Buparlisib in Metastatic Transitional Cell Carcinoma of the Urothelium
Buparlisib in Metastatic Transitional Cell Carcinoma of the Urothelium
The purpose of this study is to learn what effects, good and/or bad, Buparlisib has on
 advanced urothelial cancer. Buparlisib is a pill that works by shutting down some of the
 signals in cancer cells that make tumors grow. It is being tested in patients in research
 studies such as this one. As of 2010, more than 80 patients with various types of cancer have
 received treatment with Buparlisib in research studies.

 This clinical research study is divided into two parts. The goal of the first part of this
 study is to learn if the study drug Buparlisib can shrink or slow the growth of cancer in
 patients with urothelial tumors. The goal of the second part of this study is to learn if the
 study drug Buparlisib can shrink or slow the growth of urothelial tumors in patients known to
 have certain genetic alterations that cause these types of tumors. The study doctor will
 inform the patient which part of the study is currently enrolling participants. Participants
 in both parts of the study will receive the same treatment and tests.

 The safety of this drug will also be studied in both parts. The physical state, changes in
 the size of the tumor, and laboratory findings taken while on-study will help us decide if
 Buparlisib is safe and effective.
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 or chronic hepatic or renal disease or pancreatitis

 -  Patients with the following mood disorders as judged by the Investigator or a
 psychiatrist, or as a result of patient's mood assessment questionnaire:

 o Medically documented history of or active major depressive episode, bipolar disorder
 (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt
 or ideation, or homicidal ideation (immediate risk of doing harm to others)

 -  ≥ CTCAE grade 3 anxiety

 o Meet the cut-off score of ≥ 10 in the PHQ-9 or a cut-off of ≥ 15 in the GAD-7 mood
 scale, respectively, or select a positive response of "1", "2", or "3" to question
 number 9 regarding the potential for suicidal thoughts in the PHQ-9 (independent of
 the total score of the PHQ-9)

 -  Patients with diarrhea ≥ CTCAE grade 2 or other impairment of gastrointestinal (GI)
 function or GI disease that may significantly alter the absorption of Buparlisib120
 (e.g., ulcerative diseases, uncontrolled, nausea, vomiting, malabsorption syndrome, or
 small bowel resection)

 -  Patient has active cardiac disease including any of the following:

 Left ventricular ejection fraction (LVEF) < 50% as determined by Multiple Grated
 acquisition (MUGA) scan or echocardiogram (ECHO)

 -  QTc > 480 msec on screening ECG (using the QTcF formula)

 -  Angina pectoris that requires the use of anti-anginal medication

 -  Ventricular arrhythmias except for benign premature ventricular contractions

 -  Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with
 medication

 -  Conduction abnormality requiring a pacemaker

 -  Valvular disease with document compromise in cardiac function

 -  Symptomatic pericarditis

 -  Patients with uncontrolled diabetes mellitus or steroid-induced diabetes
 mellitus.

 -  Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g.,
 active or uncontrolled infection) that could cause unacceptable safety risks or
 compromise compliance with the protocol

 -  Significant symptomatic deterioration of lung function. If clinically indicated,
 pulmonary function tests including measures of lung volumes, DLCO, O2 saturation at
 rest on room air should be considered to exclude pneumonitis or pulmonary infiltrates

 -  Patients who have been treated with any hematopoietic colony-stimulating growth
 factors (e.g., G-CSF, GM-CSF) ≤ 2 weeks prior to starting study drug.
 Erythropoietin or darbepoetin therapy, if initiated at least 2 weeks prior to
 enrollment, may be continued

 -  Patients who are currently receiving treatment with any medication that has the
 potential to prolong the QT interval or inducing Torsades de Pointes and the
 treatment cannot either be discontinued or switched to a different medication
 prior to starting study drug. Refer to Appendix A for a list of prohibited
 QT-prolonging medications.

 Patients receiving chronic treatment with steroids or another immunosuppressive agent o
 Note: Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways diseases),
 eye drops or local injections (e.g. intra-articular) are allowed. Patients with previously
 treated brain metastases who are on stable low dose corticosteroid treatment (e.g.,
 dexamethasone 2 mg/day, prednisolone 10 mg/day) for at least 14 days before start of study
 treatment are eligible.

 -  Patients who have taken herbal medications and certain fruits within 7 days prior to
 starting study drug. Herbal medications include, but are not limited to, St. John's
 wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe,
 saw palmetto, and ginseng. Fruits include the CYP3A inhibitors Seville oranges,
 grapefruit, pummelos, or exotic citrus fruits.

 -  Patients who are currently treated with drugs known to be moderate and strong
 inhibitors or inducers of isoenzyme CYP3A, and the treatment cannot be discontinued or
 switched to a different medication prior to starting study drug. Please refer to
 Appendix A for a list of moderate to strong inhibitors of CYP3A4 (Please note that
 co-treatment with weak inhibitors of CYP3A4 is allowed).

 -  Patients who have received chemotherapy or targeted anticancer therapy ≤ 4 weeks (6
 weeks for nitrosourea, antibodies or mitomycin-C) prior to starting study drug or
 whose side effects from chemotherapy or targeted anticancer therapy have not recovered
 to a grade 1 before starting the trial.

 -  Patients who have received any continuous or intermittent small molecule therapeutics
 (excluding monoclonal antibodies) ≤ 5 effective half lives prior to starting study
 drug or who have not recovered from side effects of such therapy.

 Patients who have received wide field radiotherapy ≤ 4 weeks or limited field radiation for
 palliation ≤ 2 weeks prior to starting study drug or who have not recovered from side
 effects of such therapy

 -  Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug,
 patients who have not recovered from side effects of any major surgery, or patients
 who may require major surgery during the course of the study

 -  Patients who are currently taking therapeutic doses of warfarin sodium or any other
 coumarin-derivative anticoagulant.

 Women who are pregnant or breast feeding or adults of child-bearing potential not employing
 an effective method of birth control. Women of child-bearing potential, must have a
 negative serum pregnancy test ≤ 48 hours prior to initiating treatment. Effective methods
 of birth control.

 -  Known diagnosis of human immunodeficiency virus (HIV) infection

 -  History of another malignancy within 3 years, except non-melanoma skin cancer, excised
 carcinoma in situ of the cervix or adenocarcinoma of the prostate that has been
 surgically treated with a post-treatment PSA that is non-detectable

 -  Patients who are unwilling or unable to abide by the study protocol or cooperate fully
 with the investigator