This Study is Comparing Morning vs Random Scheduling of Standard of Care Pembrolizumab Checkpoint Inhibitor Immunotherapy Infusions in Patients With Metastatic Non-small Cell Lung Cancer

Timing of Immunotherapy for the Modulation of Efficacy: a Pilot Study in Metastatic Non-Small Cell Lung Cancer

This clinical trial is comparing morning infusions of the study drug (pembrolizumab) to random infusion scheduling for patients with non-small cell lung cancer.

Participants will be randomized to either the Intervention (Morning Group) where Infusion start times are restricted between 0800 AM and 1000 AM or to the Control (Standard of Care) group where scheduling will occur as standard of care scheduling, in which infusions are scheduled without respect to a specific time of day.

There are past studies that suggest the timing of treatment may influence immune response and outcomes. This idea is called chronotherapy. Chronotherapy explores the notion that the timing of drug administration in relation to the body's internal clock can optimize treatment effectiveness. The timing of the infusions for the morning group was therefore, chosen based on data from these past studies that looked at circadian variation in immune system function with the intent to focus on similar infusion windows.

The aim of this study is to provide confirmation that the intervention is possible to achieve and use these results to design a larger study. Circadian timing of drug administration, if effective, would represent an intervention that could improve survival outcomes at no additional cost or apparent increase in toxicity, which is truly rare in oncology.

Participants are asked to participate in the study intervention for 18 weeks (6 cycles of pembrolizumab), after which participants would continue with ad hoc scheduling as per standard of care.

Inclusion Criteria:

1. Patients with histologic diagnosis mNSCLC with PDL1 staining ≥ 50% on standard of care IHC testing

2. Patients must be eligible for treatment with standard-of-care pembrolizumab

3. Patients must be 18 years of age or older.

4. Patients must be capable of providing consent to enrolment and willing to comply with study, treatment and follow-up.

5. Patients with a performance status of Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (Oken et al., 1982) will be eligible for enrolment

6. Women of childbearing potential (WOCBP) must have a negative serum (or urine) pregnancy test within 7 days prior to the first dose of pembrolizumab. WOCBP is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy or bilateral salpingectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in a woman over age 45 years in the absence of other biological or physiological causes.

7. Patients of childbearing / reproductive potential should use adequate birth control methods, as defined by the investigator, during the study treatment period. A highly effective method of birth control is defined as those that result in low failure rate (i.e. less than 1% per year) when used consistently and correctly.

   Note: abstinence is acceptable if this is established and preferred contraception for the patient and is accepted as a local standard.

8. Absence of any condition hampering compliance with the study protocol and follow- up schedule; those conditions should be discussed with the patient before registration in the trial.

9. The following adequate organ function laboratory values must be met:

Hematological:

• Absolute neutrophil count (ANC) >1.0
• Platelet count >100
• Hemoglobin >90 mg/dL

Renal:

o Serum creatinine <3x upper limited of normal (ULN)

Hepatic:

• Total serum bilirubin <2x ULN
• AST and ALT <3x ULN

Coagulation:

o International Normalized Ratio (INR) <1.5x ULN (unless patient is receiving anticoagulant therapy and if PT or PTT is within therapeutic range of intended use of anticoagulants)

Exclusion Criteria:

1. Concurrent therapy with systemic therapy other than pembrolizumab (such as chemotherapy, targeted therapy, other checkpoint inhibitors, or hormonal therapy).
2. Treatment plan includes local therapy such as radiation or surgery.
3. Untreated symptomatic brain metastases, or previously treated brain metastases requiring corticosteroids for symptom control. Patients with untreated asymptomatic brain metastases, where all lesions are < 2cm in size with no vasogenic edema, are eligible.
4. Presence of leptomeningeal disease.
5. Known history of human immunodeficiency virus (HIV), active Hepatitis B or Hepatitis C. Testing for HIV, HBV or HCV is not mandatory for enrolment to study but may occur at the discretion of the investigator.
6. Active autoimmune disease that has required systemic treatment in past 12 months (i.e. with use of disease modifying agents, requiring >10mg prednisone or equivalent or other immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
7. Participant unwilling to agree to their treatment times being scheduled as per study protocol during the study treatment period (Cycles 1-6).