This is a randomized single-institution, phase II, open-label clinical trial of neoadjuvant
pembrolizumab with or without low-dose stereotactic radiation therapy (SRT) in stage I-IIIA
non-small lung cancer (NSCLC) patients who are planned to undergo surgical resection of their
lung cancer.
Two consecutive run-in cohorts will administer pembrolizumab or pembrolizumab with SRT of 12
Gy to the lateral aspect of the primary tumor. Patients will receive pembrolizumab for 2
cycles prior to surgery or SRT and surgery. Surgical resection of all involved areas of tumor
will occur within 6 weeks of the last administration of pembrolizumab. It should be noted
that surgery is expected to occur within a much shorter window and 6 weeks would represent
the greatest allowable amount of delay.
If during the run-in, only the pembrolizumab-alone cohort meets pre-specified safety
parameters, subsequently enrolled patients will enter a larger expansion cohort, with
treatment given according to that cohort only. If during the run-in both cohorts meet
pre-specified safety parameters, subsequently enrolled patients will enter the expansion
cohort and be randomized between preoperative pembrolizumab versus pembrolizumab with SRT of
12 Gy.
Diagnosis/Condition for Entry into the Trial
1. Histologically or cytologically confirmed non-small cell lung cancer, performed on a
biopsy that occurred within the last 60 days.
2. Positron Emission Tomography (PET)-CT within the last 30 days showing radiographic
stage I to IIIa lung cancer (mediastinal staging biopsy is allowed but not required).
3. Documentation that the patient is a candidate for surgical resection of their lung
cancer by an American Board of Thoracic Surgery-certified surgeon.
4. Measurable disease as defined by RECIST v1.1.
5. Adequate tissue specimens for correlative biomarker analysis. The patient should be
willing to provide tissue from a newly obtained core or excisional biopsy of a tumor
lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior
to initiation of treatment on Day 1. Subjects for whom newly-obtained samples cannot
be provided (e.g. inaccessible or subject safety concern) may submit an archived
specimen only upon agreement from the Principal Investigator.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
7. Resolution of all acute toxic effects of prior chemotherapy, radiotherapy or surgical
procedures to NCI CTCAE Version 4.0 grade 1.
Inclusion Criteria:
1. Be willing and able to provide written informed consent/assent for the trial.
2. Be at least 18 years of age on day of signing informed consent.
3. Demonstrate adequate organ function as defined below. All screening labs should be
performed within 10 days of treatment initiation.
System Laboratory Value Hematological Absolute neutrophil count (ANC) greater than or
equal to 1,500 /microliter (mcL) Platelets greater than or equal to 100,000 / mcL
Hemoglobin greater than or equal to 9 g/dL or ≥5.6 mmol/L without transfusion or
erythropoietin (EPO) dependency (within 7 days of assessment)
Renal Serum creatinine OR Measured or calculated creatinine clearance (GFR can also be
used in place of creatinine or CrCl) less than or equal to 1.5 X upper limit of normal
(ULN) OR
Greater than or equal to 60 mL/min for subject with creatinine levels greater than 1.5
X institutional ULN Hepatic Serum total bilirubin Less than or equal to 1.5 X ULN
aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT),
alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase (SGPT) Less than or
equal to 2.5 X ULN
Coagulation International Normalized Ratio (INR) or Prothrombin Time (PT)
Activated Partial Thromboplastin Time (aPTT) Less than or equal to 1.5 X ULN unless
subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic
range of intended use of anticoagulants Less than or equal to 1.5 X ULN unless subject
is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of
intended use of anticoagulants
Creatinine clearance should be calculated per institutional standard.
4. Female subject of childbearing potential should have a negative urine or serum
pregnancy within 72 hours prior to receiving the first dose of study medication. If
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
will be required.
5. Female subjects of childbearing potential must be willing to use an adequate method of
contraception for the course of the study through 120 days after the last dose of
study medication.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.
6. Male subjects of childbearing potential must agree to use an adequate method of
contraception starting with the first dose of study therapy through 120 days after the
last dose of study therapy.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception
for the subject.
Exclusion Criteria:
1. Is ineligible for an operation based on medical or oncologic contraindications to
surgery.
2. Has history of non-infectious pneumonitis/interstitial lung disease that required
steroids, or has current pneumonitis/interstitial lung disease.
3. Has evidence of interstitial lung disease.
4. Has an active second malignancy, i.e. patient known to have potentially fatal cancer
present for which he/she may be (but not necessarily) currently receiving treatment.
Patients with a history of malignancy that has been completely treated, with no
evidence of that cancer currently, are permitted to enroll in the trial if curative
therapy has been completed, such as basal cell carcinoma of the skin or squamous cell
carcinoma of the skin that has undergone potentially curative therapy or in situ
cervical cancer.
5. Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 4 weeks of the first dose of treatment.
6. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment.
7. Has a known history of active Bacillus Tuberculosis (TB)
8. Hypersensitivity to pembrolizumab or any of its excipients.
9. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
Day 1 or who has not recovered (i.e., Less than or equal to Grade 1 or at baseline)
from adverse events due to agents administered more than 4 weeks earlier.
10. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to study Day 1 or who has not recovered (i.e., less than or equal
to Grade 1 or at baseline) from adverse events due to a previously administered agent.
- Note: Subjects with less than or equal to Grade 2 neuropathy are an exception to
this criterion and may qualify for the study.
- Note: If subject received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting
therapy.
11. 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 (eg., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.
12. Has an active infection requiring systemic therapy.
13. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator.
14. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
15. Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through 120 days after the last dose of trial treatment.
16. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
17. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
18. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (HCV) (e.g., HCV
RNA [qualitative] is detected).
19. Has received a live vaccine or live-attenuated vaccine within 30 days prior to the
first dose of the study drug. Administration of killed vaccines is allowed.
