The purpose of this study is to measure the effect of IPI-549 in combination with nivolumab when compared to nivolumab monotherapy in advanced urothelial cancer patients.

Study IPI-549-02 is a multi-national, prospective, randomized, active-control Phase II trial to evaluate the efficacy and safety of IPI 549 administered in combination with nivolumab compared to nivolumab monotherapy.

The study will enroll approximately 160 checkpoint-naïve, advanced urothelial cancer patients who have progressed or recurred following treatment with platinum-based chemotherapy. Patients will be randomized 2:1 to receive intravenous (IV) nivolumab 480 mg every 4 weeks (Q4W) in combination with oral (PO) IPI 549 40 mg once daily (QD) or IV nivolumab 480 mg Q4W in combination with placebo PO QD.

Eligible patients who have confirmed progression of disease during treatment with nivolumab monotherapy may crossover to the combination treatment arm.

Inclusion Criteria:

• Histologically or cytologically confirmed urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra
• Measurable disease by CT or MRI as defined by RECIST v1.1
• Disease progression or recurrence after treatment:
• i) With at least 1 platinum-based chemotherapy regimen for the treatment of metastatic (Stage IV) or locally advanced unresectable disease; or
• ii) With disease recurrence within 1 year of completing a platinum-based neoadjuvant or adjuvant therapy
• Subject that have received more than 2 prior lines of chemotherapy must not have liver metastases
• Tumor tissues (archived or new biopsy) must be provided for biomarker analysis
• Eastern Cooperative Oncology Group (ECOG) performance status ≤1
• Blood sample must be provided for mMDSC levels for randomization into the study

Exclusion Criteria:

• Active brain metastases or leptomeningeal metastases
• Any serious or uncontrolled medical disorder that may interfere with study treatment/interpretation
• Prior malignancy active within the previous 3 years except for local or organ confined early stage cancer that has been apparently cured
• Active, known, or suspected autoimmune disease
• A condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 day of study drug administration
• Prior therapy with anti-tumor vaccines, any T cell co-stimulation or checkpoint pathways, or IPI-549
• Prior surgery or gastrointestinal dysfunction that may affect drug absorption
• Past medical history of interstitial lung disease
• History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control
• Positive test for hepatitis B, C or HIV
• Dependent on continuous supplemental oxygen