Part 1: Dose escalation of APG-115 will use standard 3+3 design. APG-115 is administered
orally once daily (QD) on Day 1-5 every 28-day cycle. The starting target dose is 100 mg
(dose level; DL1) and will be increased in subsequent cohorts to 150 mg (DL2), 200 mg (DL3),
and 250 mg (DL4), accordingly.
Part 2: Dose escalation of APG-115 in combination with 5-AZA will use standard 3+3 design.
5-AZA is administered at 75 mg/m˄2/d subcutaneously daily on Day 1-7 every 28 days.
1. Patients with a diagnosis of histologically confirmed relapsed or refractory AML,
CMML, or high-risk MDS (overall revised international prognostic scoring system
(IPSS-R) score > 3, including intermediate, high, or very high risk) by World Health
Organization (WHO) classification for which no available standard therapies are
indicated or anticipated to result in a durable response.
2. Adequate organ function as defined below:
1. Liver function (total bilirubin < or = 1.5 x upper limit of normal (ULN),
aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) <3 x ULN
2. Kidney function (defined as a calculated creatinine clearance ≥ 60 mL/min;
determined via urine collection for 24-hour creatinine clearance or by the
Cockcroft Gault formula)
3. Known cardiac ejection fraction of > or = 45% within the past 3 months
3. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
4. A negative serum pregnancy test is required within 1 week for all women of
childbearing potential prior to enrolling on this trial.
5. Patient must have the ability to understand the requirements of the study and signed
informed consent. A signed informed consent by the patient or legally authorized
representative is required prior to their enrollment on the protocol.
6. Subject must have a projected life expectancy of at least 12 weeks.
7. Subject has a white blood cell count < 25 × 10˄9/L. Note: Hydroxyurea is permitted to
meet this criteria.
1. Pregnant women are excluded.
2. Uncontrolled intercurrent illness including, but not limited to active uncontrolled
infection, symptomatic congestive heart failure (NYHA Class III or IV), unstable
angina pectoris, clinically significant cardiac arrhythmia, or psychiatric
illness/social situations that would limit compliance with study requirements.
3. Have had leukemia therapy for 14 days prior to starting investigational drug. However,
patients with rapidly proliferative disease may receive hydroxyurea as needed until 24
hours prior to starting therapy on this protocol and during the first cycle of study.
4. Have acute promyelocytic leukemia.
5. Active infection requiring systemic antibiotic/antifungal medication, known clinically
active hepatitis B or C, or HIV infection.
6. Have received allogeneic hematopoietic stem cell transplant (HSCT) within 12 months
prior to the first dose, or who have active/ongoing graft-versus host disease (GVHD),
or require continued treatment with systemic immunosuppressive agents (calcineurin
inhibitors within 4 weeks prior to the first dose), or received autologous
hematopoietic stem cell transplantation within 6 months prior to the first dose.
7. Documented hypersensitivity to any of the components of the therapy program
8. Active, uncontrolled central nervous system (CNS) leukemia will not be eligible.
9. Men and women of childbearing potential who do not practice contraception. Women of
childbearing potential and men must agree to use at least 1 form of barrier birth
control (such as condom) prior to study entry and for the duration of study
10. Any prior systemic MDM2-p53 inhibitor treatment
11. Any other condition or circumstance that would, in the opinion of the investigator,
make the patient unsuitable for participation in the study.
12. History of other malignancies within 2 years prior to study entry, with the exception
1. Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of
2. Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin
3. Previous malignancy confined and surgically resected (or treated with other
modalities) with curative intention: requires discussion with sponsor
13. Failure to have recovered (Grade > 1) from prior treatment (including chemotherapy,
targeted therapy, immunotherapy, experimental agents, radiation, or surgery)
14. Significant screening electrocardiogram (ECG) abnormalities including left bundle
branch block, 2nd degree atrioventricular (AV) block type II, 3rd degree block, or
corrected QT interval (QTc) ≥470 msec