PRIMARY OBJECTIVES:
I. To obtain early indication of efficacy by evaluation of non-progression rate (NPR) at 27
weeks as defined as the percentage of patients who are alive and progression-free at 27 weeks
as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 or
immune-related(ir)RECIST or method of tumor evaluation criteria best suitable and accepted
for the tumor type evaluated in patients with advanced tumor types receiving pembrolizumab.
SECONDARY OBJECTIVES:
I. To correlate efficacy by evaluation of tumor size to programmed cell death 1 ligand 1
(PD-L1) status among patients with advanced tumor types receiving pembrolizumab.
II. To evaluate safety and tolerability of pembrolizumab in patients with advanced tumors.
III. To evaluate the percentage of patients with objective response (complete response [CR]
or partial response [PR]), clinical benefit (CR, PR, or stable disease [SD] >= 4 months),
progression free survival (PFS), overall survival (OS), and duration of response (DOR) as
assessed by RECIST v1.1 in patients with advanced tumor types receiving pembrolizumab.
IV. To evaluate the percentage of patients with objective response (CR or PR), clinical
benefit (CR, PR, or SD >= 4 months), PFS, and DOR as assessed by irRECIST in patients with
advanced tumor types receiving pembrolizumab.
V. To correlate the NPR at 27 weeks (9 cycles), objective response (CR or PR), clinical
benefit CR, PR, or SD >= 4 months), PFS, OS, and DOR to PD-L1 status among patients with
advanced tumor types receiving pembrolizumab.
EXPLORATORY OBJECTIVES:
I. To evaluate the potential role of tumor-associated immune biomarkers for prediction of
therapy effectiveness in patients with advanced tumor types receiving pembrolizumab.
II. To correlate the potential role of tumor-associated immune biomarkers for prediction of
therapy effectiveness to PD-L1 status among patients with advanced tumor types receiving
pembrolizumab.
III. To identify imaging characteristics associated with immunological changes in tumor
following treatment with pembrolizumab.
IV. To compare tumor mutation burden and serial assessment of mutation status in biopsies
obtained at baseline and progression in patients with advanced tumor types receiving
pembrolizumab.
V. To evaluate patient-reported outcomes (PRO) utilizing the National Cancer Institute (NCI)
Patient-Reported Outcomes of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)
questionnaires.
OUTLINE:
Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats
every 21 days for up to 24 months in the absence of disease progression or toxicity. Patients
with clinical response or disease stabilization may continue treatment for up to an
additional 12 months.
After completion of study treatment, patients are followed up at 30 days and then every 12
weeks.
Inclusion Criteria:
- Be willing and able to provide written informed consent/assent for the trial
- Have measurable disease based on RECIST 1.1 or irRECIST; only cohort 9 and 10 can have
evaluable disease (non-measurable lesions); tumor lesions situated in a previously
irradiated area are considered measurable if progression has been demonstrated in such
lesions; patients may have bone metastatic disease evaluable according to tumor
evaluation criteria best suitable and accepted for the tumor type evaluated
- Have one of the following advanced (unresectable and/or metastatic) solid tumor
indications that has progressed following standard therapies, where standard therapies
are available:
- Squamous cell carcinoma of the skin
- Small cell malignancies of non-pulmonary origin
- Adrenocortical carcinoma
- Medullary renal cell carcinoma
- Carcinoma of unknown primary
- Penile carcinoma
- Vascular sarcoma
- Germ cell tumor
- Paraganglioma-pheochromocytoma
- Other rare tumors (except those tumor types listed in exclusion)
- Have failed prior treatment within 6 months of consent date
- Have biopsiable disease; subjects must have at least one lesion amenable to biopsy;
tumor lesions used for biopsy should not be lesions used as target lesions; in cohort
9: paraganglioma-pheochromocytoma or cohort 10, where there is prominent bony disease,
biopsies may not be possible due to the nature of the disease
- Be willing to provide archival tissue; if archival tissue is not available, or a newly
obtained core or excisional biopsy of a tumor lesion will be obtained; newly-obtained
is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of
treatment on day 1; in cohort 9: paraganglioma-pheochromocytoma or cohort 10, where
there is prominent bony disease, biopsies may not be possible due to the nature of the
disease
- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
performance scale
- Absolute neutrophil count (ANC) >= 1,000/mcL (performed within 28 days of treatment
initiation)
- Platelets >= 75,000/mcL (performed within 28 days of treatment initiation)
- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO)
dependency (within 7 days of assessment) (performed within 28 days of treatment
initiation)
- Serum 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 upper limit of normal (ULN) OR >= 60 mL/min for subject with creatinine levels >
1.5 X institutional ULN (performed within 28 days of treatment initiation)
- Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total
bilirubin levels > 1.5 ULN (performed within 28 days of treatment initiation)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X
ULN OR =< 5 X ULN for subjects with liver metastases (performed within 28 days of
treatment initiation)
- Albumin > 2.5 mg/dL (performed within 28 days of treatment initiation)
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless
subject is receiving anticoagulant therapy as long as PT or partial thromboplastin
time (PTT) is within therapeutic range of intended use of anticoagulants (performed
within 28 days of treatment initiation)
- 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
of anticoagulants (performed within 28 days of treatment initiation)
- 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
- 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
- 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
- For subjects in cohort 2 (small cell malignancies of non-pulmonary origin),
confirmation of no brain metastases via imaging
Exclusion Criteria:
- Is currently participating and receiving study therapy or concurrent chemotherapy,
immunotherapy, biologic, or hormonal therapy for cancer treatment at the time of
administration of first dose of trial treatment; continuation of hormone replacement
therapy is permitted; stable regimens of hormonal therapy i.e. for prostate cancer
(e.g. leuprolide, a gonadotrophin releasing hormone [GnRH] agonist), ovarian, or
breast cancer are not exclusionary
- 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
- Has a known history of active TB (bacillus tuberculosis)
- Hypersensitivity to pembrolizumab or any of its excipients
- 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
- Has a known additional malignancy that is progressing or requires active treatment;
exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer, and
diseases for which the treatment could reasonably include pembrolizumab and are not
part of the excluded tumor type list or not eligible for the phase I trial
- 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; this exception does not include
carcinomatous meningitis which is excluded regardless of clinical stability
- 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; immunosuppressive corticosteroid doses (> 10 mg prednisone
daily or equivalent) within 4 weeks prior to the first dose of pembrolizumab; Note:
corticosteroids given within 24 hours of an imaging study for purposes of
pre-medication in patients with hypersensitivity to radiologic contrast agents are
allowed
- Has known history of, or any evidence of active, non-infectious pneumonitis
- Has an active infection requiring systemic therapy
- 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
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial
- 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
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
- Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is
detected)
- Has received a live vaccine within 30 days of planned start of study therapy; Note:
seasonal influenza vaccines for injection are generally inactivated flu vaccines and
are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live
attenuated vaccines, and are not allowed
- Is participating in cohort 10 and has melanoma; non-small cell lung cancer;
hepatocellular carcinoma; Merkel cell carcinoma; colon or rectal adenocarcinoma; anal
canal squamous cell carcinoma; pancreas adenocarcinoma; esophageal squamous cell
carcinoma or adenocarcinoma (including gastroesophageal [GE] junction); biliary tract
adenocarcinoma (gallbladder and biliary tree but excluding ampulla of vater cancers);
carcinoid tumors; neuroendocrine carcinomas (well or moderately differentiated
pancreatic neuroendocrine tumor); estrogen receptor (ER)-positive human epidermal
growth factor receptor 2 (HER2)-negative breast cancer; triple negative breast cancer;
ovarian epithelial, fallopian tube or primary peritoneal carcinoma; endometrial
carcinoma; cervical squamous cell cancer; vulvar squamous cell carcinoma; small cell
lung cancer; mesothelioma (malignant pleural mesothelioma); thyroid cancer (papillary
or follicular subtype); salivary gland carcinoma; nasopharyngeal carcinoma;
glioblastoma multiforme; leiomyosarcoma; prostate adenocarcinoma; gastric
adenocarcinoma; or small bowel malignancy
