 1 Participants |
| Group III (Placebo) | Analgesic Use | Analgesic Use at 6 Months? | Yes | 2 Participants |
| Group III (Placebo) | Analgesic Use | Analgesic use at Baseline? | Yes | 11 Participants |
| Group III (Placebo) | Analgesic Use | Analgesic Use at 6 Months? | No | 2 Participants |
Comparison: Analgesic Use at 6 Monthsp-value: <1Fisher Exact
Comparison: Analgesic Use at 6 Monthsp-value: <0.5758Fisher Exact
Comparison: Analgesic use at Baselinep-value: <1Fisher Exact
Comparison: Analgesic use at Baselinep-value: 0.593Fisher Exact
Secondary
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.
Time frame: Baseline to 6 months
Population: Two patients on the Naloxegol 12.5 mg arm did not complete all of the questions for the Fact-L at 6 months.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Expected Accrued Patients | Change in Function Subscales | Physical Well Being | 4.7 units on a scale |
| Expected Accrued Patients | Change in Function Subscales | Social Function Well Being | 6.0 units on a scale |
| Expected Accrued Patients | Change in Function Subscales | Emotional Well Being | 2.5 units on a scale |
| Expected Accrued Patients | Change in Function Subscales | Functional Well Being | 6.5 units on a scale |
| Group II (Placebo, Higher Dose Naloxegol) | Change in Function Subscales | Functional Well Being | 5.0 units on a scale |
| Group II (Placebo, Higher Dose Naloxegol) | Change in Function Subscales | Physical Well Being | 0.0 units on a scale |
| Group II (Placebo, Higher Dose Naloxegol) | Change in Function Subscales | Emotional Well Being | 3.0 units on a scale |
| Group II (Placebo, Higher Dose Naloxegol) | Change in Function Subscales | Social Function Well Being | 5.0 units on a scale |
| Group III (Placebo) | Change in Function Subscales | Functional Well Being | 4.0 units on a scale |
| Group III (Placebo) | Change in Function Subscales | Social Function Well Being | -2 units on a scale |
| Group III (Placebo) | Change in Function Subscales | Emotional Well Being | 0 units on a scale |
| Group III (Placebo) | Change in Function Subscales | Physical Well Being | -0.3 units on a scale |
Secondary
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.
Time frame: Baseline to 6 months
Population: Two patients on the Naloxegol 12.5 mg arm did not complete all of the questions for the Fact-L at 6 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Expected Accrued Patients | Change in Lung Cancer Subscale of the Functional Assessment of Cancer Therapy-Lung | 6.0 units on a scale |
| Group II (Placebo, Higher Dose Naloxegol) | Change in Lung Cancer Subscale of the Functional Assessment of Cancer Therapy-Lung | 1.0 units on a scale |
| Group III (Placebo) | Change in Lung Cancer Subscale of the Functional Assessment of Cancer Therapy-Lung | 1.0 units on a scale |
Secondary
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.
Time frame: Baseline to 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Expected Accrued Patients | Change in Trial Outcome Index | 21.0 units on a scale |
| Group II (Placebo, Higher Dose Naloxegol) | Change in Trial Outcome Index | 14.0 units on a scale |
| Group III (Placebo) | Change in Trial Outcome Index | 9.0 units on a scale |
Secondary
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
Time frame: Baseline to 6 months
Population: Only 19 patients completed the primary endpoint of staying on treatment and completing QOL booklets for 6 months.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Expected Accrued Patients | Level of Pain | Average Pain Scores at Baseline ( | 6.5 units on a scale |
| Expected Accrued Patients | Level of Pain | Average Pain Scores at 6 Months | 0.0 units on a scale |
| Group II (Placebo, Higher Dose Naloxegol) | Level of Pain | Average Pain Scores at Baseline ( | 5.0 units on a scale |
| Group II (Placebo, Higher Dose Naloxegol) | Level of Pain | Average Pain Scores at 6 Months | 3.7 units on a scale |
| Group III (Placebo) | Level of Pain | Average Pain Scores at Baseline ( | 4.5 units on a scale |
| Group III (Placebo) | Level of Pain | Average Pain Scores at 6 Months | 2.2 units on a scale |
Comparison: Average Pain Scores at Baselinep-value: 0.6024Wilcoxon (Mann-Whitney)
Comparison: Average Pain Scores at Baselinep-value: <0.3116Wilcoxon (Mann-Whitney)
Comparison: Average Pain Scores at 6 Monthsp-value: <0.7712Wilcoxon (Mann-Whitney)
Comparison: Average Pain Scores at 6 Monthsp-value: <1Wilcoxon (Mann-Whitney)
Secondary
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.
Time frame: Baseline to 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Expected Accrued Patients | Opioid-induced Constipation Rating Scale | 0 units on a scale |
| Group II (Placebo, Higher Dose Naloxegol) | Opioid-induced Constipation Rating Scale | 0 units on a scale |
| Group III (Placebo) | Opioid-induced Constipation Rating Scale | 0 units on a scale |
p-value: <0.593Wilcoxon (Mann-Whitney)
p-value: <0.3105Wilcoxon (Mann-Whitney)
Secondary
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.
Time frame: From randomization to death or loss to follow-up, whichever occurs first, assessed up to 2 years
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Expected Accrued Patients | Overall Survival | Censored | 9 Participants |
| Expected Accrued Patients | Overall Survival | Death | 6 Participants |
| Group II (Placebo, Higher Dose Naloxegol) | Overall Survival | Censored | 6 Participants |
| Group II (Placebo, Higher Dose Naloxegol) | Overall Survival | Death | 9 Participants |
| Group III (Placebo) | Overall Survival | Censored | 7 Participants |
| Group III (Placebo) | Overall Survival | Death | 6 Participants |
Secondary
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.
Time frame: Baseline to 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Expected Accrued Patients | Patient-reported Outcome Assessed by a Urinary Retention Linear Analogue Self-Assessment | 0.0 units on a scale |
| Group II (Placebo, Higher Dose Naloxegol) | Patient-reported Outcome Assessed by a Urinary Retention Linear Analogue Self-Assessment | 0.0 units on a scale |
| Group III (Placebo) | Patient-reported Outcome Assessed by a Urinary Retention Linear Analogue Self-Assessment | 0.0 units on a scale |
p-value: <1Wilcoxon (Mann-Whitney)
p-value: <0.3339Wilcoxon (Mann-Whitney)
Secondary
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?
Time frame: Up to 2 years
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Expected Accrued Patients | Patient-reported Outcome Assessed by Patient-Reported Outcome-Common Terminology Criteria for Adverse Events | None | 7 Participants |
| Expected Accrued Patients | Patient-reported Outcome Assessed by Patient-Reported Outcome-Common Terminology Criteria for Adverse Events | Mild | 0 Participants |
| Expected Accrued Patients | Patient-reported Outcome Assessed by Patient-Reported Outcome-Common Terminology Criteria for Adverse Events | Moderate | 0 Participants |
| Expected Accrued Patients | Patient-reported Outcome Assessed by Patient-Reported Outcome-Common Terminology Criteria for Adverse Events | Missing | 0 Participants |
| Group II (Placebo, Higher Dose Naloxegol) | Patient-reported Outcome Assessed by Patient-Reported Outcome-Common Terminology Criteria for Adverse Events | Missing | 0 Participants |
| Group II (Placebo, Higher Dose Naloxegol) | Patient-reported Outcome Assessed by Patient-Reported Outcome-Common Terminology Criteria for Adverse Events | None | 5 Participants |
| Group II (Placebo, Higher Dose Naloxegol) | Patient-reported Outcome Assessed by Patient-Reported Outcome-Common Terminology Criteria for Adverse Events | Moderate | 2 Participants |
| Group II (Placebo, Higher Dose Naloxegol) | Patient-reported Outcome Assessed by Patient-Reported Outcome-Common Terminology Criteria for Adverse Events | Mild | 0 Participants |
| Group III (Placebo) | Patient-reported Outcome Assessed by Patient-Reported Outcome-Common Terminology Criteria for Adverse Events | Missing | 1 Participants |
| Group III (Placebo) | Patient-reported Outcome Assessed by Patient-Reported Outcome-Common Terminology Criteria for Adverse Events | Mild | 1 Participants |
| Group III (Placebo) | Patient-reported Outcome Assessed by Patient-Reported Outcome-Common Terminology Criteria for Adverse Events | Moderate | 1 Participants |
| Group III (Placebo) | Patient-reported Outcome Assessed by Patient-Reported Outcome-Common Terminology Criteria for Adverse Events | None | 2 Participants |
p-value: <0.68182Fisher Exact
p-value: <0.1091Fisher Exact
Secondary
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.
Time frame: From randomization to disease progression/relapse, death, or loss to follow-up, whichever occurs first, assessed up to 2 years
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Expected Accrued Patients | Progression-free Survival Assessed by Using the Standard Response Evaluation Criteria in Solid Tumors 1.1 Criteria | Death | 5 Participants |
| Expected Accrued Patients | Progression-free Survival Assessed by Using the Standard Response Evaluation Criteria in Solid Tumors 1.1 Criteria | Censored | 8 Participants |
| Expected Accrued Patients | Progression-free Survival Assessed by Using the Standard Response Evaluation Criteria in Solid Tumors 1.1 Criteria | Progression | 2 Participants |
| Group II (Placebo, Higher Dose Naloxegol) | Progression-free Survival Assessed by Using the Standard Response Evaluation Criteria in Solid Tumors 1.1 Criteria | Death | 4 Participants |
| Group II (Placebo, Higher Dose Naloxegol) | Progression-free Survival Assessed by Using the Standard Response Evaluation Criteria in Solid Tumors 1.1 Criteria | Censored | 6 Participants |
| Group II (Placebo, Higher Dose Naloxegol) | Progression-free Survival Assessed by Using the Standard Response Evaluation Criteria in Solid Tumors 1.1 Criteria | Progression | 5 Participants |
| Group III (Placebo) | Progression-free Survival Assessed by Using the Standard Response Evaluation Criteria in Solid Tumors 1.1 Criteria | Censored | 7 Participants |
| Group III (Placebo) | Progression-free Survival Assessed by Using the Standard Response Evaluation Criteria in Solid Tumors 1.1 Criteria | Progression | 5 Participants |
| Group III (Placebo) | Progression-free Survival Assessed by Using the Standard Response Evaluation Criteria in Solid Tumors 1.1 Criteria | Death | 1 Participants |
Secondary
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.
Time frame: Up to 2 years
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Expected Accrued Patients | Unexpected Clinical Outcomes With Chemotherapy | Treatment (Intervention) Completed Per Protocol Criteria | 2 Participants |
| Expected Accrued Patients | Unexpected Clinical Outcomes With Chemotherapy | Patient Withdrawal/Refusal After Beginning Protocol Therapy (Intervention) | 3 Participants |
| Expected Accrued Patients | Unexpected Clinical Outcomes With Chemotherapy | Adverse Events/Side Effects/Complications | 1 Participants |
| Expected Accrued Patients | Unexpected Clinical Outcomes With Chemotherapy | Patient Off-Treatment (Intervention) For Other Complicating Disease | 1 Participants |
| Expected Accrued Patients | Unexpected Clinical Outcomes With Chemotherapy | Death On Study | 2 Participants |
| Expected Accrued Patients | Unexpected Clinical Outcomes With Chemotherapy | Other | 4 Participants |
| Expected Accrued Patients | Unexpected Clinical Outcomes With Chemotherapy | Patient Withdrawal/Refusal Prior To Beginning Protocol Therapy (Intervention) | 2 Participants |
| Expected Accrued Patients | Unexpected Clinical Outcomes With Chemotherapy | Missing | 2 Participants |
| Group II (Placebo, Higher Dose Naloxegol) | Unexpected Clinical Outcomes With Chemotherapy | Adverse Events/Side Effects/Complications | 1 Participants |
| Group II (Placebo, Higher Dose Naloxegol) | Unexpected Clinical Outcomes With Chemotherapy | Patient Withdrawal/Refusal Prior To Beginning Protocol Therapy (Intervention) | 0 Participants |
| Group II (Placebo, Higher Dose Naloxegol) | Unexpected Clinical Outcomes With Chemotherapy | Patient Off-Treatment (Intervention) For Other Complicating Disease | 0 Participants |
| Group II (Placebo, Higher Dose Naloxegol) | Unexpected Clinical Outcomes With Chemotherapy | Death On Study | 6 Participants |
| Group II (Placebo, Higher Dose Naloxegol) | Unexpected Clinical Outcomes With Chemotherapy | Other | 3 Participants |
| Group II (Placebo, Higher Dose Naloxegol) | Unexpected Clinical Outcomes With Chemotherapy | Treatment (Intervention) Completed Per Protocol Criteria | 1 Participants |
| Group II (Placebo, Higher Dose Naloxegol) | Unexpected Clinical Outcomes With Chemotherapy | Patient Withdrawal/Refusal After Beginning Protocol Therapy (Intervention) | 5 Participants |
| Group II (Placebo, Higher Dose Naloxegol) | Unexpected Clinical Outcomes With Chemotherapy | Missing | 0 Participants |
| Group III (Placebo) | Unexpected Clinical Outcomes With Chemotherapy | Adverse Events/Side Effects/Complications | 1 Participants |
| Group III (Placebo) | Unexpected Clinical Outcomes With Chemotherapy | Patient Withdrawal/Refusal After Beginning Protocol Therapy (Intervention) | 6 Participants |
| Group III (Placebo) | Unexpected Clinical Outcomes With Chemotherapy | Treatment (Intervention) Completed Per Protocol Criteria | 2 Participants |
| Group III (Placebo) | Unexpected Clinical Outcomes With Chemotherapy | Patient Off-Treatment (Intervention) For Other Complicating Disease | 0 Participants |
| Group III (Placebo) | Unexpected Clinical Outcomes With Chemotherapy | Patient Withdrawal/Refusal Prior To Beginning Protocol Therapy (Intervention) | 2 Participants |
| Group III (Placebo) | Unexpected Clinical Outcomes With Chemotherapy | Other | 2 Participants |
| Group III (Placebo) | Unexpected Clinical Outcomes With Chemotherapy | Death On Study | 4 Participants |
| Group III (Placebo) | Unexpected Clinical Outcomes With Chemotherapy | Missing | 0 Participants |
Other Pre-specified
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.
Time frame: Up to 2 years