MDM2 Inhibitor AMG-232 and Decitabine in Treating Patients With Relapsed, Refractory, or Newly-Diagnosed Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To evaluate the toxicities of MDM2 inhibitor AMG-232 (AMG-232) in combination with
decitabine (20 mg/m^2 for 10 days), and to determine the maximum tolerated dose
(MTD)/recommended phase 2 dose (RP2D) of AMG-232 in combination with a standard dose of
decitabine.

SECONDARY OBJECTIVES:

I. To evaluate the pharmacokinetic (PK) profiles of AMG-232 and decitabine when used in
combination.

II. To evaluate tumor suppressor protein 53 (p53) signaling induced by AMG-232 and decitabine
as measured by macrophage inhibitory cytokine-1 (MIC-1) induction.

III. To correlate AMG-232 and decitabine exposure with pharmacodynamics endpoints (efficacy,
toxicity, changes in p53 signaling).

TERTIARY OBJECTIVES:

I. To evaluate the response rate (RR) and progression free survival (PFS) of AMG-232 and
decitabine in acute myeloid leukemia (AML).

II. To evaluate potential predictive biomarkers of response to AMG-232 and decitabine in AML.

III. To evaluate the pharmacodynamic (PD) effects of AMG-232 and decitabine in AML blasts.

IV. To determine the variability of decitabine incorporation into genomic deoxyribonucleic
acid (DNA) and correlate with systemic pharmacokinetics and exposure-response relationships.

OUTLINE: This is a dose-escalation study of MDM2 inhibitor AMG-232.

Patients receive decitabine intravenously (IV) over 1 hour on days 1-10 and MDM2 inhibitor
AMG-232 orally (PO) once daily (QD) on days 4-10 and 18-24. Treatment repeats every 28 days
for up to 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Inclusion Criteria:

- Relapsed/refractory AML (>= 5% blasts in bone marrow or extramedullary leukemia) or
newly diagnosed AML patients who are not candidates for (age >= 70 years; adverse
cytogenetics, e.g., as defined by the Medical Research Council [MRC] Prognostic
Groupings; secondary AML; organ dysfunction arising from significant co-morbidities
not directly linked to leukemia; Eastern Cooperative Oncology Group [ECOG] = 2) or not
willing to undergo intensive chemotherapy; Note that both relapsed/refractory and
newly diagnosed AML patients will be eligible for the dose escalation part of the
study, but only newly diagnosed patients will be eligible for the dose expansion
cohort

- Patients must have measureable disease as defined the presence of >= 5% blasts in bone
marrow or extramedullary leukemia

- Eligible patient must show evidence of wild-type (WT) p53 as assessed by central DNA
sequencing conducted at Dr. Jeffrey Sklar's laboratory at Yale University Cancer
Center; note, that since patients with AML have a rapidly proliferating disease,
patient can be enrolled and begin treatment prior to obtaining the results of this
test; patients who are found to the TP53 mutated will be removed from study and can
continue on single agent decitabine; however patients will continue to be followed for
toxicity

- ECOG performance status =< 2 (Karnofsky >= 60%)

- Total bilirubin < 1.5 x institutional upper limit of normal (ULN) (< 2.0 x ULN for
subjects with documented Gilbert's syndrome or < 3.0 x ULN for subjects for whom the
indirect bilirubin level suggests an extrahepatic source of elevation)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x
ULN

- Alkaline phosphatase < 2.0 x ULN (if liver or bone metastases are present, < 3.0 x
ULN)

- Body surface area (BSA)-normalized creatinine clearance >= 30 mL/min/1.73 m^2 (using
Cockcroft-Gault creatinine clearance [CrCl])

- Prothrombin time (PT) or partial thromboplastin time (PTT) < 1.5 x upper limit of
normal (ULN), OR international normalized ratio (INR) < 1.5

- Patient must be willing to submit the blood sampling and bone marrow sampling for the
PK and PD analyses and exploratory biomarkers

- Women of child-bearing potential must agree to use adequate contraception prior to
study entry and for the duration of study participation through 5 weeks (women) after
receiving the last dose of AMG 232; should a woman become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she should inform
her treating physician immediately; men treated or enrolled on this protocol must also
agree to use adequate contraception prior to the study, for the duration of study
participation, and 3 months after completion of AMG 232 administration

- Adequate methods of effective birth control include sexual abstinence (men,
women); vasectomy; or a condom with spermicide (men) in combination with barrier
methods, hormonal birth control or intrauterine device (IUD) (women)

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

Exclusion Criteria:

- Acute promyelocytic leukemia with t(15;17)(q22;q12) and/or PML-RARA molecular
rearrangement

- Patients with previously untreated AML with core binding factor (CBF) chromosomal
aberrations (inv[16]/t[16;16] or t[8;21]); Note that patients with relapsed or
refractory AML with CBF chromosomal aberrations will be eligible

- Unresolved toxicities from prior anti-tumor therapy, defined as not having resolved to
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 0 or 1, or to
levels dictated in the eligibility criteria with the exception of alopecia (grade 2 or
3 toxicities from prior antitumor therapy that are considered irreversible [defined as
having been present and stable for > 6 months], such as ifosfamide-related
proteinuria, may be allowed if they are not otherwise described in the exclusion
criteria AND there is agreement to allow by both the investigator and sponsor)

- Patients who are receiving any other investigational agents

- Major surgery within 28 days of study day 1

- Patients with known central nervous system involvement at the time of study entry will
be excluded from this clinical trial

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to AMG 232 or decitabine

- All herbal medicines (e.g., St. John's wort), vitamins, and supplements consumed by
the subject within the 30 days prior to receiving the first dose of AMG 232, and
continuing use, if applicable, will be reviewed by the principal investigator

- Use of any known CYP2C8 substrates with a narrow therapeutic window is not allowed
during the study and patients must come off 14 days prior to receiving the first dose
of AMG 232

- Use of any known CYP3A4 substrates with narrow therapeutic window (such as alfentanil,
astemizole, cisapride, dihydroergotamine, pimozide, quinidine, sirolimus, or
terfanide) within the 14 days prior to receiving the first dose of AMG 232; other
medications (such as fentanyl and oxycodone) may be allowed per investigator's
assessment/evaluation

- Treatment with medications known to cause corrected QT (QTc) interval prolongation
within 7 days of study day 1 is not permitted unless approved by the sponsor; use of
ondansetron is permitted for treatment of nausea and vomiting

- Current use of warfarin, factor Xa inhibitors and direct thrombin inhibitors

- Note: Low molecular weight heparin and prophylactic low dose warfarin are
permitted; PT/PTT must meet the inclusion criteria; subjects taking warfarin must
have their INR followed closely

- Uncontrolled intercurrent illness including, but not limited to, active infection,
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or
psychiatric illness/social situations that would limit compliance with study
requirements; patients receiving an anti-microbial agent may be eligible if the
patient remains afebrile and hemodynamically stable for 72 hours; patients with
myocardial infarction within 6 months of study day 1, symptomatic congestive heart
failure (New York Heart Association (NYHA) class III and higher), unstable angina, or
cardiac arrhythmia requiring medication are excluded

- Patients with gastrointestinal (GI) tract disease causing the inability to take oral
medication, malabsorption syndrome, requirement for intravenous alimentation, prior
surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g.,
Crohn's disease, ulcerative colitis)

- Patients with history of bleeding diathesis

- Positive hepatitis B surface antigen (HepBsAg) (indicative of chronic hepatitis B),
positive hepatitis total core antibody with negative HBsAG (suggestive of occult
hepatitis B), or detectable hepatitis C virus ribonucleic acid (RNA) by a
polymerase-chain reaction (PCR) assay (indicative of active hepatitis C - screening is
generally done by hepatitis C antibody [HepCAb], followed by hepatitis C virus RNA by
PCR if HepCAb is positive)

- Human immunodeficiency virus (HIV)-patients positive for human immunodeficiency virus
(HIV) are NOT excluded from this study, but HIV-positive patients must have:

- A stable regimen of highly active anti-retroviral therapy (HAART)

- No requirement for concurrent antibiotics or antifungal agents for the prevention
of opportunistic infections

- A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard
PCR-based test

- Men and women of reproductive potential who are unwilling to practice acceptable
methods of effective birth control while on study through 5 weeks (women) or 3 months
(men) after receiving the last dose of AMG 232; acceptable methods of effective birth
control include sexual abstinence (men, women); vasectomy; or a condom with spermicide
(men) in combination with barrier methods, hormonal birth control or intrauterine
device (IUD) (women)

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with AMG 232

- Women who are lactating/breast feeding or who plan to breastfeed while on study
through 1 week after receiving the last dose of study drug

- Patients with a baseline QTc > 500 msec and patients with a family history of
prolonged QT syndrome

- Patients with known TP53 mutations or chromosome 17 or 17p deletions