The goal of Phase I of this clinical research study is to find the highest tolerable dose of
ONC201 alone or in combination with low dose cytarabine (LDAC) that can be given to patients
with relapsed or refractory AML, ALL, or MDS. The goal of Phase II of this study is to learn
if the dose of ONC201 given alone or in combination with LDAC that is found in Phase I can
help to control the disease.
The safety of the study drug will be studied in both phases of this study. This is the first
study using ONC201 in humans.
ONC201 given alone or in combination with LDAC is in a very early stage of development for
use in humans. Providing direct medical benefit to you is not the purpose of this study.
While Phase II will look at the effectiveness of the study drug given alone or in combination
with LDAC, the main purpose of this study is to learn about the safety of the drug.
Study Groups If you are found to be eligible to take part in this study, you will be enrolled
in a study group (Arm) based on the type of disease you have and/or when you joined this
study. Up to 15 groups of up to 6 participants per group will be enrolled in Phase I of the
study, and up to 20 participants will be enrolled in Phase II. All will take part at MD
Anderson.
If you are enrolled in Phase I Arms A, B, C, D or E, the dose and frequency of ONC201 alone
or in combination with LDAC you receive will depend on when you join the study. The first
group of participants will receive the lowest dose level of ONC201. If no intolerable side
effects are seen, the next group of participants will receive a higher dose than the group
before them. This will continue until the highest tolerable dose of ONC201 is found. The dose
you receive may be too low to have an effect on your disease, or so high that it causes bad
side effects.
If you are enrolled in Phase II, you will receive ONC201 alone or in combination with LDAC at
the highest dose level that was tolerated by participants in the Phase I portion of the
study.
Study Drug Administration:
In Arms A, B, C, and D, each study drug cycle is 21 days. If you are enrolled in Arm E or in
the Phase 2 study, each cycle will be 28 days.
You will take ONC201 capsules by mouth as directed by your doctor 2 hours before or after a
meal. If you vomit after taking ONC201, you should not retake the dose. Your doctor will tell
you how many capsules to take and how often to take them (either 1 or 2 times every week,
depending on what group you are assigned to). You must not crush or chew the capsules or
dissolve them in liquid.
LDAC will be injected under the skin on Days 3-12 of each 4 week cycle. You or your caregiver
will be taught how to inject the LDAC.
You will be given a study drug diary to write down any missed doses. You will give your study
drug diary to the study doctor at each clinic visit.
Your dose may be increased or decreased if you have any side effects, if you respond to the
study drug, or if the doctor thinks that the next higher dose level is safe.
Study Visits:
On Day 1 of Cycle 1:
- You will have a physical exam, including vital signs, weight, and discussion about any
other medications you are taking.
- Blood (about 2 tablespoons) will be drawn for routine tests.
- You will have 1 EKG before your dose of study drug and then 3 more times over the next 2
hours after the first dose.
- Blood (about 1 teaspoon) will be drawn for PK testing 5 times over the next 24 hours
after the dose of study drug.
- Blood (about 1 teaspoon) will be drawn for PD testing before your dose of study drug.
For Arm D, during Cycle 1 and Cycle 2, blood (about 1 teaspoon) will be collected for PK
testing at pre-dose, and at 30 minutes (± 15 minutes), 2 hours (± 30 minutes), 4 hours (± 30
minutes), and 6 hours (± 30 minutes) after you receive ONC201 on Day 1 and Day 2.
For Arm E, during Cycle 1, blood (about 1 teaspoon) will be collected for PK testing at
pre-dose, and 30 minutes (± 15 minutes), 2 hours (± 30 minutes), 4 hours (± 30 minutes), and
6 hours (± 30 minutes) after you receive ONC201 on Days 1, 2, 3, 12, 22 and 23.
On Days 2-4 of Cycle 1:
- On Day 2 only, you will have an EKG.
- Blood (about 1 teaspoon) will be drawn for PK and/or PD testing.
On Days 8 and 15 of Cycle 1:
- Blood (about 2 tablespoons) will be drawn for routine tests.
- You will have an EKG, vital signs, and discussion about any other medications you are
taking.
- On Day 8 only, blood (about 2 teaspoons) will be drawn for PK and PD testing. On Day 22
of Cycle 1 (Arm E only)
- Blood (about 2 tablespoons) will be drawn for routine tests. On Day 1 of Cycles 2 and
beyond
- You will have a physical exam, including vital signs and a discussion of any other
medications you are taking.
- You will have an EKG before your dose of study drug.
- Blood (about 2 tablespoons) will be drawn for routine tests.
- Blood (about 2 teaspoons) will be drawn for PK and PD testing.
- On Cycle 2 only, you will have a bone marrow aspirate/biopsy for PD testing.
On Day 21 of Cycle 3, and then any time the doctor thinks it is needed after that, you will
have a bone marrow aspirate/biopsy for cytogenetic, biomarker, and PD testing. Biomarkers are
found in the blood/tissue and may be related to your reaction to the study drug.
Length of Study:
You may continue taking the study drug for as long as the doctor thinks it is in your best
interest. You will no longer be able to take the study drug if the disease gets worse, if
intolerable side effects occur, or if you are unable to follow study directions.
Your participation on the study will be over after the end-of-study visit.
End-of-Study Visit:
About 1 month after your last dose of study drug:
- You will have a physical exam, including vital signs and a discussion of any other
medications you are taking.
- You will have an EKG.
- Blood (about 2 tablespoons) will be drawn for routine tests.
- If the doctor thinks it is needed, blood (about 2 teaspoons) will be drawn for PK and PD
testing.
- If the doctor thinks it is needed, you will have a bone marrow aspirate/biopsy to check
for any genetic mutations.
This is an investigational study. ONC201 is not FDA-approved or commercially available. It is
currently being used for research purposes only. The study doctor can explain how the study
drug is designed to work.
Up to 120 patients will take part in this study. All will be enrolled at MD Anderson.
Inclusion Criteria:
1. For Arms A, B, C, D 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. For Arm E, in addition to patients with relapsed or refractory acute
leukemias or high-risk MDS, patients with untreated high-risk MDS or acute leukemias
will also be eligible provided they are not eligible for more intensive therapies.
2. Age >/=18 years.
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
4. 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.
5. Must be able and willing to give written informed consent.
6. 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.
7. Patients must have the following clinical laboratory values unless considered due to
leukemic organ involvement: (1) Serum creatinine < 2.0 mg/dl; (2) Total bilirubin </=
1.5 x the upper limit of normal (ULN) unless considered due to Gilbert's syndrome; (3)
Alanine aminotransferase (ALT), or aspartate aminotransferase (AST) </= 3 x the ULN
unless considered due to organ leukemic involvement.
8. Patients with known central nervous system (CNS) disease are allowed if there is no
evidence of active CNS disease as documented by negative imaging or spinal fluid
analysis carried out at least 2 weeks prior to study drug administration. Information
obtained from standard of care historical data will be used for this purpose.
9. Relapse > 6 months since autologous or allogeneic stem cell transplantation provided:
(1) No active graft-versus-host disease (GVHD > grade 1); (2) No treatment with high
dose steroids for GVHD (up to >/= 20 mg Prednisolone or equivalent per day); (3) No
treatment with immunosuppressive drugs with the exception of low dose cyclosporine and
tacrolimus.
Exclusion Criteria:
1. 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.
2. 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).
3. 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.
4. 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.
5. 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])
6. Active drug use or alcoholism.
