| Eligibility |
Inclusion Criteria:
- Male or female patients 60 years or older.
- 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be withdrawn by the patient at any time without prejudice to future medical care.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 [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 (e.g., calendar, ovulation,
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods
of contraception.]
- Patients must have a diagnosis of AML according to the World Health Organization (WHO)
criteria. Therapy-related and secondary AML (arising after a period of myelodysplasia
[MDS]) allowed. Prior treatment for MDS with hypomethylator-based therapy and
lenalidomide allowed, but not allowed if used after the diagnosis of AML is made,
since enrollment to this study is not for relapsed AML.
- Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance
status 0, 1, or 2. Performance status of 3 permissible if related to disease.
- Patients must meet the following clinical laboratory criteria:
- Total bilirubin = 1.5 x the upper limit of the normal range (ULN) unless related
to disease or patient known to have underlying Gilbert's disease.
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) = 3 ULN.
- Calculated creatinine clearance = 30 mL/min (see Section 12.2).
Exclusion Criteria:
- Female patients who are lactating or have a positive serum pregnancy test during the
screening period.
- Failure to have fully recovered (ie, =Grade 1 toxicity) from the reversible effects of
prior chemotherapy as stated in Section 5.1.4.
- 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.
- Suspected AML-related central nervous system involvement. A lumbar puncture (LP) is
not required to exclude central nervous system (CNS) disease.
- 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.
- Ongoing or active systemic infection, 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.
- 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 non-melanoma skin cancer or carcinoma in situ of any type are
not excluded if they have undergone complete resection.
- Patient has = Grade 1 neuropathy, sensory, with or without pain, motor, or autonomic,
on clinical examination during the screening period.
- Participation in other clinical trials involving investigational agents within 21 days
of the start of this trial and throughout the duration of this trial.
- Prior chemotherapy treatment for AML (Prior treatment with hydroxyurea and/or
leukapheresis to control white blood cell count acceptable). Prior chemotherapy for
MDS or myeloproliferative neoplasms (MPN) such as azacitidine, decitabine, and
thalidomide, is permitted, but such treatments once MDS or MPN has transformed to AML
is not permitted.
- Acute promyelocytic leukemia(APL) by WHO criteria [AML with t(15;17)]
- Cardiac ejection fraction (EF) < 40%
- Systemic treatment, during or within 48 hours of the first dose of MLN9708, 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.
The washout period will be extended to 2 days if patients are receiving extended
release ciprofloxacin. For this protocol prophylactic antibiotics are not recommended,
at least not until 48 hours after the last dose of study drug (given on Day 12), when
the patient may be neutropenic. For patients with fever and/or infections, cefepime
and ambisome are acceptable.
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