The investigators hypothesize that the combination of Pevonedistat/Low-Dose Cytarabine (LDAC)
therapy will be tolerable, that a recommended phase 2 dose of Pevonedistat in combination
with LDAC will be identified, and that the combination therapy will show evidence of clinical
activity in adult patients with Relapsed/Refractory Acute Myelogenous Leukemia (AML) and
Advanced Myelodysplastic Syndromes (MDS).
This is a phase 1, dose escalation study of PEVONEDISTAT (formerly MLN4924) in combination
with fixed doses of low dose Cytarabine (LDAC) utilizing a traditional 3+3 design. Eligible
patients will be enrolled in cohorts of three starting at Dose Level 1. Dose escalation will
proceed provided that:
1. All patients enrolled on the previous cohort have completed the first cycle of treatment
2. The number of patients who experience dose limiting toxicity (DLT) is within the
appropriate guidelines (i.e., 0 out of 3; 1 out of 6).
3. Dose levels for escalation/de-escalation:
- Dose Level -1: Pevonedistat 10 mg/m2, LDAC 20 mg/m2
- Dose Level 1 (starting dose): Pevonedistat 15mg/m2, LDAC 20 mg/m2
- Dose Level 2: Pevonedistat 20 mg/m2, LDAC 20 mg/m2
- Dose Level 3: Pevonedistat 25 mg/m2, LDAC 20 mg/m2
A more conservative dose-escalation, with evaluation of intermediate doses and/or expansion
of an existing dose level, is permissible if such measures are needed for patient safety or
for a better understanding of Pevonedistat dose-related toxicity, exposure, or
pharmacodynamics. Such changes will be discussed among the protocol investigators and will be
approved by the appropriate regulatory agencies.
Up to 16 cycles of 28 days are planned. If patients are receiving clinical benefit, treatment
can continue beyond 16 cycles.
Patients will be followed for a minimum of 30 days after the last dose of Pevonedistat/LDAC
combination therapy. After this 30 day period, patients will be followed only for the
resolution of any ongoing adverse events. Resolution is defined as a return to baseline
status or the stabilization of an event with the expectation that it will remain chronic. Any
follow-up visit scheduled after this 30 day period will be done at the discretion of the
Principal Investigator (PI) or treating physician.
A. Confirmed diagnosis of one of the following:
1. Relapsed/refractory Acute Myelogenous Leukemia (AML) where no alternative life
prolonging therapy exists. Treatment naïve patients may also be considered eligible if
in the opinion of the investigator, these patients are unlikely to benefit from
alternative therapy (eg conventional chemotherapy, hypomethylating agents).
2. Relapsed/refractory Myelodysplasic Syndrome (MDS) following at least two courses of a
hypomethylating agent (eg azacitidine or decitabine). Patients intolerant of
hypomethylating agents (irrespective of the number of cycles administered) will also
be considered eligible. MDS eligibility limited to patients with intermediate, high or
very high risk based on IPSS-R.
B. Adult male or female patients 18 years of age or older.
C. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2
D. Patients must satisfy the following laboratory criteria:
1. Albumin > 2.7 g/dL
2. Total bilirubin ≤ upper limit of normal (ULN) except in patients with Gilbert's
syndrome. Patients with Gilbert's syndrome may enroll if direct bilirubin ≤1.5 x ULN
of the direct bilirubin
3. Alanine transaminase (ALT) and Aspartate transaminase (AST) must be ≤ 2.5 × ULN
4. Creatinine 1.5 x ULN or calculated creatinine clearance > 50ml/min
5. Hemoglobin > 8 g/dL (prior red blood cell (RBC) transfusion allowed). Patients may be
transfused to achieve this value. Elevated indirect bilirubin due to post-transfusion
hemolysis is allowed.
6. White blood cell (WBC) count < 50,000/µL before administration of PEVONEDISTAT on
Cycle 1 Day 1. Note: Hydroxyurea may be used to control the level of circulating
leukemic blast cell counts to not lower than 10,000/µL during the study.
E. Suitable venous access to allow for all study related blood sampling (safety and
F. Estimated life expectancy, in the judgment of the Investigator, which will permit
receipt of at least 6 weeks of treatment.
G. 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.
H. Female patients who:
1. Are postmenopausal (see Appendix for definition) for at least 1 year before the
screening visit, OR
2. Are surgically sterile, OR
3. If they are of childbearing potential:
- Agree to practice 1 highly effective method and 1 additional effective (barrier)
method of contraception, at the same time, from the time of signing the informed
consent through 4 months after the last dose of study drug (female and male
condoms should not be used together), 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, postovulation methods] withdrawal, spermicides only, and
lactational amenorrhea are not acceptable methods of contraception).
I. Male patients, even if surgically sterilized (ie, status postvasectomy), who:
1. Agree to practice effective barrier contraception during the entire study treatment
period and through 4 months after the last dose of study drug (female and male condoms
should not be used together), OR
2. 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, postovulation methods for the female partner] withdrawal, spermicides
only, and lactational amenorrhea are not acceptable methods of contraception).
J. Able to undergo bone marrow aspiration at screening.
A. Treatment with clinically significant metabolic enzyme inducers within 14 days before
the first dose of the study drug. Strong CYP3A inhibitors and CYP3A inducers are not
permitted during the study.
B. Therapy with any investigational products, anti-neoplastic therapy, or radiotherapy
within 14 days prior to Cycle 1 Day 1. Patients actively receiving hydroxyurea are eligible
and may continue to receive hydroxyurea during protocol treatment.
C. Candidates for standard and/or potentially curative treatments (a candidate is defined
as a patient that is both eligible and willing to have these treatments)
D. Major surgery within 14 days before the first dose of any study drug or a scheduled
surgery during study period.
E. Grade 2 or higher diarrhea as defined by NCI CTCAE Version 4.03 despite optimal
anti-diarrheal supportive care within 7 days prior to Cycle1 Day1.
F. Known cardiopulmonary disease defined as one of the following:
1. Uncontrolled high blood pressure (ie, systolic blood pressure > 180 mm Hg, diastolic
blood pressure > 95 mm Hg).
2. Cardiomyopathy or history of ischemic heart disease; patients with ischemic heart
disease who have had acute coronary syndrome (ACS), MI, and/or revascularization
greater than 6 months before screening and who are without cardiac symptoms may
3. Clinically significant arrhythmia including:,history of polymorphic ventricular
fibrillation or torsade de pointes); permanent atrial fibrillation [a fib], defined as
a fib for ≥6 months; persistent a fib, defined as sustained afib >7 days and/or
requiring cardioversion in the 4 weeks before screening; Grade 3 a fib defined as
symptomatic and incompletely controlled medically, or controlled with device (e.g.,
pacemaker), or ablation. Patients with paroxysmal a fib are permitted to enroll.
However, patients with < Grade 3 atrial fibrillation (a fib) for a period of at least
6 months may enroll provided that their rate is controlled on a stable regimen.
4. Implantable cardioverter defibrillator;
5. Congestive heart failure (New York Heart Association (NYHA) Class III or IV; or Class
II with a recent decompensation requiring hospitalization or referral to a heart
failure clinic within 4 weeks before screening), myocardial infarction and/or
revascularization (eg, coronary artery bypass graft, stent) within 6 months of first
dose of study drug.
6. Moderate to severe aortic and/or mitral stenosis or other valvulopathy (ongoing);
7. Pulmonary hypertension.
8. Patients with Grade 2 or higher prolonged rate corrected QT (QTc) interval (≥
481msec), calculated according to institutional guidelines.
9. Left ventricular ejection fraction (LVEF) < 50% as assessed by echocardiogram or
radionuclide angiography - LVEF assessment is not required for screening, and will
only be done at the investigators discretion if clinically indicated..
10. Known moderate to severe chronic obstructive pulmonary disease (COPD), interstitial
lung disease, and pulmonary fibrosis.
G. Active uncontrolled infection or severe infectious disease, such as severe pneumonia,
meningitis, or septicemia.
H. Known human immunodeficiency virus (HIV) seropositive.
I. Known hepatitis B surface antigen seropositive (Note: Patients who have isolated
positive hepatitis B core antibody (ie, in the setting of negative hepatitis B surface
antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B
viral load. Patients who have positive hepatitis C antibody may be included if they have an
undetectable hepatitis C viral load.)
J. Known or suspected active hepatitis C infections (Patients who are hepatitis C surface
antigen-positive are eligible).
K. Females of child bearing potential who refuse to either practice 2 effective methods of
contraception at the same time or abstain from heterosexual intercourse from the time of
signing the informed consent through 30 days after the last dose of study drug.
L. Males of child bearing potential who refuse to practice effective barrier contraception
during the entire study treatment period and through 4 months after the last dose of study
drug. (Includes males surgically sterilized - i.e. status post vasectomy).
M. Female patients who are both lactating and breastfeeding or have a positive serum
pregnancy test during the screening period or a positive urine pregnancy test on Day 1
before first dose of study drug.
N. Female patients who intend to donate eggs (ova) during the course of this study or 4
months after receiving their last dose of study drug(s).
O. Male patients who intend to donate sperm during the course of this study or 4 months
after receiving their last dose of study drug(s).
P. Any serious medical or psychiatric illness that could, in the investigator's opinion,
potentially interfere with the completion of study procedures.
Q. Symptomatic central nervous system (CNS) involvement.
R. Diagnosed or treated for another malignancy within 2 years before randomization 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 resection.
S. Known hepatic cirrhosis or severe pre-existing hepatic impairment.
T. Systemic anti-neoplastic therapy or radiotherapy within 14 days before the first dose of
any study drug, except for hydroxyurea.
U. Patients with uncontrolled coagulopathy or bleeding disorder.
V. Life-threatening illness unrelated to cancer.