PRIMARY OBJECTIVE:
I. To assess the objective response rate (complete and partial responses), following the
administration of cabozantinib for 12 weeks in patients with locally advanced biopsy-proven
non-metastatic clear cell renal cell carcinoma (ccRCC) prior to undergoing surgery.
SECONDARY OBJECTIVES:
I. To assess the safety, and tolerability of neoadjuvant cabozantinib.
II. To determine the clinical outcome (disease-free survival [DFS], overall survival [OS]) of
patients with non-metastatic ccRCC who treated with neoadjuvant cabozantinib.
III. To evaluate the surgery related outcomes.
IV. To evaluate correlative studies, including biomarkers, quality of life, and
frailty/sarcopenia assessment of patients with non-metastatic ccRCC who treated with
neoadjuvant cabozantinib.
OUTLINE:
Patients receive cabozantinib orally (PO) once daily (QD) for 12 weeks in the absence of
disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months.
Inclusion Criteria:
- Patients with 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.
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.
- Patients must have adequate organ and marrow function, based upon meeting all of the
following laboratory criteria within 14 days before first dose of study treatment:
- Absolute neutrophil count (ANC) ≥ 1500/mm³ (≥ 1.5 GI/L) without granulocyte
colony-stimulating factor support.
- White blood cell count ≥ 2500/mm³ (≥ 2.5 GI/L).
- Platelets ≥ 100,000/mm³ (≥ 100 GI/L) without transfusion.
- Hemoglobin ≥ 9 g/dL.
- Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline
phosphatase (ALP) ≤ 3 x upper limit of normal (ULN). ALP ≤ 5 x ULN with
documented bone metastases.
- Total bilirubin ≤ 1.5 x ULN (for subjects with Gilbert's disease ≤ 3 x ULN).
- Serum albumin ≥ 2.8 g/dl.
- Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 40 mL/min (≥
0.67 mL/sec) using the Cockcroft-Gault equation:
- Males: (140 - age) x weight (kg)/(serum creatinine [mg/dL] × 72)
- Females: [(140 - age) x weight (kg)/(serum creatinine [mg/dL] × 72)] × 0.85
- Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol).
- No hormonal therapy, chemotherapy, immunotherapy, or any other systemic therapy for a
malignancy, in the 5 years prior to current study enrollment.
- Sexually active fertile subjects and their partners must agree to use medically
accepted methods of contraception (eg, barrier methods, including male condom, female
condom, or diaphragm with spermicidal gel) during the course of the study and for 4
months after the last dose of study treatment.
- Female subjects of childbearing potential must not be pregnant at screening. Females
of childbearing potential are defined as premenopausal females capable of becoming
pregnant (ie, females who have had any evidence of menses in the past 12 months, with
the exception of those who had prior hysterectomy). However, women who have been
amenorrheic for 12 or more months are still considered to be of childbearing potential
if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body
weight, ovarian suppression or other reasons.
- Capable of understanding and complying with the protocol requirements and must have
signed the informed consent document.
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.
- Known brain metastases or cranial epidural disease.
- Concomitant anticoagulation with oral anticoagulants (eg, warfarin, direct thrombin
and Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel). Allowed
anticoagulants are the following:
- Low-dose aspirin for cardioprotection (per local applicable guidelines) is
permitted.
- Low-dose low molecular weight heparins (LMWH) are permitted.
- Anticoagulation with therapeutic doses of LMWH is allowed in subjects without
known brain metastases who are on a stable dose of LMWH for at least 6 weeks
before first dose of study treatment, and who have had no clinically significant
hemorrhagic complications from the anticoagulation regimen or the tumor.
- The subject has prothrombin time (PT)/international normalized ratio (INR) or partial
thromboplastin time (PTT) test ≥ 1.3 × the laboratory ULN within 14 days before the
first dose of study treatment.
- The subject has uncontrolled, significant intercurrent or recent illness including,
but not limited to, the following conditions:
- Cardiovascular disorders:
- Congestive heart failure New York Heart Association Class 3 or 4, unstable
angina pectoris, serious cardiac arrhythmias.
- Uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm
Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive
treatment.
- Stroke (including transient ischemic attack [TIA]), myocardial infarction
(MI), or other ischemic event, or thromboembolic event (eg, deep venous
thrombosis, pulmonary embolism) within 6 months before first dose.
- Gastrointestinal (GI) disorders including those associated with a high risk of
perforation or fistula formation:
- The subject has evidence of tumor invading the GI tract, active peptic ulcer
disease, active inflammatory bowel disease (eg, Crohn's disease),
diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis,
acute pancreatitis, acute obstruction of the pancreatic duct or common bile
duct, or gastric outlet obstruction.
- Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal
abscess within 6 months before first dose. Note: Complete healing of an
intra-abdominal abscess must be confirmed before first dose.
- Clinically significant hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 ml) of
red blood, or other history of significant bleeding (eg, pulmonary hemorrhage)
within 12 weeks before first dose.
- Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease
manifestation.
- Other clinically significant disorders that would preclude safe study
participation.
- Serious non-healing wound/ulcer/bone fracture.
- Uncompensated/symptomatic hypothyroidism.
- Moderate to severe hepatic impairment (Child-Pugh B or C).
- Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 8 weeks
before first dose of study treatment. Complete wound healing from major surgery must
have occurred 1 month before first dose and from minor surgery (eg, simple excision,
tooth extraction) at least 10 days before first dose. Subjects with clinically
relevant ongoing complications from prior surgery are not eligible.
- Prolongation of the QT corrected for HR using Fridericia's method (QTcF) interval
defined as > 500 msec per electrocardiogram (ECG) within 28 days before first dose of
study treatment. Note: If a single ECG shows a QTcF with an absolute value > 500 ms,
two additional ECGs at intervals of approximately 3 min must be performed within 30
min after the initial ECG, and the average of these three consecutive results for QTcF
will be used to determine eligibility.
- Pregnant or lactating females.
- Inability to swallow tablets.
- Previously identified allergy or hypersensitivity to components of the study treatment
formulations.
- Diagnosis of another malignancy within 2 years before first dose of study treatment,
except for superficial skin cancers, or localized, low grade tumors deemed cured and
not treated with systemic therapy. Patients with Gleason 6 (3+3) prostate cancer with
previous treatment or on active surveillance may also be allowed on protocol.
