Azacitidine, Venetoclax, and Pevonedistat in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To determine the maximum-tolerated dose (MTD) of venetoclax in combination with
azacitidine and pevonedistat in patients with previously untreated secondary acute myeloid
leukemia (AML). (Phase I) II. To determine the efficacy of the combination regimen, as
defined by the rate of complete response (CR) plus complete response with incomplete bone
marrow recovery (CRi) within 6 cycles of treatment. (Phase II)

SECONDARY OBJECTIVES:

I. To determine efficacy outcomes, including leukemia response rate (CR + CRi + partial
response [PR] + morphologic leukemia free state [MLFS]), minimal residual disease (MRD)
negativity by flow cytometry, duration of response, relapse-free survival (RFS), event-free
survival (EFS) and overall survival (OS).

II. To determine the safety of the combination regimen.

OUTLINE: This is a phase I, dose-escalation study of venetoclax followed by a phase II study.

Patients receive venetoclax orally (PO) once daily (QD) on days 1-28, azacitidine
intravenously (IV) or subcutaneously (SC) on days 1-7, and pevonedistat IV over 60 minutes on
days 1, 3, and 5. Treatment repeats every 28 days for up to 24 cycles in the absence of
disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then every 6
months thereafter.

Inclusion Criteria:

- Deemed by the treating physician not to be eligible for intensive chemotherapy

- Patients must have a new diagnosis (i.e., no prior therapy for AML) of AML per World
Health Organization (WHO) 2016 criteria and any one of the following: a) A history of
myelodysplastic syndrome (MDS); b) A history of a myeloproliferative neoplasm (MPN)
including polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis (MF,
whether primary [pre-fibrotic or overt] or post-polycythemia vera [PV]/essential [E]),
chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia (CEL),
MPN-unclassifiable (MPN-U) or myeloid neoplasm with a rearrangement of PDGFRA, PDGFRB
or FGFR1; c) A history of MDS/MPN such as chronic myelomonocytic leukemia (CMML),
MDS/MPN-unclassifiable (MDS/MPN-U), MDS/MPN with ringed sideroblasts and
thrombocytosis (MDS/MPN-RS-T) or atypical chronic myeloid leukemia (aCML), BCR-ABL
negative; d) An MDS-related cytogenetic abnormality other than del9q; e) The presence
of dysplasia in >= 50% cells in >= 2 myeloid lineages, unless accompanied by mutant
NPM1 or biallelic CEBPA mutations; f) Exposure to prior chemotherapy or radiation
therapy for another malignancy

- Eastern Cooperative Oncology Group (ECOG) performance status from 0-2

- Total bilirubin =< upper limit of normal (ULN) except in patients with Gilbert's
syndrome or if elevation is attributed to underlying leukemia. Patients with Gilbert's
syndrome or with elevated bilirubin attributed to underlying leukemia may enroll if
direct bilirubin =< 1.5 x ULN of the direct bilirubin (repeat if more than 3 days
before the first dose)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN
(repeat if more than 3 days before the first dose)

- Creatinine clearance >= 40 mL/min (repeat if more than 3 days before the first dose)

- White blood cell (WBC) count < 50,000/MuL before administration of pevonedistat on
cycle 1 day 1. Note: Hydroxyurea may be used to control leukocytosis for the first 28
days of study treatment (i.e., cycle 1). Use of hydroxyurea beyond this point may be
permitted as clinically indicated, on a case-by-case basis and after discussion with
the principal investigator (PI). (repeat if more than 3 days before the first dose)

- Albumin > 2.7 g/dL (repeat if more than 3 days before the first dose)

- Hemoglobin > 8 g/dL. Patients may be transfused to achieve this value. Elevated
indirect bilirubin due to post-transfusion hemolysis is allowed (repeat if more than 3
days before the first dose)

- 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: a) 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 b) 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, postovulation methods] withdrawal, spermicides only, and
lactational amenorrhea are not acceptable methods of contraception.)

- Male patients, even if surgically sterilized (i.e., status postvasectomy), who: a)
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 b) 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, postovulation methods for the female
partner] withdrawal, spermicides only, and lactational amenorrhea are not acceptable
methods of contraception.)

- 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

Exclusion Criteria:

- Treatment with any investigational products within 2 weeks before the first dose of
any study drug (cycle 1 day 1 [C1D1])

- Patients whose only site of disease is extramedullary

- Acute promyelocytic leukemia as diagnosed by morphologic examination of bone marrow,
by fluorescent in situ hybridization or cytogenetics of peripheral blood or bone
marrow, or by other accepted analysis

- Any serious medical or psychiatric illness that could, in the investigator's opinion,
potentially interfere with the completion of study procedures

- Active uncontrolled infection or severe infectious disease, such as severe pneumonia,
meningitis, or septicemia

- Major surgery within 14 days before the first dose of any study drug

- Diagnosed or treated for another malignancy within 2 years 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

- Life-threatening illness unrelated to cancer, leading to expected life expectancy
(unrelated to leukemia) < 1 year

- Patients with uncontrolled coagulopathy or bleeding disorder not related to leukemia

- Known human immunodeficiency virus (HIV) seropositive

- Known hepatitis B surface antigen seropositive or known or suspected active hepatitis
C infection. Note: Patients who have isolated positive hepatitis B core antibody
(i.e., 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

- Known hepatic cirrhosis or severe pre-existing hepatic impairment

- Known cardiopulmonary disease defined as: a) Unstable angina; b) Congestive heart
failure (New York Heart Association [NYHA] class III or IV); c) Myocardial infarction
(MI) within 6 months prior to first dose (patients who had ischemic heart disease such
as an acute coronary syndrome [ACS], MI, and/or revascularization greater than 6
months before screening and who are without cardiac symptoms may enroll); d)
Symptomatic cardiomyopathy; e) Clinically significant arrhythmia: f) History of
polymorphic ventricular fibrillation or torsade de pointes; g) Persistent atrial
fibrillation (a fib) requiring cardioversion in the 4 weeks before screening; h) Grade
3 a fib defined as symptomatic and incompletely controlled medically, or controlled
with device (e.g. pacemaker), or ablation and i) Implantable cardioverter
defibrillator; j) Moderate to severe aortic and/or mitral stenosis or other
valvulopathy (ongoing); k) Symptomatic pulmonary hypertension

- Uncontrolled high blood pressure (i.e., systolic blood pressure > 180 mm Hg, diastolic
blood pressure > 100 mm Hg)

- Prolonged rate corrected QT (QTc) interval >= 500 msec, calculated according to
institutional guidelines

- Left ventricular ejection fraction (LVEF) < 50% as assessed by echocardiogram or
radionuclide angiography

- Known moderate to severe chronic obstructive pulmonary disease, interstitial lung
disease, and pulmonary fibrosis

- Known central nervous system (CNS) involvement

- Treatment with strong CYP3A4 inducers within 14 days before the first dose of the
study drug. Strong CYP3A4 inducers are not permitted during this study

- Systemic antineoplastic therapy or radiotherapy for other malignant conditions within
14 days (or 3 half-lives, whichever is shorter) before the first dose of any study
drug, except for hydroxyurea or up to 2 total grams of intravenous cytarabine for
cytoreduction. Prior hypomethylating agent (HMA) therapy is allowed, unless given for
AML

- Female patients who are either lactating and/or 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

- 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)

- 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)

- Known hypersensitivity to azacitidine, mannitol or pevonedistat, any of their
components, or compounds of similar chemical composition