Ixazomib (MLN9708) in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

PRIMARY OBJECTIVE:

Determine the best response including complete remission (CR), CR with incomplete recovery
(CRi), and partial remission (PR) after 3 cycles of treatment with MLN9708 (ixazomib) in
participants with nucleophosmin (NPM)1-mutated acute myeloid leukemia (AML) (following the
LeukemiaNet1 guidelines for response criteria).

SECONDARY OBJECTIVES:

- Determine the duration of remission in all responders after treatment with MLN9708
defined as the time of documented remission until relapse.

- Determine the 1 year overall survival, which will be measured from time of study entry
to the earlier of death from any cause or end of follow up at 1 year.

- Establish toxicity and tolerability of MLN9708 treatment in AML, including
non-hematologic toxicities grade 3 or above as specified by Common Terminology Criteria
for Adverse Events (CTCAE) version 4.0.

OUTLINE:

Participants receive ixazomib orally (PO) on days 1, 4, 8, and 11. Treatment repeats every 21
days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Inclusion Criteria:

- Diagnosis of relapsed or refractory AML of any French American British (FAB) subtype
except M3 and NPM1 genetic mutation detected by molecular assay; AML patients treated
at Stanford have NPM1 molecular mutation status checked routinely at time of diagnosis
in a Clinical Laboratory Improvement Amendment (CLIA)-certified laboratory

- Male or female patients and no race-ethnic restrictions

- Patients are unwilling, or who are determined to be medically unfit for or resistant
to standard intensive induction chemotherapy; patients who are medically unfit will be
determined by the treating primary hematologist and the principal investigator
(including but not limited to evaluation of co-morbidities, and response and
complications to previous AML treatment strategy)

- Eastern Cooperative Oncology Group (ECOG) 0 to 2

- Ability to understand and the willingness to sign a written informed consent document

- Female 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, AND

- Must also adhere to the guidelines of any treatment-specific pregnancy prevention
program, if applicable, 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

- Must also adhere to the guidelines of any treatment-specific pregnancy prevention
program, if applicable, 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)

- Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN

- Calculated creatinine clearance ≥ 30 mL/min

Exclusion Criteria:

- Female patient who are lactating or have a positive serum pregnancy test during the
screening period

- Major surgery within 14 days before enrollment

- Radiotherapy within 14 days before enrollment; if the involved field is small, 7 days
will be considered a sufficient interval between treatment and administration of
MLN9708

- Known active and uncontrolled central nervous system (CNS) involvement of leukemia (a
lumbar puncture does not need to be performed as a part of screening)

- Have a significant uncontrolled infection active infection

- Have other severe concurrent disease or serious organ dysfunction involving the heart,
kidney, liver or other organ system that may place the patient at undue risk to
undergo treatment including uncontrolled hypertension, uncontrolled cardiac
arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial
infarction within the past 6 months

- Systemic treatment, within 14 days before the first dose of MLN9708, 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

- Known ongoing or active systemic infection, active hepatitis B or C virus infection,
or known human immunodeficiency virus (HIV) positive

- Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral
absorption or tolerance of MLN9708 including difficulty

- 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; this does not preclude
previous diagnosis of acute myeloid leukemia or myelodysplastic syndrome

- Patient has ≥ grade 3 peripheral neuropathy, or grade 2 with pain on clinical
examination during the screening

- Participation in other clinical trials, including those with other investigational
agents not included in this trial, within 21 days of the start of this trial and
throughout the duration of this trial

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