PRIMARY OBJECTIVE:
I. To determine whether immune checkpoint blockade using pembrolizumab eliminates persistent
(on two computed tomography [CT] scans at least 3 months apart with no evidence of shrinkage
or regression) high-risk indeterminate pulmonary nodules (IPNs) (estimated risk of being
diagnosed with lung cancer within 2-4 years >= 15% for patients with no history of lung
cancer or > 10% for patients with history of stage I-II non-small cell lung cancer (NSCLC)
who complete surgery and standard adjuvant chemotherapy if indicated) at 6 months after
treatment.
SECONDARY OBJECTIVES:
I. To determine whether immune checkpoint blockade using pembrolizumab decreases the
incidence of lung cancers confirmed by histology (biopsy or resection).
II. To determine whether immune checkpoint blockade using pembrolizumab prolongs cancer free
survival (disease free survival [DFS]) compared with observation in patients with high-risk
IPNs.
III. To determine whether immune checkpoint blockade using pembrolizumab prolongs lung
cancer-specific survival compared with observation in patients with high-risk IPNs.
IV. To determine whether immune checkpoint blockade using pembrolizumab prolongs overall
survival (OS) compared with observation in patients with high-risk IPNs.
V. To assess the safety and tolerability of pembrolizumab in patients with high-risk IPNs.
VI. To assess quality of life patient reported outcomes in patients treated with
pembrolizumab compared with patients under observation.
VII. To determine whether immune checkpoint blockade using pembrolizumab decreases the solid
component of high-risk IPNs.
VIII. To assess the health-related quality of life (QoL) on subjects enrolled in the study.
EXPLORATORY OBJECTIVES:
I. To explore the radiographic (including radiomic features) evolution of high-risk IPNs with
and without treatment of pembrolizumab and to assess their association with risks of risk of
lung cancer as well as their association with clinical benefit/toxicities in patients treated
with pembrolizumab.
II. To explore the germline deoxyribonucleic acid (DNA) profile and genomic evolution of
circulating tumor DNA (ctDNA) of patients with high-risk IPNs and assess their association
with risks of risk of lung cancer as well as their association with clinical
benefit/toxicities in patients treated with pembrolizumab.
III. To explore the T cell receptor (TCR) repertoire evolution of patients with high-risk
IPNs and assess their association with risks of risks of lung cancer as well as their
association with clinical benefit/toxicities in patients treated with pembrolizumab.
IV. To explore the evolution of serum soluble factors, such as IFN-gamma and interferon
inducible factors (such as CXCL9 and CXCL10), IL-12, TNFalpha, IL-10, TGF-beta, VEGF, IL-6,
IL-8, IL-17, IL-18, C-reactive protein etc. and assess their association with risks of risks
of lung cancer as well as their association with clinical benefit/toxicities in patients
treated with pembrolizumab.
V. To explore the evolution of immunophenotyping or characterization of the immune cell
subsets in the periphery, including, but not limited to, T cells, B cells, natural killer
[NK] cells, or subpopulations of the aforementioned immune cell types and assess their
association with risks of risks of lung cancer as well as their association with clinical
benefit/toxicities in patients treated with pembrolizumab.
VI. To explore the evolution of microbiome and assess their association with risks of lung
cancer as well as their association with clinical benefit/toxicities in patients treated with
pembrolizumab.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM A: Patients receive standard of care.
ARM B: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Cycles
repeat every 3 weeks for up to 4 cycles in the absence of disease progression or unacceptable
toxicity.
After conclusion of study treatment, patients are followed up at 30 days, at 1.5, 3, and 6
months, and then every 12 weeks thereafter.
Inclusion Criteria:
- Patients are eligible to be included in the study only if one of the following
criteria applies:
- 1(a) Patients with no history of lung cancer, who have IPNs detected by low dose
CT (LDCT)-guided lung cancer screening or imaging studies for other reasons
(incidentalomas) with 15-30% cancer probability by Brock University cancer
prediction equation as following. This is one of the most frequently utilized
cancer risk prediction equations and has been confirmed to be highly effective in
catching the disease in its very early stages by large national studies.
- 1(b) Patients with no history of lung cancer, who have IPNs detected by
LDCT-guided lung cancer screening or imaging studies for other reasons
(incidentalomas) with > 30% cancer probability by Brock University cancer
prediction equation as following, but biopsy reveals no clear evidence of
malignancy.
- 1(c) Patients with history of stage I-II non-small cell lung cancer (NSCLC), who
have completed curative treatment (surgery and/or radiation) with or without
chemotherapy, who have persistent IPNs (on two CT scans at least 3 months apart
with no evidence of shrinkage or regression) with 10-30% cancer probability by
Brock University cancer prediction equation as following.
- 1(d) Patients with history of stage I-II NSCLC, who have completed curative
treatment (surgery and/or radiation) with or without chemotherapy, who have
persistent IPNs (on two CT scans at least 3 months apart with no evidence of
shrinkage or regression) with > 30% cancer probability by Brock University cancer
prediction equation as following, but biopsy reveals no clear evidence of
malignancy.
- Brock University cancer prediction equation. This calculator estimates the
probability that a lung nodule described above will be diagnosed as cancer within
a two to four year follow-up period. Equation parameters, such as sex, have two
or more discrete values that may be used in the calculation.
- Diagnosis of high-risk IPNs
- A male participant must agree to use a contraception during the treatment period and
for at least 12 weeks while receiving pembrolizumab plus an additional 120 days (a
spermatogenesis cycle) for study treatments with evidence of genotoxicity at any dose
after the last dose of study treatment and refrain from donating sperm during this
period.
- A female participant is eligible to participate if she is not pregnant, not
breastfeeding, and at least one of the following conditions applies: a) Not a woman of
childbearing potential (WOCBP) or b) A WOCBP who agrees to follow the contraceptive
guidance during the treatment period and for at least 120 days for the study
treatments with risk of genotoxicity after the last dose of study treatment.
- The participant (or legally acceptable representative if applicable) provides written
informed consent for the trial.
- Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
Evaluation of ECOG is to be performed within 7 days prior to the date of
allocation/randomization.
- Absolute neutrophil count (ANC) >= 1500 per microliter (within 10 days prior to the
start of study treatment).
- Platelets >= 100,000 per microliter (within 10 days prior to the start of study
treatment).
- Hemoglobin >= 9.0 grams per microliter or >= 5.6 millimoles/liter (within 10 days
prior to the start of study treatment) (*criteria must be met without erythropoietin
dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks).
- Creatinine OR measured or calculated creatinine clearance (glomerular filtration rate
[GFR] can also be used in place of creatinine or creatinine clearance [CrCL]) =< 1.5 x
ULN OR >= 30 milliliters per minute (min) for participant with creatinine levels > 1.5
x institutional upper limit of normal (ULN) (creatinine clearance (CrCl) should be
calculated per institutional standard.) (within 10 days prior to the start of study
treatment).
- Total bilirubin =< 1.5 x ULN OR direct bilirubin =< for participants with total
bilirubin levels > 1.5 x ULN (within 10 days prior to the start of study treatment).
- Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT) and
alanine aminotransferase (ALT) serum glutamate pyruvate transaminase (SGPT) =< 2.5 x
ULN (within 10 days prior to the start of study treatment).
- International normalized ratio (INR) OR prothrombin time (PT), activated partial
thromboplastin time (aPTT) =< 1.5 x ULN unless participant is receiving anticoagulant
therapy as long as PT or aPTT is within therapeutic range of intended use of
anticoagulants (within 10 days prior to the start of study treatment).
- PT(INR), aPTT only required for patients having a biopsy and/or if clinically
indicated
Exclusion Criteria:
- A WOCBP who has a positive urine pregnancy test within 72 hours prior to
randomization. If the urine test is positive or cannot be confirmed as negative, a
serum pregnancy test will be required.
- Note: in the event that 72 hours have elapsed between the screening pregnancy
test and the first dose of the study treatment, another pregnancy test (urine or
serum) must be performed and must be negative in order for subject to start
receiving study medication.
- Has received prior therapy with anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an
agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4,
OX-40, CD137).
- Has received prior system anti-cancer therapy including investigational agents within
4 weeks (could consider shorter interval for kinase inhibitors or other short
half-life drugs) prior to randomization.
- Note: Participants must have recovered from all adverse events (AEs) due to
previous therapies to =< grade 1 or baseline. Participants with =< grade 2
neuropathy may be eligible.
- Note: If participant received major surgery, they must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting
study treatment.
- Has received prior chest radiotherapy and the radiation field overlaps with IPNs.
- Has received a live vaccine within 30 days prior to the first dose of study drug.
Examples of live vaccines include, but are not limited to, the following: measles,
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
are generally killed virus vaccines and are allowed; however, intranasal influenza
vaccines (e.g., Flumist) are live attenuated vaccines and are not allowed.
- Is currently participating in or has participated in a study of investigational agent
or has used an investigational device within 4 weeks prior to the first dose of study
treatment.
- Note: Participants who have entered the follow-up phase of an investigational
study may participate as long as it has been 4 weeks after the last dose of the
previous investigational agent.
- Has a diagnosis of immunodeficiency or is receiving chronic system steroid therapy (in
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior to the first dose of study drug.
- Has a known additional metastatic malignancy that is progressing or requiring active
treatment.
- Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma
of the skin, carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ),
or potentially curable early-stage malignancies including localized NSCLC, head
and neck squamous carcinoma, breast cancer, bladder cancer etc., that have
undergone potentially curative therapy (surgery and/or radiation with or without
chemotherapy) are not excluded.
- Has severe hypersensitivity (>= grade 3) to pembrolizumab and/or any of its
excipients.
- Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids, or 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.
- Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis.
- Has an active infection requiring systemic therapy.
- Has a known history of human immunodeficiency virus (HIV).
- Has a known history of hepatitis B (defined as hepatitis B surface antigens [HBsAg]
reactive) or known active hepatitis C (defined as hepatitis C virus [HCV] ribonucleic
acid [RNA] [qualitative] is detected) infection.
- Note: No testing for hepatitis B and hepatitis C is required unless mandated by
local health authority.
- Has a known history of active TB (Bacillus tuberculosis).
- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the study, interfere with the subject's
participation for the full duration of the study, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator.
- Has known psychiatric or substance abuse disorders that would interfere with the
cooperation with requirements of the trial.
- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the study, starting with the screening visit through 120 days
after the last dose of trial treatment.
