ONC201 in Treating Patients With Relapsed or Refractory Acute Leukemia or High-Risk Myelodysplastic Syndrome

PRIMARY OBJECTIVES:

To determine recommended phase II dose for oral ONC201 ([Akt/ERK inhibitor ONC201) alone or in combination with VENETOCLAX in patients with relapsed or refractory acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS) or acute lymphoblastic leukemia (ALL). (Phase I) II. To identify toxicities associated with oral ONC201 alone or in combination with VENETOCLAX in patients with relapsed or refractory AML, MDS or ALL. (Phase I) III. To determine the objective response rate to ONC201 alone in patients with relapsed or refractory AML, MDS or ALL. (Phase II)

SECONDARY OBJECTIVES:

I. To determine the pharmacokinetics (PK) of oral ONC201 alone or in combination with VENETOCLAX. (Phase I) II.To observe the anti-tumor effects of oral ONC201 alone or in combination with VENETOCLAX in patients with relapsed or refractory AML, MDS or ALL. (Phase I) III. Confirm tolerability of recommended phase II dose. (Phase II) IV. Assess clinical outcomes associated with ONC201 alone or in combination with VENETOCLAX in patients with relapsed or refractory AML, MDS or ALL. (Phase II) V. Correlate clinical outcome with tumor and serum biomarkers. (Phase II)

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study. Patients are assigned to 1 of 5 arms.

ARM A: Patients receive Akt/ERK inhibitor ONC201 orally (PO) once every 3 weeks. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive Akt/ERK inhibitor ONC201 PO once every week. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

ARM C: Patients receive Akt/ERK inhibitor ONC201 PO on the first two consecutive days of every week. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

ARM D: Patients receive Akt/ERK inhibitor ONC201 PO once daily (QD). Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

ARM E: Patients receive Akt/ERK inhibitor ONC201 PO twice weekly. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM F: Patients receive Akt/ERK inhibitor ONC201 PO twice weekly for 4 weeks and venetoclax daily on days 1-21 every 28 day cycle.

After completion of study treatment, patients are followed up at 28 days.

Inclusion criteria

• For Arms A, B, C, D, E, F patients must have relapsed or refractory acute leukemias or high-risk MDS for which no standard therapies are anticipated to result in a durable remission
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) must use acceptable contraceptive methods (abstinence, intrauterine device [IUD], oral contraceptive or double barrier device, such as a condom, diaphragm, or cervical/vault cap), for 16 weeks after the last dose of study drug, and must have a negative serum or urine pregnancy test within 1 week prior to beginning treatment on this trial; nursing patients are excluded; sexually active men must also use acceptable contraceptive methods for the duration of time on study and for at least 16 weeks after the last dose of study drug; pregnant and nursing patients are excluded because the effects of ONC201on a fetus or nursing child are unknown
• Must be able and willing to give written informed consent
• The interval from prior treatment to time of study drug administration should be at least 2 weeks for cytotoxic agents or at least 5 half-lives for noncytotoxic agents; if the patient is on hydroxyurea to control peripheral blood leukemic cell counts, the patient must be off hydroxyurea for at least 24 hours before initiation of treatment on this protocol; persistent clinically significant toxicities from prior therapy must not be greater than grade 1
• Serum creatinine < 2.0 mg/dl
• Total bilirubin =< 1.5 x the upper limit of normal (ULN) unless considered due to Gilbert's syndrome
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) =< 3 x the ULN unless considered due to organ leukemic involvement
• Relapse > 6 months since autologous or allogeneic stem cell transplantation provided:

• No active graft-versus-host disease (GVHD > grade 1)
• No treatment with high dose steroids for GVHD (up to >= 20 mg prednisolone or equivalent per day)
• No treatment with immunosuppressive drugs with the exception of low dose cyclosporine and tacrolimus

Exclusion criteria

• Uncontrolled intercurrent illness including, but not limited to uncontrolled infection, symptomatic congestive heart failure (New York Heart Association class III and IV), uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Active heart disease including myocardial infarction within previous 3 months, symptomatic coronary artery disease, arrhythmias not controlled by medication, or uncontrolled congestive heart failure (New York Heart Association class III and IV)
• Patients receiving any other standard or investigational treatment for their hematologic malignancy within past 2 weeks for cytotoxic agents or at least 5 half-lives for noncytotoxic agents
• Subject has been diagnosed or treated for another malignancy within 3 years of enrolment, except in situ malignancy, or low-risk prostate, skin or cervix cancer after curative therapy
• Known history of seropositive for human immunodeficiency virus (HIV) antibodies (HIV1 and HIV2), hepatitis C antibody (Hep C Ab) or a hepatitis B carrier (positive for hepatitis B surface antigen [HBsAg])
• Active drug use or alcoholism
• Known or active central nervous system (CNS) involvement by leukemia
• White blood cell count more than 25 x 109/L prior to initiation of venetoclax