Buparlisib in Metastatic Transitional Cell Carcinoma of the Urothelium

Inclusion Criteria

• Age ≥ 18 years
• Karnofsky Performance Status (KPS) ≥60%
• Urothelial carcinoma of the bladder, urethra, ureter or renal pelvis, with histologic confirmation at MSKCC. Patients with unresected primary tumors may be enrolled as long as evidence of metastatic disease is also present.
• Patients must have progressive metastatic disease. Progressive disease will be defined as new or progressive lesions on cross-sectional imaging (RECIST Version 1.1).
• Patients must have been previously treated, as defined by the following:
• Patients must have received treatment with at least one prior cytotoxic chemotherapy agent but not more than four prior cytotoxic chemotherapy agents for urothelial carcinoma. Up to four prior chemotherapy agents are allowed, since conventional chemotherapy ranges from just one drug (e.g., gemcitabine) to regimens that contain four agents (e.g., M-VAC is a four-drug regimen containing methotrexate, vinblastine, doxorubicin, and cisplatin).

The prior therapy must have consisted of at least one of the following: cisplatin, carboplatin, paclitaxel, docetaxel, or gemcitabine.

o The prior cytotoxic agents may have been administered in the perioperative or metastatic setting and may have been administered sequentially (e.g., first-line treatment followed by second-line treatment at time of progression) or as part of a single regimen.

• Patients must have at least one site of measurable disease per RECIST 1.1 criteria that has not been previously irradiated. If the patient has had previous radiation to the marker lesion(s), there must be evidence of progression since the radiation.
• Patients enrolling in the Phase II study must have pre-treatment tumor tissue available for PI3K/Akt pathway marker analysis: One paraffin block, frozen curls or 10 freshly-prepared unstained slides from the most representative single paraffinembedded tumor tissue block should be submitted. Slides from the primary tumor are preferred. If both the primary and metastatic tumor blocks are available, 10 slides from each of the sites should be submitted. If tissue from the primary tumor is not available, a paraffin block or unstained slides from a metastatic site are acceptable. Fine needle aspirates (FNAs) have insufficient tumor tissue and are not permitted.
• Patients enrolling in the Expansion Cohort must have prior mutational testing demonstrating alterations within the PI3K/Akt/mTOR pathway predicted to result in pathway activation.
• Life expectancy of ≥ 12 weeks
• Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L,
• Hemoglobin >9 g/dL
• Total calcium (corrected for serum albumin) within normal limits (bisphosphonate use for malignant hypercalcemia control is not allowed)
• Corrected Calcium = (0.8 * (Normal Albumin - Pt's Albumin)) + Serum Ca
• Potassium and magnesium within normal limits
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal range [or ≤ 3.0 x upper limit of normal (ULN) if liver metastases are present]
• Serum bilirubin within normal range (or ≤ 1.5 x ULN if liver metastases are present; or total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in patients with welldocumented Gilbert syndrome)
• Serum creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 50 mL/min
• INR ≤ 2
• Serum amylase and lipase ≤ ULN
• Fasting plasma glucose ≤ 120 mg/dL (6.7 mmol/L)
• Ability to swallow oral medication

Exclusion Criteria

• Patients who have received prior treatment with a P13K inhibitor.
• Patients receiving any other investigational therapies.
• Patients with a known hypersensitivity to Buparlisib 120 or to its excipients
• Patients with untreated brain metastases are excluded. However, patients may participate in this trial if > 4 weeks from completion of therapy (radiation and/or surgery) for CNS metastases, are clinically stable at the time of registration and are not receiving corticosteroid therapy
• Patients with acute