PRIMARY OBJECTIVE:
I. To assess the objective response rate (complete and partial responses), following the
administration of lenvatinib and pembrolizumab for a total of 4 cycles (12 weeks) in patients
with locally-advanced, biopsy-proven non-metastatic clear cell renal cell carcinoma (ccRCC)
prior to undergoing nephrectomy (partial or radical).
SECONDARY OBJECTIVES:
I. To assess the safety and tolerability of neoadjuvant lenvatinib plus pembrolizumab in a
presurgical population.
II. To determine the clinical outcomes including disease-free survival (DFS) and overall
survival (OS) of patients with non-metastatic ccRCC treated with neoadjuvant lenvatinib and
pembrolizumab.
III. To evaluate surgery-related complications and outcomes as per the Clavien-Dindo
classification system.
EXPLORATORY OBJECTIVES:
I. To evaluate changes in biomarkers of immune activation and gene expression before, during
and after treatment.
II. To assess the quality of life, frailty and sarcopenia of patients before and after
treatment.
OUTLINE:
Patients receive lenvatinib orally (PO) once daily (QD) on days 1-21 and pembrolizumab
intravenously (IV) over 30 minutes on day 1. Treatments repeat every 21 days for up to 4
cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up within 14 days, then every 12
weeks thereafter.
Inclusion Criteria:
- Patients with a renal mass consistent with a clinical stage >= T3Nx or TanyN+ or
deemed unresectable by surgeon
- Renal cell carcinoma with clear cell component on pre-treatment biopsy of the primary
tumor
- The participant (or legally acceptable representative if applicable) provides written
informed consent and the willingness and ability to comply with all aspects of the
protocol
- Have an Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Absolute neutrophil count (ANC) >= 1500/uL (specimens must be collected within 72
hours prior to the start of study treatment)
- Platelets >= 100 000/uL (specimens must be collected within 72 hours prior to the
start of study treatment)
- Hemoglobin >= 9.0 g/dL (specimens must be collected within 72 hours prior to the start
of study treatment)
- Criteria must be met without erythropoietin dependency and without packed red
blood cell (pRBC) transfusion within last 4 weeks
- International normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x upper limit of
normal (ULN) unless participant is receiving anticoagulant therapy as long as PT or
activated partial thromboplastin time (aPTT) is within therapeutic range of intended
use of anticoagulants (specimens must be collected within 72 hours prior to the start
of study treatment)
- 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 (specimens must be collected within 72 hours prior to
the start of study treatment)
- Serum creatinine =< 1.5 x ULN OR measured or calculated creatinine clearance
(glomerular filtration rate [GFR] can also be used in place of creatinine or
creatinine clearance [CrCl]) >= 40 mL/min (>= 0.67 mL/sec) for participant with
creatinine levels > 1.5 x institutional ULN (specimens must be collected within 72
hours prior to the start of study treatment)
- Creatinine clearance (CrCl) calculated per the Cockcroft and Gault formula
- Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with total
bilirubin levels > 1.5 x ULN (specimens must be collected within 72 hours prior to the
start of study treatment)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (=< 5 x
ULN for participants with liver metastases) (specimens must be collected within 72
hours prior to the start of study treatment)
- All females must have a negative serum or urine pregnancy test (minimum sensitivity 25
IU/L or equivalent units of beta-human chorionic gonadotropin [beta-hCG]) at the
screening visit and the baseline visit. A pregnancy test needs to be performed within
72 hours of the first dose of study drug. Women of childbearing potential (WOCBP) must
agree to use a highly effective method of contraception for the entire study period
and for 120 days after study discontinuation
- Male subjects who are partners of women of childbearing potential must use a condom
and their female partners of childbearing potential must use a highly effective method
of contraception beginning at least 1 menstrual cycle prior to starting study drugs,
throughout the entire study period, and for 120 days after the last dose of study
drug, unless the male subjects are totally sexually abstinent or have undergone a
successful vasectomy with confirmed azoospermia or unless the female partners have
been sterilized surgically or are otherwise proven sterile
Exclusion Criteria:
- Evidence of metastatic disease on pre-treatment imaging
- The subject has received of any type of cytotoxic, biologic or other systemic
anticancer therapy for kidney cancer
- The subject has received any other type of investigational agent within 28 days before
the first dose of study treatment
- Excluding the primary tumor leading to enrollment in this study, any other active
malignancy (except for localized prostate cancer, definitively treated melanoma
in-situ, basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the
bladder or cervix) within the past 24 months
- Prior treatment with lenvatinib or any agent directed against PD-1, PD-L1 or PD-L2, or
another stimulatory or co inhibitory T-cell receptor (e.g. CTLA-4, OX 40, CD137)
- 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
- Subjects having > 1+ proteinuria on urinalysis will undergo 24-hour urine collection
for quantitative assessment of proteinuria. Subjects with urine protein >= 1 g/24-hour
will be ineligible
- Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition
that might affect the absorption of lenvatinib
- The subject has uncontrolled, significant intercurrent or recent illness including,
but not limited to, the following conditions:
- Cardiovascular disorders:
- New York Heart Association congestive heart failure of grade II or above,
unstable angina, myocardial infarction within the past 6 months, or serious
cardiac arrhythmia associated with significant cardiovascular impairment
within the past 6 months
- Uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm
Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive
treatment
- Prolongation of corrected QT (QTc) interval to > 480 msec per
electrocardiogram (ECG) within 28 days before first dose of study treatment
- Clinically significant hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 ml) of
red blood, or other history of significant bleeding (e.g. pulmonary hemorrhage)
within 3 weeks prior to the first dose of study drug
- Serious non-healing wound/ulcer/bone fracture
- History of organ allograft (subject has had an allogenic tissue/solid organ
transplant)
- Biologic response modifiers (e.g. granulocyte colony-stimulating factor) within 4
weeks before study entry. Chronic erythropoietin therapy is permitted provided that no
dose adjustments were made within 2 months before first dose of study treatment
- Subjects must have recovered adequately from any toxicity and/or complications from
major surgery prior to starting therapy
- 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
- Has a diagnosis of immunodeficiency or is 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 study drug
- 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 active Hepatitis B (e.g., hepatitis B surface antigen [HBsAg])
or hepatitis C (e.g., HCV RNA qualitative is detected)
- Has uncontrolled HIV defined by a CD4+ count < 350 cells/uL, an AIDS-defining
opportunistic infection within the last 12 months prior to study enrollment or
documented multidrug resistance that prevents effective HIV therapy
- 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
