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

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.

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

- Initiation of first-line chemotherapy with a platinum-pemetrexed-based regimen within
14 days of registration or planning to initiate within 14 days 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; prior palliative radiation permitted; prior adjuvant
chemotherapy/radiation is permitted

- No past or current use of mixed opioid agonist/opioid antagonists or other opioid
antagonists

- 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; 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)

- Age ≥ 18 years

- 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)