A Phase 2 Study of ASONEP™ to Treat Unresectable and Refractory Renal Cell Carcinoma

This Phase 2a study will investigate the efficacy, safety and tolerability of ASONEP™ (sonepcizumab/LT1009) when administered intravenously once a week, every 4 weeks (or cycle), to subjects with refractory renal cell carcinoma (RCC) until the disease progresses. Subjects who have failed 3 prior treatments for RCC including vascular endothelial growth factor (VEGF) and/or mammalian target of rapamycin (mTOR) inhibitors or who have tumors that cannot be surgically removed will be eligible for screening.

LT1009-Onc-002 is a Phase 2a open-label, multi-center study designed to evaluate the efficacy and safety of ASONEP (sonepcizumab/LT1009) monotherapy in subjects with advanced, unresectable, refractory RCC who have previously failed up to 3 therapies, including VEGF and/or mTOR inhibitors. Two cohorts will be enrolled for a total of up to 39 subjects. Subjects will receive an intravenous (IV) infusion of ASONEP™ over 90 minutes at 24 mg/kg once a week and progression-free survival (PFS) will be assessed after 8 weeks of treatment. Cohort 1 will enroll approximately 22 subjects. A second cohort of up to 17 subjects will be enrolled if at least 12 out of 22 subjects from Cohort 1 demonstrated PFS at 8 weeks. Weekly dosing will take place from the date of randomization until the date of first documented progression or date of death from any cause, whichever comes first.

Eligibility Criteria:
Inclusion Criteria:

* Unresectable, locally advanced recurrent or metastatic RCC
* Histological or cytological confirmation of clear cell RCC - core tissue biopsy of either primary tumor or metastatic lesion with paraffin-embedded tissue specimens if no prior nephrectomy
* Measurable disease by RECIST 1.1
* Had one prior therapy for unresectable RCC with a VEGF/VEGFR targeted therapy (sunitinib, sorafenib, other VEGFR TKI or bevacizumab) - One prior treatment with an mTOR inhibitor (everolimus, temsirolimus or sirolimus) for unresectable disease permitted-Prior immunotherapy (immunomodulators such as cytokines, interleukins, vaccines, etc.) such as IL-2 also permitted
* Male or non-pregnant, non-nursing female
* Life expectancy ≥3 months
* ECOG performance status of 0, 1 or 2
* Must not be receiving any concurrent anticancer therapy
* Baseline CT or MRI scans of measurable disease sites by RECIST 1.1 performed within 2 weeks of Day 0 - For subjects with bone metastases, baseline bone scan performed within 4 weeks of study entry
* Adequate organ and immune function (within 7 days of Day 0):

Hemoglobin \>9 g/dL-Absolute neutrophil count \>1500 cells/uL without growth factors-Platelet count ≥100x10\^9/L without transfusion-Serum creatinine \<2.0x ULN or creatinine clearance \>40 mL/min-Total bilirubin \<1.5x ULN-AST/ALT \<2.5x ULN (or \<5.0x ULN if liver metastases present)-INR and aPTT \<1.5x ULN

* Subject lesions for arterial spin labeling (ASL) MRI ≥2.5cm by CT imaging
* Must understand, be able and willing to fully comply with study procedures

Exclusion Criteria:

* Prior treatment with \>3 VEGF pathway and/or mTOR inhibitors for RC cancer
* History of other CNS disease (spinal cord compression, or evidence of symptomatic brain or leptomeningeal carcinomatosis)
* Major surgery within 4 weeks of Day 0
* Radiation therapy within 4 weeks of baseline/infusion. Prior palliative radiation to metastatic lesions is acceptable if there is at least one measurable, non-radiated lesion
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring parenteral antibiotics on Day 0
* Known or suspected intolerance or hypersensitivity to study materials or any excipients
* Evidence of bowel obstruction because of theoretical possibility of GI perforation with an anti-angiogenesis agent
* Severe hemorrhage within 4 weeks of screening
* History of GI perforation
* History of non-healing wounds including ulcer or delayed bone fractures
* Prolonged QTc interval on baseline ECG (\>450 msec for males or \>470 msec for females), cardiac dysrhythmias including atrial fibrillation, torsade de pointes, ventricular tachycardia or fibrillation, pathologic sinus bradycardia (\<60 bpm), heart block (excluding 1st degree block, being PR interval prolongation only), congenital long QT syndrome or new ST segment elevation or depression or new Q wave on ECG
* Secondary malignancy within the last 5 years, except for adequately-treated basal cell carcinoma, squamous cell skin cancer, superficial bladder tumors, or in situ cervical cancer
* Previously enrolled in an sonepcizumab study or into this study and subsequently withdrawn
* History of alcohol or other substance abuse within the last year
* Use of corticosteroids or other immunosuppression (if taking systemic steroids \[vs. topical\], at least 4 weeks must have passed since the last dose)
* Growth factors within 1 week of screening
* Serious medical conditions that might be aggravated by treatment or limit compliance
* Cerebrovascular accident or transient ischemic attack, or pulmonary embolism within 6 months prior to screening
* Participation in another clinical trial
* Other severe or intercurrent acute or chronic medical or psychiatric condition or laboratory abnormality that may increase risk associated with study participation or study drug administration