Clinical trial NCT02406521 (phase 1, status: completed)
Conditions: metastatic renal cell carcinoma
ICD codes: C22.0, C4A.9, C7B.1, C4A.0, C4A.31, C4A.51, C4A.8
Drugs: pazopanib, sorafenib, radium-223
SMILES: ClCCN(CCCl)P1(=O)NCCCO1, CNC(=O)C1=NC=CC(OC2=CC=C(NC(=O)NC3=CC(=C(Cl)C=C3)C(F)(F)F)C=C2)=C1, Cl[223Ra]Cl
Eligibility criteria:

        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