PRIMARY OBJECTIVE:
I. To determine the impact of pembrolizumab-based therapy on the composition, phenotype, and
function of tumor-infiltrating immune cells (TIICs) in subjects with advanced renal cell
carcinoma (RCC) undergoing cytoreductive nephrectomy (CN)/metastasectomy (MET).
SECONDARY OBJECTIVES:
I. To determine the clinical efficacy of preoperative pembrolizumab-based therapy in subjects
with advanced RCC undergoing CN/MET.
II. To explore the clinical efficacy of continued pembrolizumab-based therapy following
CN/MET in subjects with advanced RCC.
III. To determine the safety and tolerability of pembrolizumab-based therapy in subjects with
advanced RCC undergoing CN/MET.
EXPLORATORY OBJECTIVES:
I. To explore the clinical efficacy of preoperative pembrolizumab-based therapy in subjects
with advanced RCC, by pathologic response. (Clinical) II. To explore the relationship between
changes in TIICs and clinical efficacy in subjects with advanced RCC treated with
pembrolizumab-based therapy. (Scientific) III. To characterize changes in the frequency and
number of circulating T cells induced by pembrolizumab-based therapy in subjects with
advanced RCC. (Scientific) IV. To determine the impact of pembrolizumab-based therapy on the
composition and phenotype of the tumor microenvironment (including tumor and stromal cells)
in subjects with advanced RCC. (Scientific) V. To determine whether locally advanced versus
metastatic RCC exhibit differences in immune composition or phenotype at baseline and in
response to pembrolizumab-based therapy. (Scientific) VI. To determine the change in T cell
repertoire within the tumor and blood induced by pembrolizumab-based therapy in subjects with
advanced RCC. (Scientific) VII. To explore molecular profiles to identify potentially
predictive biomarkers for subjects with advanced RCC treated with immunotherapy (Scientific)
OUTLINE: Patients are assigned to 1 of 2 cohorts.
COHORT A: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1.
Treatment repeats every 21 days for 3 cycles in the absence of disease progression or
unacceptable toxicity. Within 14-21 days following the end of treatment, patients will
undergo standard of care CN or MET. Patients with progressive disease (PD) may undergo CN or
MET per physician discretion. Within 21-42 days after surgery, patients with no disease (R0
resection) or microscopic disease (R1 resection) receive pembrolizumab IV every 42 days for
up to 9 cycles (1 year) and patients with macroscopic disease (R2 resection) receive
pembrolizumab IV every 42 days for up to 18 cycles (2 years) in the absence of disease
progression or unacceptable toxicity
COHORT B: Patients receive pembrolizumab IV over 30 minutes on day 1 and standard of care
axitinib orally (PO) twice daily (BID) on days 1-42. Treatment repeats every 21 days for 3
cycles in the absence of disease progression or unacceptable toxicity. Within 14-21 days
following the end of treatment, patients undergo standard of care CN or MET. Patients with PD
may undergo CN or MET per physician discretion. Within 21-42 days after surgery, patients
with an R0 or R1 resection receive pembrolizumab IV over 30 minutes on day 1 and axitinib PO
BID on days 1-42. Treatments repeat every 42 days for up to 9 cycles (1 year) in the absence
of disease progression or unacceptable toxicity. Patients with an R2 resection receive
pembrolizumab IV over 30 minutes on day 1 and axitinib PO BID on days 1-42. Treatment repeats
every 42 days for up to 18 cycles (2 years) in the absence of disease progression or
unacceptable toxicity.
Follow-up will occur at treatment discontinuation, 30 days post-discontinuation, and then
every 12 weeks for up to 1 year post-discontinuation. Subjects who discontinue study
participation due to progressive disease will return for a mandatory safety follow-up visit
within 30 days of(+7 days) after the final dose of study treatment.
Inclusion Criteria:
- Histologically confirmed renal cell carcinoma (RCC) with a clear cell component
- Locally advanced or metastatic disease (primary intact or status post nephrectomy with
recurrent disease)
- Planned CN and/or MET
- Availability of pre-treatment tumor specimen:
- Archival, diagnostic tissue specimen is permissible, if:
- Obtained within 120 days of study enrollment
- Assessed by the principal investigator (PI) to be adequate for planned
analyses
- Core biopsy, nephrectomy, or MET specimen; fine needle aspirate (FNA)
specimens are not acceptable
- Fresh tumor specimen acquisition: participants who do not have archival tissue
adequate for planned analyses must consent to fresh tumor specimen acquisition
- Core biopsy, nephrectomy, or MET specimen
- Participants who undergo nephrectomy or MET prior to study enrollment
are still eligible for the study, as long as they still have measurable
disease (Response Evaluation Criteria in Solid Tumors (RECIST) 1.1)
that is amenable to CN or MET
- FNA specimens are not acceptable
- Measurable disease per RECIST 1.1 as assessed by the investigator. Lesions situated in
a previously irradiated area are considered measurable if progression has been
demonstrated in such lesions
- Subject (or legally acceptable representative if applicable) must provide written
informed consent for the trial
- Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
performance scale
- Absolute neutrophil count (ANC) >= 1,500/microliter (uL) (within 10 days of treatment
initiation)
- Platelets >= 100,000/uL (within 10 days of treatment initiation)
- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO)
dependency (within 7 days of assessment)
- Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated
creatinine clearance (CrCl) (glomerular filtration rate (GFR) can also be used in
place of creatinine or CrCl) >= 60 mL/min for subject with creatinine levels > 1.5 x
institutional ULN (within 10 days of treatment initiation)
- Creatinine clearance should be calculated per institutional standard
- Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with
total bilirubin levels > 1.5 ULN (within 10 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 (within 10 days of treatment initiation)
- Albumin >= 2.5 mg/dL (within 10 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 activated partial
thromboplastin time (aPTT) is within therapeutic range of intended use of
anticoagulants (within 10 days of treatment initiation)
- Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving
anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended
use of anticoagulants (within 10 days of treatment initiation)
- Negative urine or serum pregnancy test within 72 hours prior to receiving the first
dose of study medication (day 1) (female participants of childbearing potential). If
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
will be required
- Male and female participants 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
Exclusion Criteria:
- RCC WITHOUT a clear cell component
- Prior systemic therapy for the treatment of RCC
- No measurable disease (e.g. only bone metastases)
- Not a candidate for CN and/or MET
- Currently participating in or has participated in a study of an 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 since the last dose of the
previous investigational agent
- Diagnosis of immunodeficiency or receiving chronic systemic 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 trial treatment
- Known history of active Bacillus tuberculosis (TB)
- Severe hypersensitivity (>= grade 3) to pembrolizumab/axitinib or any of their
excipients
- Prior systemic anti-cancer monoclonal antibody (mAb), targeted small molecule therapy,
or radiation therapy within 2 weeks prior to the first dose of study treatment (day 1)
- 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 subject received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting study
treatment
- Participants must have recovered from all radiation-related toxicities, not
require corticosteroids, and not have had radiation pneumonitis. A 1-week washout
is permitted for palliative radiation (=< 2 weeks of radiotherapy) to non-central
nervous system (CNS) disease
- Known additional malignancy that is progressing or has required active treatment
within the past 2 years
- Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma
of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in
situ) that have undergone potentially curative therapy are not excluded
- Known active CNS metastases and/or carcinomatous meningitis. Participants with
previously treated brain metastases may participate provided they are radiologically
stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging
(note that the repeat imaging should be performed during study screening), clinically
stable and without requirement of steroid treatment for at least 14 days prior to
first dose of study treatment. This exception does not include carcinomatous
meningitis, which is excluded regardless of clinical stability
- 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 and is allowed
- History of (non-infectious) pneumonitis that required treatment with steroids or has
current pneumonitis
- Active infection requiring systemic therapy
- Any arterial thromboembolic events, including but not limited to myocardial
infarction, transient ischemic attack, cerebrovascular accident, or unstable angina,
within 6 months prior to randomization
- Uncontrolled or poorly controlled hypertension despite standard medical therapy
- Serious or nonhealing wound, ulcer, or bone fracture within 28 days of study
enrollment
- 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
- Known psychiatric or substance abuse disorders that would interfere with cooperation
with the requirements of the trial
- 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
- Any prior therapy with an 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., cytotoxic
T-lymphocyte-associated protein 4 (CTLA-4), OX-40, CD137)
- Known history of human immunodeficiency virus (HIV) infection. No HIV testing is
required unless mandated by local health authority
- Known history of hepatitis B (defined as hepatitis B surface antigen reactive) or
known active hepatitis C virus (defined as hepatitis C virus (HCV) ribonucleic acid
(RNA) [qualitative] is detected) infection. No testing for hepatitis B and hepatitis C
is required unless mandated by local health authority
- 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
- History of grade 3-4 gastrointestinal (GI) bleeding within 12 weeks prior to study
enrollment
- Solid organ or hematologic transplant
- Encephalopathy in the last 6 months. Those participants on rifaximin or lactulose to
control their encephalopathy are not allowed
- Evident ascites on physical examination
- Note: Medically controlled ascites and ascites detectable on imaging studies only
is allowed
- Female of childbearing potential who has a positive urine pregnancy test within 72
hours prior to allocation. If the urine test is positive or cannot be confirmed as
negative, a serum pregnancy test will be required
- Has had an allogenic tissue/solid organ transplant
