Ixazomib, Mitoxantrone Hydrochloride, Etoposide, and Intermediate-Dose Cytarabine in Relapsed or Refractory Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and the
recommended Phase 2 dose of MLN9708 (ixazomib) in combination with mitoxantrone
hydrochloride, etoposide, intermediate-dose cytarabine (MEC) in patients with relapsed/
refractory acute myeloid leukemia (AML).

SECONDARY OBJECTIVES:

I. To describe the non-dose limiting toxicities associated with MLN9708 in combination with
MEC in patients with relapsed/ refractory AML.

II. To describe any preliminary evidence of clinical activity of this combination (compete
response [CR] rate) in relapsed/ refractory AML.

III. To determine the median cluster of differentiation (CD)74 antigen expression in patients
achieving a response versus those patients not achieving a response.

IV. To determine if gene expression profile pre- and post-treatment correlates with response
to therapy.

OUTLINE: This is a dose-escalation study of ixazomib.

Patients receive ixazomib orally (PO) on days 1, 4, 8, and 11, mitoxantrone hydrochloride
intravenously (IV), etoposide IV over 1 hour, and intermediate-dose cytarabine IV over 6
hours on days 1-6.

After completion of study treatment, patients are followed up for 4-5 weeks.

Inclusion Criteria:

- 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be withdrawn by the patient at any time without prejudice to future medical care

- 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 [e.g., calendar, ovulation,
symptothermal, post-ovulation methods] and withdrawal are not acceptable methods
of contraception)

- Male patients, even if surgically sterilized (i.e., 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 (e.g., calendar, ovulation,
symptothermal, post-ovulation methods] and withdrawal are not acceptable methods
of contraception)

- Subjects with a prior diagnosis of AML (excluding acute promyelocytic leukemia) based
on World Health Organization Classification who did not achieve complete response (CR)
with their previous therapy or who have relapsed after achieving a complete response
(CR) are eligible; any number of relapses will be eligible.

- Patients must have > 5% blasts in the bone marrow at the time of study enrollment

- Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, 2, or 3

- Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN) within 14 days of
enrollment

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN within
14 days of enrollment

- Calculated creatinine clearance ≥ 30 mL/min within 14 days of enrollment

- Patients with secondary AML, and patients with a prior autologous and allogeneic bone
marrow transplant are eligible

- Patients with an allogeneic transplant must meet the following conditions: the
transplant must have been performed more than 90 days before registration to this
study, the patient must not have ≥ grade 2 acute graft versus host disease (GvHD) or
either moderate or severe limited chronic GvHD, or extensive chronic GvHD of any
severity; the patient must be off all immunosuppression for at least 2 weeks

- Echocardiogram or multi gated acquisition (MUGA) scan demonstrating an ejection
fraction ≥ 45%

Exclusion Criteria:

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

- Failure to have fully recovered (i.e., ≤ grade 1 toxicity) from the reversible effects
of prior chemotherapy, excluding alopecia

- 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 the
MLN9708

- Central nervous system involvement; a lumbar puncture does not need to be performed
unless there is clinical suspicion of leptomeningeal disease

- Uncontrolled infections

- Evidence of current uncontrolled cardiovascular conditions, including uncontrolled
hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure,
unstable angina, or myocardial infarction within the past 6 months

- Systemic treatment, within 3 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

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

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

- Patients with prior malignancy are eligible; however, the patient must be in remission
from the prior malignancy and have completed all chemotherapy and radiotherapy at
least 6 months prior to registration and all treatment-related toxicities must have
resolved; patients with basal cell or squamous cell carcinoma of the skin are eligible
regardless of disease status

- Patient has ≥ grade 2 peripheral neuropathy within 14 days of trial enrollment

- Participation in other clinical trials, including those with other investigational
agents not included in this trial, within 14 days of the start of this trial and
throughout the duration of this trial

- Any standard therapy for leukemia within 14 days before enrollment (except for hydrea)

- Patients who have received prior pulmonary radiation