| Eligibility |
Inclusion Criteria:
- All patients must have histologic demonstration of metastatic or locally unresectable
transitional cell carcinoma of the urothelium; variant histology is allowed as long as
there is an urothelial component present; the principal investigator (PI), will serve
as the final arbiter of eligibility
- All patients must have measurable or evaluable disease; in general, liver and lung
lesions should be at least 1 cm, and patients with node-only disease should have
lesions of >= 1.5 cm in greatest dimension; patients with disease confined to bone may
be eligible if a measurable lytic defect is present or a serum marker is elevated (> 4
x upper limit of normal [ULN]); the principal investigator is the final arbiter in
questions related to measurability; patients with a three-dimensional mass or pelvic
sidewall fixation on bladder examination under anesthesia are considered to have
measurable disease
- Patients must have had at least one prior therapy to be eligible for either phase I or
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 what
those regimens contained (i.e. prior bortezomib or combination gemcitabine and
adriamycin is acceptable)
- Phase II: patients are eligible if their previous chemotherapy regimen did not contain
bortezomib, carfilzomib, or other known proteasome inhibitor or a combination of
gemcitabine >= 800 mg/m^2 plus adriamycin >= 30 mg/m^2; patients who receive
sequential or alternating therapy as part of front-line treatment will be counted as
having one prior regimen; patients who have failed prior neoadjuvant chemotherapy 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 acquisition scan
[MUGA], echocardiogram [ECHO], stress test, or ventriculography) of at least 45%
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (serum glutamic
oxaloacetic transaminase [SGOT]) levels =< 3 x the upper limit of normal
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) =< 2; patients with
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 their ability 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 of
contraception, at the same time, from the time of signing the informed consent
form through 90 days after the last dose of study drug, OR
- Agree to practice true abstinence when this is in line with the preferred and
usual lifestyle of the subject; (periodic abstinence [eg, calendar, ovulation,
symptothermal, post-ovulation methods] and withdrawal are not acceptable methods
of contraception)
- Male patients, even if surgically sterilized (ie, status post-vasectomy), must
agree to one of the following:
- Agree to practice effective barrier contraception during the entire study
treatment 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 preferred
and usual lifestyle of the subject; (periodic abstinence [eg, calendar,
ovulation, symptothermal, post-ovulation methods] and withdrawal are not
acceptable methods of contraception)
- Voluntary written consent must be given before performance of any study related
procedure not part of standard medical care, with the understanding that consent may
be 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 meet
eligibility 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 measured by
24 hour urine
- Patient has >= grade 3 peripheral neuropathy, or grade 2 with pain on clinical
examination 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 the
various formulations of any agent
- Female subject is pregnant or breast-feeding
- Confirmation that the subject is not pregnant must be established by a negative
serum beta-human chorionic gonadotropin (beta-hCG) pregnancy test (unless there
is reasonable certainty that beta-hCG is coming from the tumor); pregnancy
testing is not required for post-menopausal or surgically sterilized women
- Participation in other clinical trials with investigational agents not included in
this trial, within 30 days of the start of this trial and throughout the duration of
this trial
- Patients with significant atherosclerotic disease, as defined by:
- Myocardial infarction within 6 months prior to enrollment or has New York Heart
Association (NYHA) class III or IV heart failure uncontrolled angina, severe
uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
ischemia or active conduction system abnormalities
- Symptomatic congestive heart failure
- Claudication limiting activity and
- History of cerebrovascular events within the last year (including transient
ischemic attack [TIA])
- Unstable angina
- Patients with known active brain metastases; (subjects with previously treated brain
metastases are eligible provided they are stable [defined as without evidence of
progression by imaging for at least four weeks prior to the first dose of trial
treatment] and neurologic symptoms have returned to baseline)
- Radiotherapy within 28 days before enrollment; if the involved field is small, 14 days
will be considered a sufficient interval between treatment and administration of the
therapy
- Diagnosed or treated for another malignancy within 2 years before study enrollment or
previously diagnosed with another malignancy and have any evidence of residual
disease; patients with pathologically confirmed completely resected prostate cancer no
higher than stage pT2a and no biochemical relapse, or pT2c tumors involving less than
5% of the prostate and no biochemical relapse, nonmelanoma skin cancer or carcinoma in
situ of any type are not excluded if they have undergone complete resection
- Systemic treatment, within 14 days before the first dose of ixazomib, with strong
inhibitors 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 Ginkgo
biloba or St. John's wort
- Failure to have fully recovered (ie, =< grade 1 toxicity) from the reversible effects
of prior chemotherapy
- Major surgery within 14 days before enrollment; the PI will serve as the final arbiter
as to what constitutes major surgery
- Infection requiring current intravenous antibiotic therapy; the PI will serve as the
final 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's opinion,
potentially interfere with the completion of treatment according to this protocol
- Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral
absorption or tolerance of ixazomib including difficulty swallowing; patients who have
had cystectomy with conduit, neobladder, or pouch using a portion of their terminal
ileum are allowed if, the patient is stable without clinically significant metabolic
disturbances OR stoma- and/or anastomosis-related complications OR post-surgical gut
abnormalities that would compromise drug absorption
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