This clinical research study is made up of 2 phases.
The goal of Phase 1 of this study is to learn the highest tolerated dose of the combination
of ixazomib, gemcitabine, and doxorubicin that can be given to patients with urothelial
The goal of Phase 2 of this study is to learn if the combination of ixazomib, gemcitabine,
and doxorubicin can help to control urothelial cancer.
The safety of the drug combinations will be studied in both phases.
This is an investigational study. Ixazomib is not FDA approved or commercially available for
the treatment of urothelial cancer. Gemcitabine and doxorubicin are FDA approved and
commercially available for several other types of cancer. Their use in combination with
ixazomib in urothelial cancer is investigational.
The study doctor can explain how the study drugs are designed to work.
Up to 57 participants will be enrolled in this study. All will take part at MD Anderson.
If you are found to be eligible to take part in this study, you will be assigned to a study
group based on when you join this study. Up to 6 groups of up to 4 participants will be
enrolled in Phase 1 of the study, and up to 33 participants will be enrolled in Phase 2.
If you are enrolled in Phase 1, the combination dose of ixazomib, gemcitabine, and
doxorubicin you receive will depend on when you join this study. The first group of
participants will receive the lowest combination dose level. Each new group will receive a
higher dose of the drug combination than the group before it, if no intolerable side effects
were seen. This will continue until the highest tolerable dose of the drug combination is
If you are enrolled in Phase 2, you will receive the drug combination at the highest dose
that was tolerated in Phase 1.
Study Drug Administration:
On Day 1 of every 14-day cycle, you will take ixazomib 1 time by mouth, receive gemcitabine
by vein over about 90 minutes, and receive doxorubicin by vein over 15-30 minutes.
Gemcitabine and doxorubicin may be given through a catheter. A catheter is a sterile flexible
tube that will be placed into a large vein while you are under anesthesia. Your doctor will
explain this procedure to you in more detail, and you will be required to sign a separate
You should not chew, break, or open the capsules of ixazomib. If the capsules break, be
careful not to spread their dust while cleaning it up. The product may be harmful to breathe
in, swallow, or touch. Gloves and protective clothing should be worn during cleanup and
return of broken capsules and powder to minimize skin contact.
The area should be ventilated and the site washed with soap and water after material pick-up
is complete. The material should be disposed of as hazardous medical waste in compliance with
federal, state, and local regulations.
In case of contact with the powder (such as from a broken capsule), skin should be washed
right away with soap and large amounts of water for at least 15 minutes. In case of contact
with the eyes, large amounts of water should be used to flush the eyes for at least 15
minutes. Call the study staff right away if this happens.
On Day 1 of each cycle:
- You will have a physical exam.
- Blood (about 3-4 tablespoons) will be drawn for routine tests.
- Every 3 cycles starting with Cycle 4 (Cycles 4, 7, 10, and so on), you will also have an
x-ray and CT scans or MRIs to check the status of the disease.
On Day 8 of Cycles 1 and 2, blood (about 3-4 tablespoons) will be drawn for routine tests.
If the disease gets worse, you will have either an ECHO or MUGA scan to check your heart
function, if your doctor thinks it is needed.
At any time that the doctor thinks it is needed, you will have a bone scan to check the
status of the disease.
Length of Treatment:
You may continue receiving the study drugs for as long as the doctor thinks it is in your
best interest. You may no longer be able to take the study drugs if the disease gets worse,
if intolerable side effects occur, or if you are unable to follow study directions.
1. 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 PI will serve as the final arbiter of
2. 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 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.
3. 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.
4. 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).
5. 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.
6. 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 MUGA, ECHO, stress test, or
ventriculography) of at least 45%.
7. Have preserved hepatic function as shown by alanine aminotransferase (ALT) and AST
(SGOT) levels </= 3 x the upper limit of normal.
8. 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
(ex: perineal pain impacting their ability to sit or ambulate, etc.)
9. Male or Female patients 18 years or older who: a) Are postmenopausal for at least 1
year before the screening visit, OR; b) Are surgically sterile, OR; c) 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 ; d) 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: e) Agree to practice
effective barrier contraception during the entire study treatment period and through
90 days after the last dose of study drug, OR;
10. (Cont. #9) f) 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.)
11. 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.
1. 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.
2. An absolute neutrophil count of < 1.0 x 10^9/L.
3. A calculated creatinine clearance of < 30 mL/min using Cockcroft Gault or measured by
24 hour urine
4. Patient has >/= Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical
examination during the screening period.
5. Total bilirubin >/= 1.5 x the upper limit of the normal range (ULN).
6. Known allergy to any of the study medications, their analogues, or excipients in the
various formulations of any agent.
7. 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.
8. 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
9. Patients with significant atherosclerotic disease, as defined by: a) Myocardial
infarction within 6 months prior to enrollment or has New York Heart Association
(NYHA) Class III or IV heart failure (See Appendix 5) uncontrolled angina, severe
uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
ischemia or active conduction system abnormalities.; b) Symptomatic congestive heart
failure.; c) Claudication limiting activity and ; d) History of cerebrovascular events
within the last year (including TIA).; e) Unstable angina.
10. 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.]
11. 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
12. 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.
13. Systemic treatment, within 14 days before the first dose of ixazomib, with strong
inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of
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.
14. Failure to have fully recovered (ie, </= Grade 1 toxicity) from the reversible effects
of prior chemotherapy.
15. Major surgery within 14 days before enrollment. The PI will serve as the final arbiter
as to what constitutes major surgery.
16. Infection requiring current intravenous antibiotic therapy. The PI will serve as the
final arbiter regarding eligibility.
17. Ongoing or active systemic infection with the following: known active hepatitis B or C
virus infection, or known human immunodeficiency virus (HIV) positive.
18. Any serious medical or psychiatric illness that could, in the investigator's opinion,
potentially interfere with the completion of treatment according to this protocol.
19. Known 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.
20. Patient has >/= Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical
examination during the screening period.