The goal of Phase 1 of this clinical research study is to find the highest tolerable dose of
the combination of Keytruda (pembrolizumab, also called MK-3475) and radiation therapy
(either conventional or stereotactic body radiation therapy [SBRT]). The safety of this
combination will also be studied.
The goal of Phase 2 of this study is to learn if this combination therapy can help to control
This is an investigational study. Radiation therapy (both conventional and SBRT) is FDA
approved for the local control of metastatic and primary tumors. Pembrolizumab is FDA
approved and commercially available for the treatment of melanoma that is metastatic or
cannot be removed by surgery. Its use in patients with metastatic NSCLC is investigational.
Up to 104 participants will be enrolled in this study. All will take part at MD Anderson.
If you are found to be eligible to take part in this study, you will be assigned to a study
group based on when you join this study. Up to 24 participants will be enrolled in Phase 1 of
the study, and up to 80 participants will be enrolled in Phase 2.
If you are enrolled in Phase 1, the dose of pembrolizumab you receive will depend on when you
join this study. The first set of participants will receive the lowest dose level of
pembrolizumab. Each new set will receive a higher dose of pembrolizumab than the set before
it, if no intolerable side effects were seen. This will continue until the highest tolerable
dose of pembrolizumab is found.
In addition to pembrolizumab, you will receive either SBRT or conventional radiation therapy,
depending on what type of radiation therapy the doctor thinks will be better for you.
If you are enrolled in Phase 2, you will receive pembrolizumab at the highest dose that was
tolerated in Phase 1.
Your radiation therapy assignment will be decided based on what treatment your doctor thinks
would be better for you:
If the doctor thinks SBRT would be better for you, you will be randomly assigned (as in the
flip of a coin) to either Group 1 or Group 2:
- If you are in Group 1, you will receive SBRT and pembrolizumab.
- If you are in Group 2, you will receive pembrolizumab alone. However, if the disease has
gotten worse after 5 weeks or possibly later, you may be able to also start receiving
SBRT. If your doctor thinks it would be safer, you may cross over to Group 4 (described
below) and receive conventional radiation therapy instead of SBRT.
If the doctor thinks conventional radiation therapy would be better for you, you will be
randomly assigned to either Group 3 or Group 4:
- If you are in Group 3, you will receive conventional radiation therapy and
- If you are in Group 4, you will receive pembrolizumab alone. However, if the disease has
gotten worse after 5 weeks or possibly later, you may be able to continue receiving
pembrolizumab and start receiving conventional radiation therapy.
These treatments are randomly assigned because no one knows if one study group is better, the
same, or worse than the other group. You will have an equal chance of being in either group.
Some participants will also be assigned to Group 5 and will have their radiation treatment
details decided by the treating doctor. If you are in Group 5, you will receive pembrolizumab
along with SBRT or conventional radiation therapy to one or more tumors and low dose
radiation to others.
Study Therapy Administration:
You will receive pembrolizumab by vein over about 30 minutes on Day 1 of each 3-week cycle.
Radiation will consist of either 4 or 15 daily treatments lasting about 30-45 minutes each
day while you stay in the same position. Depending on what group you are in and the status of
the disease, you will either start radiation on the same day as your first pembrolizumab
dose, or if the disease has gotten worse. The doctor will discuss the radiation therapy
schedule with you.
On Day 1 of each cycle:
- You will have a physical exam.
- Blood (about 1 tablespoon) will be drawn for routine tests.
One (1) day before the start of Cycles 3, 5, 8, 11, and 14, you will have a CT, PET, MRI,
x-ray, and/or ultrasound scan.
Leftover tumor tissue from an earlier procedure will be used for biomarker testing.
Biomarkers are found in the blood and tissue and may be related to your reaction to the study
Length of Study:
You may receive up to 16 cycles of pembrolizumab. You will receive up to 15 radiation
treatments, depending on what group you are in. You will no longer be able to take the study
drug if intolerable side effects occur or if you are unable to follow study directions.
If the disease has gotten worse, you may be able to continue study therapy, as described
Your participation on the study will be over after the follow-up visits.
About 30 days after your last dose of pembrolizumab:
- You will have a physical exam.
- Blood (about ½ teaspoon) will be drawn for routine tests.
- You will have a CT, PET, MRI, x-ray, and/or ultrasound scan.
- You may have lung function tests performed.
About every 12 weeks for 2 years after you finish your last pembrolizumab cycle, the
following tests and procedures may be performed. Instead of any of these follow-up visits, it
is possible the study staff may call you instead and ask how you are doing.
- You may have a physical exam.
- Blood (about 1 tablespoon) may be collected for routine tests.
- You may have a CT, PET, MRI, x-ray and/or ultrasound scan.
Starting 2 years after you finish your last pembrolizumab cycle, you will have a physical
exam and/or a CT, PET, MRI, x-ray, and/or ultrasound scan every 12 weeks if your doctor
thinks it is needed. If you have these procedures performed at another hospital, information
about your medical history, physical exam, lung function, and scans will be sent to MD
Anderson for review.
1. Pathologically confirmed non-small lung cancer
2. Stage IV metastatic disease (only during the phase II)
3. At least one thoracic or liver lesion amenable to radiation, for group 5 we need one
area that can safely receive SBRT or WFRT, not restricted to lung or liver sites.
4. At least one additional non-contiguous lesion to the irradiated lesion amenable to
5. Be willing and able to provide written informed consent/assent for the trial
6. Be >/= 18 years of age on day of signing informed consent
7. Have measurable disease based on immune related response criteria (irRC) criteria
8. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
9. Demonstrate adequate organ function described in inclusion #12 and #13, all screening
labs should be performed within 28 days prior to study registration up to the first
dose of study drug.
10. Patients with brain metastasis will be included as long as they are free of neurologic
symptoms related to metastatic brain lesions and who do not require or receive
systemic corticosteroid therapy in the 14 days prior to beginning MK-3475 therapy
11. Adequate Organ Function Laboratory Values: *Hematological; Absolute neutrophil count
(ANC) >/=1,500 /mcL, Platelets >/=100,000 / mcL, Hemoglobin >/=9 g/dL or >/=5.6 mmol/L
* Renal; Serum creatinine or Measured or calculated creatinine clearance (glomerular
filtration rate [GFR] can also be used in place of creatinine or CrCl) </=1.5 X upper
limit of normal (ULN) or >/=60 mL/min for subject with creatinine levels >1.5 X
institutional ULN [Creatinine clearance should be calculated per institutional
standard] *Hepatic; Serum total bilirubin </=1.5 X ULN or Direct bilirubin </=ULN for
subjects with total bilirubin levels >1.5 ULN, aspartate aminotransferase (AST) serum
glutamic-oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT) serum
glutamic-pyruvic transaminase (SGPT) </=2.5 X ULN or </=5 X ULN for subjects with
12. Inclusion #12 continued: *Coagulation; International Normalized Ratio (INR) or
Prothrombin Time (PT) </=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,
Activated Partial Thromboplastin Time (aPTT) </=1.5 X ULN unless subject is receiving
anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
13. 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.
14. Female subjects of childbearing potential should be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the course
of the study through 120 days after the last dose of study medication. Subjects of
childbearing potential are those who have not been surgically sterilized or have not
been free from menses for > 1 year.
15. Male subjects should 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.
16. We will allow XRT prior to study entry to other sites, with no washout period, prior
to study entry as long as at least one measurable sites of disease is kept
1. Is currently participating in or has participated in a study of an investigational
agent (except glutamine) or using an investigational device within 4 weeks of the
first dose of treatment or 5 half-lives, whichever is shorter.
2. 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. Unless the steroid therapy is for physiological replacement.
3. Has a diagnosis of active scleroderma, lupus, or other autoimmune disease which by the
opinion of the treating radiation oncologist precludes safe radiation therapy.
4. Has had prior radiation therapy to all available thoracic and liver lesions such that
additional radiation therapy is unsafe by the opinion of the treating radiation
5. Has had a prior monoclonal antibody within 4 weeks or 5 half-lives, which ever is
shorter, prior to study Day 1 or who has not recovered (i.e., </= Grade 1 or at
baseline) from adverse events due to agents administered more than 4 weeks earlier.
6. Has had prior chemotherapy or targeted small molecule therapy within 2 weeks prior to
study Day 1 or who has not recovered (i.e., </= Grade 1 or at baseline) from adverse
events due to a previously administered agent. *Note: Subjects with </= 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.
7. Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
skin, or in situ cervical cancer that has undergone potentially curative therapy.
8. Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Subjects with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging for at least four weeks
prior to the first dose of trial treatment and any neurologic symptoms have returned
to baseline), have no evidence of new or enlarging brain metastases, and are not using
steroids for at least 7 days prior to trial treatment.
9. Has an active autoimmune disease requiring systemic treatment within the past 3 months
or a documented history of clinically severe autoimmune disease, or a syndrome that
requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or
resolved childhood asthma/atopy would be an exception to this rule. Subjects that
require intermittent use of bronchodilators or local steroid injections would not be
excluded from the study. Subjects with hypothyroidism stable on hormone replacement or
Sjorgen's syndrome will not be excluded from the study.
10. Has evidence of interstitial lung disease or active, non-infectious pneumonitis
11. Has an active infection requiring systemic therapy or hospital admission
12. 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.
13. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial
14. 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.
15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)
16. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected)
17. Has received a live vaccine within 30 days prior to the first dose of trial treatment
18. Symptomatic brain metastasis
19. Has experienced a dose limiting toxicity on treatment with either prior radiation or
anti PD-1 or PD-L1 inhibitor therapy