Ixazomib Citrate With Gemcitabine Hydrochloride and Doxorubicin Hydrochloride in Treating Patients With Urothelial Cancer That is Metastatic or Cannot Be Removed by Surgery

Inclusion Criteria:

• All patients must have histologic demonstration of metastatic or locallyunresectable transitional cell carcinoma of the urothelium; variant histology isallowed as long as there is an urothelial component present; the principalinvestigator (PI), will serve as the final arbiter of eligibility

• All patients must have measurable or evaluable disease; in general, liver and lunglesions should be at least 1 cm, and patients with node-only disease should havelesions of >= 1.5 cm in greatest dimension; patients with disease confined to bonemay be eligible if a measurable lytic defect is present or a serum marker iselevated (> 4 x upper limit of normal [ULN]); the principal investigator is thefinal arbiter in questions related to measurability; patients with athree-dimensional mass or pelvic sidewall fixation on bladder examination underanesthesia are considered to have measurable disease

• Patients must have had at least one prior therapy to be eligible for either phase Ior II, unless they are either not candidates for or refuse cisplatin-based therapy

• Phase I: patients are eligible with any number of prior regimens regardless of whatthose regimens contained (i.e. prior bortezomib or combination gemcitabine andadriamycin is acceptable)

• Phase II: patients are eligible if their previous chemotherapy regimen did notcontain bortezomib, carfilzomib, or other known proteasome inhibitor or acombination of gemcitabine >= 800 mg/m^2 plus adriamycin >= 30 mg/m^2; patients whoreceive sequential or alternating therapy as part of front-line treatment will becounted as having one prior regimen; patients who have failed prior neoadjuvantchemotherapy will be eligible for this trial

• If prior history of ischemic heart disease or exposure to 200 mg/m^2 of doxorubicin,patients must have a measured ejection fraction (either by multigated acquisitionscan [MUGA], echocardiogram [ECHO], stress test, or ventriculography) of at least 45%

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (serum glutamicoxaloacetic transaminase [SGOT]) levels =< 3 x the upper limit of normal

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) =< 2; patientswith a PS of 3 are eligible if the performance status is due to their malignancy,and not a co-morbid medical condition (example [ex]: perineal pain impacting theirability to sit or ambulate, etc.)

• Patients who:

• Are postmenopausal for at least 1 year before the screening visit, OR

• Are surgically sterile, OR

• If they are of childbearing potential, agree to practice 2 effective methods ofcontraception, at the same time, from the time of signing the informed consentform through 90 days after the last dose of study drug, OR

• Agree to practice true abstinence when this is in line with the preferred andusual lifestyle of the subject; (periodic abstinence [eg, calendar, ovulation,symptothermal, post-ovulation methods] and withdrawal are not acceptablemethods of contraception)

• Male patients, even if surgically sterilized (ie, status post-vasectomy), mustagree to one of the following:

• Agree to practice effective barrier contraception during the entire studytreatment period and through 90 days after the last dose of study drug, OR

• Agree to practice true abstinence when this is in line with the preferredand usual lifestyle of the subject; (periodic abstinence [eg, calendar,ovulation, symptothermal, post-ovulation methods] and withdrawal are notacceptable methods of contraception)

• Voluntary written consent must be given before performance of any study relatedprocedure not part of standard medical care, with the understanding that consent maybe withdrawn by the patient at any time without prejudice to future medical care

Exclusion Criteria:

• Platelet count of < 100 x 10^9/L; platelet transfusions to help patients meeteligibility criteria are not allowed within 3 days before study enrollment

• An absolute neutrophil count of < 1.0 x 10^9/L

• A calculated creatinine clearance of < 30 mL/min using Cockcroft Gault or measuredby 24 hour urine

• Patient has >= grade 3 peripheral neuropathy, or grade 2 with pain on clinicalexamination during the screening period

• Total bilirubin >= 1.5 x the upper limit of the normal range (ULN)

• Known allergy to any of the study medications, their analogues, or excipients in thevarious formulations of any agent

• Female subject is pregnant or breast-feeding

• Confirmation that the subject is not pregnant must be established by a negativeserum beta-human chorionic gonadotropin (beta-hCG) pregnancy test (unless thereis reasonable certainty that beta-hCG is coming from the tumor); pregnancytesting is not required for post-menopausal or surgically sterilized women

• Participation in other clinical trials with investigational agents not included inthis trial, within 30 days of the start of this trial and throughout the duration ofthis trial

• Patients with significant atherosclerotic disease, as defined by:

• Myocardial infarction within 6 months prior to enrollment or has New York HeartAssociation (NYHA) class III or IV heart failure uncontrolled angina, severeuncontrolled ventricular arrhythmias, or electrocardiographic evidence of acuteischemia or active conduction system abnormalities

• Symptomatic congestive heart failure

• Claudication limiting activity and

• History of cerebrovascular events within the last year (including transientischemic attack [TIA])

• Unstable angina

• Patients with known active brain metastases; (subjects with previously treated brainmetastases are eligible provided they are stable [defined as without evidence ofprogression by imaging for at least four weeks prior to the first dose of trialtreatment] and neurologic symptoms have returned to baseline)

• Radiotherapy within 28 days before enrollment; if the involved field is small, 14days will be considered a sufficient interval between treatment and administrationof the therapy

• Diagnosed or treated for another malignancy within 2 years before study enrollmentor previously diagnosed with another malignancy and have any evidence of residualdisease; patients with pathologically confirmed completely resected prostate cancerno higher than stage pT2a and no biochemical relapse, or pT2c tumors involving lessthan 5% of the prostate and no biochemical relapse, nonmelanoma skin cancer orcarcinoma in situ of any type are not excluded if they have undergone completeresection

• Systemic treatment, within 14 days before the first dose of ixazomib, with stronginhibitors of cytochrome P450, family 1, subfamily A, polypeptide 2 (CYP1A2) (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of cytochrome P450, family 3, subfamily A (CYP3A) (clarithromycin, telithromycin, itraconazole, voriconazole,ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin,rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgobiloba or St. John's wort

• Failure to have fully recovered (ie, =< grade 1 toxicity) from the reversibleeffects of prior chemotherapy

• Major surgery within 14 days before enrollment; the PI will serve as the finalarbiter as to what constitutes major surgery

• Infection requiring current intravenous antibiotic therapy; the PI will serve as thefinal arbiter regarding eligibility

• Ongoing or active systemic infection, known active hepatitis B or C virus infection,or known human immunodeficiency virus (HIV) positive

• Any serious medical or psychiatric illness that could, in the investigator'sopinion, potentially interfere with the completion of treatment according to thisprotocol

• Known gastrointestinal (GI) disease or GI procedure that could interfere with theoral absorption or tolerance of ixazomib including difficulty swallowing; patientswho have had cystectomy with conduit, neobladder, or pouch using a portion of theirterminal ileum are allowed if, the patient is stable without clinically significantmetabolic disturbances OR stoma- and/or anastomosis-related complications ORpost-surgical gut abnormalities that would compromise drug absorption