Exploratory Study of Radium-223 and VEGF-Targeted Therapy in Patients With Metastatic Renal Cell Carcinoma and Bone Mets

The FDA (the U.S. Food and Drug Administration) has not approved the combination of sorafenib
and radium-223 or the combination of pazopanib and radium-223 as a treatment for any disease.
Sorafenib and pazopanib are both approved as single agents for the treatment of metastatic
renal cell carcinoma. Additionally, radium-223 is FDA approved for the treatment of advanced
prostate cancer and has shown to have effects on prostate cancer.

Currently, there are limited options for patients with metastatic renal cell cancer who also
have bone metastases. Bone metastases are related to a higher incidence of skeletal
complications, including skeletal pain, fractures, spinal cord compression, and an increase
in the amount of calcium in blood. Such skeletal complications could result in radiation or
surgery to the bone. Since radium-223 is shown to be effective for patients with metastatic
prostate cancer who also have bone metastases, researchers want to explore radium-223 with
VEGF-targeting therapies to understand how the drug combinations affect safety, quality of
life, incidence of skeletal complications, and the progression of cancer.

Inclusion Criteria:

- Age ≥ 18 years.

- Documented pathologic diagnosis of RCC. All subtypes eligible including but not
limited to clear cell, papillary, chromophobe, collecting duct carcinoma, medullary
carcinoma, and unclassified categories. Sarcomatoid and rhabdoid differentiation are
allowed.

- Presence of at least one metastatic bone lesion(s). Patients with non-measurable
bone-only disease are allowed.

- ECOG performance status of 0-2 (Appendix A).

- Must have adequate organ and bone marrow function.

- Absolute neutrophil count (ANC) ≥ 1500/mm3 (without use of G-CSF 4 weeks prior to
enrollment).

- Platelet count ≥100,000/mm3.

- Hemoglobin ≥ 9 g/dL (transfusions allowed).

- ALT and AST ≤ 3.0 x the upper limit of normal (ULN).

- Total bilirubin ≤ 1.5 x ULN. For participants with Gilbert's disease ≤ 3.0 mg/dL.

- Calculated creatinine clearance ≥ 30 mL/min using the Cockroft-gault equation.

- Urine protein-to-creatinine (UPC) ratio ≤ 2 mg/mg creatinine or 24-hour urine
protein < 2 g.

- Recovery to baseline or ≤ grade 1 CTCAE version 4.0 from toxicities related to any
prior treatment, unless adverse events are clinically non-significant and/or stable on
supportive therapy.

- Capable of understanding and complying with the protocol requirements and has signed
the informed consent document.

- Sexually active participants and their partners must agree to use medically accepted
methods of contraception.

- Female participants of childbearing potential must not be pregnant at screening.

- Sexually active participants (men and women) must agree to use highly effective
contraceptive methods during the course of the study and for 6 months after completing
treatment with radium-223.

Exclusion Criteria:

- For patients in the sorafenib cohort, no prior therapy with sorafenib is allowed and
at least 1 line of prior therapy is required including prior: VEGF-targeting therapy
(such as sunitinib, axitinib, tivozanib, bevacizumab), mTOR-targeting therapy (such as
everolimus, temsirolimus), immunotherapy (such as anti-PD-1 or anti-PD-L1), cytokine
therapy (such as interleukin-2, IFN-a) or cytotoxic systemic chemotherapy allowed.

- For patients in the pazopanib cohort, no prior systemic therapy for mRCC is allowed,
with the exception of prior cytokine therapy (such as interleukin-2, IFN-a),
immunotherapy (such as anti-PD-1 or anti-PD-L1), or supportive therapies (such as
zoledronic acid, denosumab).

- Receipt of any type of small molecular kinase inhibitor (including investigational
kinase inhibitors) within 2 weeks of enrollment or receipt of any anti-cancer therapy
(including investigational therapy, monoclonal antibodies, cytokine therapy) within 3
weeks of enrollment.

- Radiation therapy for bone metastases within 2 weeks, other external radiation therapy
within 4 weeks of enrollment.

- Received prior hemibody external radiotherapy.

- Prior therapy with radium-223 or systemic radiotherapy (such as samarium, strontium).

- Known brain metastases or cranial epidural disease unless adequately treated with
radiotherapy, radiosurgery, or surgery and stable for at least 4 weeks of enrollment
as documented by MRI or CT imaging. Treated brain metastases are defined as having no
ongoing requirement for steroids (must be off steroids for at least 4 weeks) and no
evidence of progression or hemorrhage after treatment for at least 4 weeks of
enrollment as documented by MRI or CT imaging.

- Imminent or established spinal cord compression based on clinical and/or imaging. In
patients with untreated imminent or established spinal cord compression, treatment
with standard of care as clinically indicated should be completed at least 4 weeks
before enrollment.

- The subject has uncontrolled, significant intercurrent or recent illness including,
but not limited to, the following conditions:

- Cardiovascular disorders:

- Symptomatic congestive heart failure, unstable angina pectoris, serious
cardiac arrhythmias.

- uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic or >
100 mm Hg diastolic despite optimal antihypertensive treatment.

- Stroke (including transient ischemic attack), myocardial infarction, or
other ischemic event within 12 weeks of enrollment.

- Thromboembolic event (such as deep venous thrombosis, pulmonary embolism)
within 4 weeks of enrollment.

- GI disorders including those associated with a high risk of perforation or
fistula formation:

- Tumors invading the GI-tract, active peptic ulcer disease, inflammatory
bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or
appendicitis, acute pancreatitis or acute obstruction of the pancreatic or
biliary duct, or gastric outlet obstruction.

- Abdominal fistula, gastrointestinal perforation, bowel obstruction, or
intraabdominal abscess within 12 weeks before enrollment. Note: Complete
healing of an intra-abdominal abscess must be confirmed before enrollment.

- Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon
(2.5 ml) of red blood, or other history of significant bleeding (such as
pulmonary hemorrhage) within 4 weeks of enrollment.

- Other clinically significant disorders such as:

- Active infection requiring systemic treatment, infection with human
immunodeficiency virus (HIV) or acquired immunodeficiency syndrome
(AIDS)-related illness, or chronic hepatitis B or C infection.

- Serious non-healing wound or ulcer.

- Malabsorption syndrome.

- Symptomatic hypothyroidism.

- Moderate to severe hepatic impairment (Child-Pugh B or C).

- Requirement for hemodialysis or peritoneal dialysis.

- History of solid organ transplantation.

- Major surgery (such as GI surgery) within 6 weeks of enrollment. However,
subjects who have had a nephrectomy may be enrolled 4 weeks after surgery,
providing there are no wound-healing complications. Subjects with clinically
relevant ongoing complications from prior surgery are not eligible. The following
are not considered to be major procedures: Thoracentesis, paracentesis, port
placement, laparoscopy, thoracoscopy, bronchoscopy, endoscopic ultrasonographic
procedures, mediastinoscopy, skin biopsies, incisional biopsies, imaging-guided
biopsy for diagnostic purposes, and routine dental procedures.

- QTcF > 470 msec within 4 weeks of enrollment. If the initial QTcF is found to be
> 470 ms, two additional EKGs separated by at least 3 minutes should be
performed. If the average of these three consecutive results for QTcF is ≤ 470
ms, the subject meets eligibility in this regard.

- Pregnant or lactating females.

- Inability to swallow tablets or capsules.

- Previously identified allergy or hypersensitivity to components of the study
treatment formulations.

- Diagnosis of another malignancy within 2 years of enrollment, except for
superficial skin cancers, or localized, low grade tumors deemed cured and not
treated with systemic therapy by the principal investigator