• Time to Response (TTR) [ Time Frame: First dosing date to date of first objective response, assessed up to 24 months ]
  TTR is defined as the time from the first dose of study treatment to first objective response [complete response (CR) or partial response (PR)] in patients with CR or PR.
• Duration of Response (DOR) [ Time Frame: Date of first objective response to date of confirmed disease progression, assessed up to 24 months ]
  DOR is defined as the time from the first objective response (CR or PR) to documented disease progression in patients with CR or PR.
• Progression-Free Survival (PFS) [ Time Frame: First dosing to date to confirmed disease progression or death, assessed up to 48 months ]
  PFS is defined as the time from the first dose of study treatment to documented disease progression or death due to any cause.
• Changes from baseline in thyroid stimulating hormone (TSH) [ Time Frame: Pre-treatment (within 7 days of first dose) to date of confirmed disease progression, assessed up to 24 months ]
  If TSH result is abnormal, subsequent testing of Free T3 and free T4 required.
• Changes from baseline in electrocardiograms (ECGs) [ Time Frame: Screening to date of confirmed disease progression, assessed up to 24 months ]
  ECGs assess heart problems by measuring the electrical activity generated by the heart as it contracts. The components that will be assessed during the ECG are P wave, QRS complex, ST segment, and T wave.
• Changes from baseline in Eastern Cooperative Oncology Group (ECOG) performance [ Time Frame: Screening to date of confirmed disease progression, assessed up to 24 months ]
  ECOG performance status describes the level of impact that disease has on the patient's daily living abilities. Scale ranges from 0 (Fully active and able to carry on all pre-disease performance without restriction) to 5 (Dead).
• Population Pharmacokinetics (PK) of IPI-549-01 [ Time Frame: Pre-dose, 0.5, 1.5, 3 and 6 hours following administration on Day 1 of Cycles 1 and 2 (each cycle is 28 days) ]
  IPI-549 blood concentrations in ng/mL.
• Pharmacokinetics (PK) of Nivolumab [ Time Frame: Pre-infusion and within 2 minutes of end of infusion on Day 1 of Cycles 1 and 4; Pre-infusion on Day 1 of Cycles 2 and 3, and every 4 cycles starting at Cycle 5 (each cycle is 28 days) ]
  Nivolumab blood concentrations will be assayed in ug/mL.
• Changes from baseline in pulse rate [ Time Frame: Screening to date of confirmed disease progression, assessed up to 24 months ]
  Pulse rate as measured in beats per minute (bpm)
• Changes from baseline in temperature [ Time Frame: Screening to date of confirmed disease progression, assessed up to 24 months ]
  Temperature as measured in celsius.
• Changes from baseline in respiration rate [ Time Frame: Screening to date of confirmed disease progression, assessed up to 24 months ]
  Respiration rate as measured in breaths per minute.
• Changes from baseline in blood pressure [ Time Frame: Screening to date of confirmed disease progression, assessed up to 24 months ]
  Systolic and diastolic blood pressure as measured in mmHg.

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.

• Bladder Cancer
• Urothelial Carcinoma
• Solid Tumor
• Advanced Cancer

• Drug: IPI-549 (eganelisib)
  IPI-549 (40mg QD) administered orally in 28-day cycles
  Other Name: IPI549
• Drug: Nivolumab
  Nivolumab (480mg Q4W) administered intravenously (IV) in 28-day cycles
  Other Name: OPDIVO®
• Drug: Placebos
  Placebo administered orally in 28-day cycles
  Other Name: Placebo

• Experimental: IPI-549 + Nivolumab
  Participants receive IPI-549 orally (PO) daily in combination with nivolumab IV infusion every 4 weeks
  Interventions:

  • Drug: IPI-549 (eganelisib)
  • Drug: Nivolumab
• Active Comparator: Placebo + Nivolumab
  Participants receive placebo orally (PO) daily in combination with nivolumab IV infusion every 4 weeks
  Interventions:

  • Drug: Nivolumab
  • Drug: Placebos

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