Any time the words "you," "your," "I," or "me" appear, it is meant to apply to the potential
The goal of this clinical research study is to learn if the combination of ixazomib,
gemcitabine, and doxorubicin can help to control renal medullary carcinoma (RMC).
This is an investigational study. Ixazomib is FDA approved and commercially available for the
treatment of multiple myeloma. Gemcitabine and doxorubicin are FDA approved and commercially
available for several other types of cancer such as urothelial or bladder cancer. It is
considered investigational to use ixazomib, gemcitabine, and doxorubicin to treat RMC.
The study doctor can explain how the study drugs are designed to work.
Up to 30 participants will be enrolled in this study. All will take part at MD Anderson
Study Drug Administration:
Each cycle is 14 days. Treatment will be given in 2 phases: Induction (Cycles 1-13) and
Maintenance (Cycles 14 and beyond).
On Day 1 of each cycle during Induction, you will take ixazomib 1 time by mouth, receive
gemcitabine by vein over about 90 minutes, and receive doxorubicin by vein over 15-30
On Day 1 of each cycle during Maintenance, you will take ixazomib 1 time by mouth and receive
gemcitabine by vein over about 90 minutes. You will not receive doxorubicin.
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 shallow capsules whole, with water, and not chew, break, or open the capsules of
ixazomib. Ixazomib should be taken on an empty stomach (no food or drink) at least 1 hour
before or at least 2 hours after food. Each capsule should be swallowed separately with about
8 ounces (1 cup) of water.
After 13 cycles, if the tumor in your kidney is still present and the doctor thinks it is
safe to do so, you will have surgery to remove as much of the tumor as possible. You will
sign a separate consent form for this surgery which describes the procedure and risks in more
After 13 cycles and/or surgery (if you have it), you may continue to receive the study drugs
for up to 2 years.
Length of Study:
You may receive the study drugs for up to 2 years, as long as the study doctor thinks it is
in your best interest. You will not 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
Your participation on the study will be over after the follow-up visits.
On Day 1 of each cycle:
- You will have a physical exam. vBlood (about 5 teaspoons) will be drawn for routine
testing. During Cycles 1 and 2, you will have these blood draws performed 1 time every
- You will have an EKG and ECHO (Cycles 6 and 13). This may be repeated if the doctor
thinks it is needed.
At Weeks 6, 12, and then every 8 weeks after that (Weeks 20, 28, 36 and so on) during Year 1
and then every 12 weeks after that:
- If the doctor thinks it is needed, you will have an MRI, CT scan, skeletal survey, or
bone scan to check the status of the disease.
- Blood (about 1 teaspoon) and will be drawn for routine testing.
About 30 and 90 days after your last dose of study drug(s):
- You will have a physical exam.
- You will have CT scan of the chest/abdomen or an MRI of abdomen/ pelvis
- If the doctor thinks it is needed and depending on why you stopped taking the study
drug(s), you will have an MRI, CT scan, skeletal survey, or bone scan to check the
status of the disease.
You will be called by a member of the study staff every 3 months to ask how you are doing and
if you have started any new anti-cancer treatments. This information may be collected from
your medical record instead. If called, this phone call should take about 5-10 minutes. These
calls will stop if the disease gets worse or you start a new anti-cancer therapy.
1. Patients with locally advanced or metastatic RMC histologically confirmed by expert
pathology review and loss of SMARCB1 staining by immunohistochemistry. Also eligible
are patients with other rare SMARCB1-negative tumors of the kidney, such as advanced
or metastatic unclassified renal cell carcinoma with medullary phenotype (a rare RMC
variant occurring in individuals without sickle hemoglobinopathies), and adult-onset
malignant rhabdoid tumors. The Principal Investigator (PI) is the final arbiter in
questions related to eligibility.
2. Patients will be eligible regardless of whether they have had prior nephrectomy or
still have their primary tumor in-situ. Patients with prior nephrectomy can be
screened for enrollment at any time following the procedure.
3. Patients must have at least one measurable site of disease, defined as a lesion that
can be accurately measured in at least one dimension (longest diameter to be recorded)
and measures >/=15 mm with conventional techniques or >/= 10 mm with more sensitive
techniques such as MRI or spiral CT scan. If the patient has had previous radiation to
the marker lesion(s), there must be evidence of progression since the radiation.
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 PI is the final arbiter in
questions related to measurability.
4. Patients can have received prior immunotherapies such as anti-PD1, anti-PD-L1, or
anti-CTLA-4 immune checkpoint inhibitors, or targeted therapies such as sunitinib,
pazopanib, axitinib, cabozantinib, bevacizumab, erlotinib, and everolimus, or any
cytotoxic chemotherapy regimens with the exception of regimens using a combination of
gemcitabine >/= 800 mg/m² plus adriamycin >/= 30 mg/m². In addition, the total
lifetime doe of doxorubicin prior to enrollment must not exceed 382 mg/m² as these
would preclude patients from receiving at least 4 cycles of induction therapy of the
trial protocol. Patients must not have received any proteasome inhibitors such as
bortezomib or carfilzomib.
5. There must be evidence of progression on or after last treatment regimen received.
6. ECOG performance status 0-2. NOTE: If subject is unable to walk due to paralysis, but
is mobile in a wheelchair, subject is considered to be ambulatory for the purpose of
assessing their performance status.
7. Age (at the time of consent/assent): >/=12 years. Adolescent patients age 12 years and
older are allowed with signed assent and parental consent according to institutional
guidelines and requirements, as long as their BSA is >/=1.2 given that this is the
lower limit for which the independence between BSA and ixazomib exposure has been
8. Within 14 days of the first dose of the study drugs, patients must have adequate organ
and marrow function prior to study entry as defined below: Hemoglobin ^a >/=9 g/dl
(treatment allowed); Absolute neutrophil count^b >/= 1000/µL; 3) Platelets ^c
>/=75,000/µL; Total Bilirubin ^d </=1.5 mg/dl; AST(SGOT) or ALT (SGPT) </=2.5 X
institutional ULN, except in known hepatic metastasis, wherein may be </=5 x ULN^e as
per current American Society of Clinical Oncology recommendations^45- Creatinine
clearance^f >30 mL/kg/1.73 m^2
9. CONTINUE FROM 8: ^aMay receive transfusion; ^b Without growth factor support
(filgrastim or pegfilgrastim) for at least 14 days; ^c.Platelet transfusions to help
patients meet eligibility criteria are not allowed within 3 days before study
enrollment.^d For patients with Gilbert's disease, total bilirubin should be </= 3
mg/dL (</= 51.3 µmol/L). ^e Approximately 15% of patients with RMC develop liver
metastases ^1 ^f If creatinine is not <1.5×ULN, then calculate by Cockcroft-Gault
methods or local institutional standard.
10. INR and PTT </=1.5 x ULN prior to study entry. Therapeutic anticoagulation with
warfarin is allowed if target INR </=3 on a stable dose of warfarin or other oral
anticoagulant, or on a stable dose of low molecular weight (LMW) heparin for > 2 weeks
(14 days) at the time of enrollment.Patients who have liver metastases resulting in
INR and/or PTT >1.5 x ULN and require chronic (>/=3 months) anticoagulation are not
11. Patients must have a measured ejection fraction of at least 45% as measured by either
multigated acquisition (MUGA) scan, echocardiogram, stress test, or ventriculography.
12. Patients with controlled brain metastases are allowed on protocol if they had solitary
brain metastases that was surgically resected or treated with radiosurgery or Gamma
knife, without recurrence or edema for 1 month (4 weeks).
13. Female patients who: a.Are postmenopausal for at least 1 year before the screening
visit, OR b.Are surgically sterile, OR c.Women of childbearing potential (WOCBP) must
have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or
equivalent units of HCG) within 24 hours prior to the start of the study drug.
14. Women must not be breastfeeding.
15. WOCBP must agree to practice 2 effective method(s) of contraception, at the same time,
from the time of enrollment for the duration of treatment with study drug (s) plus 5
half-lives of study drug (s) plus 30 days (duration of ovulatory cycle) for a total of
5 months post treatment completion, 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. a.Complete abstinence is defined as complete
avoidance of heterosexual intercourse and is an acceptable form of contraception for
all study drugs.
16. inclusion14 continued) Abstinence is only acceptable when this is in line with the
preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar,
ovulation, symptothermal, profession of abstinence for entry into a clinical trial,
post-ovulation methods) and withdrawal are not acceptable methods of contraception.
Subjects who choose complete abstinence are not required to use a second method of
contraception, but female subjects must continue to have pregnancy tests. Acceptable
alternate methods of highly effective contraception must be discussed in the event
that the subject chooses to forego complete abstinence.
17. Men who are sexually active with WOCBP, even if surgically sterilized (ie, status
post-vasectomy), must agree to follow instructions for method(s) of contraception for
the duration of treatment with study drug (s) plus 5 half-lives of study drug (s) plus
90 days duration of sperm turnover) for a total of 5 months post-treatment completion.
18. Azoospermic males and WOCBP who are continuously not heterosexually active are exempt
from contraceptive requirements. However WOCBP must still undergo pregnancy testing as
described in these sections.
1. Patients 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 nonmelanoma skin cancer or carcinoma in situ of any
type are not excluded if they have undergone complete resection. Patients with another
malignancy on watch and wait without any needing of treatment can be enrolled in this
2. Patients must not have received anticancer therapies (including chemotherapy and
targeted therapy) within 2 weeks (14 days) or 5 half-lives (whichever is shorter)
prior to study Day 1. Patients who have completed palliative radiation therapy more
than 14 days prior to study Day 1 are eligible. If the involved field is small, 7 days
will be considered a sufficient interval between treatment and administration of the
3. Patients, who have had a major surgery or significant traumatic injury (injury
requiring > 4 weeks (28 days) to heal) within 4 weeks (28 days) of start of study
drug, patients who have not recovered from the side effects of any major surgery
(defined as requiring general anesthesia) or patients that are expected to require
major surgery, other than cytoreductive nephrectomy ± retroperitoneal lymph node
dissection, during the course of the study.
4. Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS).
5. Positive test for hepatitis B virus (HBV) using HBV surface antigen (HBVsAg) test
(regardless of HBV DNA levels or IgM anti-HBc status) or positive test for hepatitis C
virus (HCV) using HCV ribonucleic acid (RNA) or HCV antibody test indicating acute or
chronic infection. If hepatitis C antibody test is positive then active infection has
to be confirmed by hepatitis C RNA testing for the patient to be excluded.
6. Patient has>/=Grade 3 peripheral neuropathy, or Grade 2 peripheral neuropathy with
pain on clinical examination during the screening period.
7. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral
absorption or tolerance of ixazomib, including difficulty swallowing, refractory
nausea and vomiting, uncontrolled diarrhea, malabsorption, significant small bowel
resection or gastric bypass surgery, use of feeding tubes. The PI is the final arbiter
in questions related to eligibility
8. Systemic treatment, within 14 days before the first dose of ixazomib, with strong
CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin,
phenobarbital), or use of St. John's wort.
9. Patients receiving any concomitant systemic therapy for renal cell cancer are
10. Participation in other clinical trials, including those with other investigational
agents not included in this trial, within 30 days of the start of this trial and
throughout the duration of this trial.
11. Patients who have any severe and/or uncontrolled medical conditions or other
conditions that could affect their participation in the study such as: a.Symptomatic
congestive heart failure of New York heart Association Class III or IV. b.Unstable
angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6
months of start of study drug, serious uncontrolled cardiac arrhythmia or any other
clinically significant cardiac disease. c.Severely impaired lung function as defined
as 02 saturation that is 92% or less at rest on room air. d.Uncontrolled diabetes as
defined by fasting serum glucose >1.5 x ULN. e.Systemic fungal, bacterial, viral, or
other infection that is not controlled (defined as exhibiting ongoing signs/symptoms
related to the infection and without improvement) despite appropriate antibiotics or
other treatment. f.Known active or symptomatic viral hepatitis or chronic liver
disease. Uncontrolled adrenal insufficiency.
12. Patients must not have history of other diseases, metabolic dysfunction, physical
examination finding, or clinical laboratory finding giving reasonable suspicion of a
disease or condition that contraindicates the use of ixazomib, gemcitabine, or
doxorubicin, or that might affect the interpretation of the results of the study or
render the subject at high risk from treatment complications
13. Uncontrolled brain or leptomeningeal metastases, including patients who continue to
require glucocorticoids for brain or leptomeningeal metastases.
14. Female patients who are pregnant or breast feeding, or adults of reproductive
potential who are not using effective birth control methods as defined above. If
barrier contraceptives are being used, these must be continued throughout the trial by
both sexes. Hormonal contraceptives are not acceptable as a sole method of
15. Failure to have fully recovered (ie, </=Grade 1 toxicity) from the reversible effects
of prior chemotherapy.
16. Known allergy to any of the study medications, their analogues, or excipients in the
various formulations of any agent.