Patient case: 1-year-old male with acute myeloid leukemia; genetic feature: IDH1

Clinical trial: CB-839 + Azacitidine for Treatment of Myelodysplastic Syndrome (MDS)

Summary: The goal of this clinical research study is to learn if CB-839 given in combination with azacitidine can help to control the disease in patients with myelodysplastic syndrome (MDS). The safety of this drug combination will also be studied.

Detailed description: Study Drug Administration:
  Every study cycle is 28 days.
  -  Participant will take CB-839 by mouth 2 times per day while participant is on study. Participant should take each dose with food, and about 12 hours apart.
  -  Participant will receive azacitidine by vein over about 10-40 minutes, or as an injection under the skin about 1 hour after taking CB-839 on Days 1-7 of every cycle. If needed, participant may receive azacitidine at participant's local doctor's office.
  It is important that participant tell the study doctor about any drugs participant is taking during the study. This includes prescription drugs, over-the-counter drugs, natural or herbal medicines, alternative medicines, and vitamins.
  Length of Study:
  Participant may continue taking the study drugs for as long as the doctor thinks it is in participant's best interest. Participant will no longer be able to take the study drugs if the disease gets worse, if intolerable side effects occur, or if participant is unable to follow study directions.
  Participation on the study will be over after the End-of-Study visit.
  Study Visits:
  Participant may visit participant's regular home doctor for any study visits in which PD or PK testing is not taking place. However, participant will need to come to MD Anderson on Day 1 of each cycle in order to get participant's supply of CB-839.
  On Day 1 of Cycle 1:
  -  Participant will have a physical exam.
  -  Blood (about 2 tablespoons) will be drawn for routine tests and pharmacokinetic (PK) testing before the dose of CB-839. PK testing measures the amount of study drug in the body at different time points.
  -  Participant will have two EKGs within 2-4 hours after the dose.
  On Days 8, 15, and 22 of Cycle 1:
  -  Participant will have a physical exam.
  -  Blood (about 2 tablespoons) will be drawn for routine testing.
  On Day 1 of Cycles 2 and 3, and Day 15 of Cycle 1, blood (about 1 tablespoon) will be drawn for PK testing before the dose. Participant should not take the morning dose of CB-839 at home before the clinic visits.
  On Day 1 of Cycle 2 and beyond:
  -  Participant will have a physical exam.
  -  Blood (about 1 tablespoon) will be drawn for routine and biomarker testing, including genetic biomarkers. Biomarkers are found in the blood/tissue and may be related to participant's reaction to the study drug.
  Participant will have a bone marrow biopsy and aspirate for biomarker and pharmacodynamic (PD) testing and to check the status of the disease on Day 1 of Cycles 2, 4, and 6, and every 3 cycles after that. PD testing measures how the level of study drug in participant's body may affect the disease.
  End-of-Study Visit:
  Within 28 days of the last dose of the study drugs:
  -  Participant will have a physical exam.
  -  Blood (about 2 tablespoons) will be drawn for routine tests.
  -  Participant will have an EKG.
  -  Participant will have a bone marrow biopsy and aspirate for biomarker and PD testing. Participant may also have blood (about 2 tablespoons) drawn for this sample instead.
  -  If participant can become pregnant, blood (about 1 tablespoon) or urine will be collected for a pregnancy test.
  This is an investigational study. CB-839 is not FDA approved or commercially available. It is currently being used for research purposes only. Azacitidine is FDA approved and commercially available for the treatment of MDS. Its use in combination with CB-839 is investigational. The study doctor can explain how the study drugs are designed to work.
  Up to 46 participants will be enrolled on this study. All will take part at MD Anderson.

Eligibility: Inclusion Criteria:
  1. Signed, informed consent must be obtained prior to any study specific procedures.
  2. 2. Subjects must be >/= 18 years of age at the time of informed consent
  3. Subjects with a histologically confirmed diagnosis of MDS, including both MDS and RAEB-T (AML with 20-30% blasts and multilineage dysplasia by FAB criteria) by World Health Organization (WHO) and chronic myelomonocytic leukemia (CMML) are eligible.
  4. Subjects with high-risk MDS (i.e. IPSS Intermediate-2 or high-risk; or R-IPSS high or very-high risk). Patients with Intermediate-1 risk by IPSS or Intermediate risk by R-IPSS and with IDH1 or IDH2, or high-risk molecular features including TP53, ASXL1, EZH2, and/or RUNX1 mutations are also eligible.
  5. Subjects with prior hypomethylating agent therapy exposure may be eligible based on discussion with the PI.
  6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.
  7. Adequate liver function, as evidenced by a serum bilirubin </= 2x the ULN (except for patients with Gilbert's disease) and ALT or AST </= 3x the laboratory ULN.
  8. Serum creatinine </= 2x the ULN
  9. Able to understand and voluntarily sign a written informed consent, and willing and able to comply with protocol requirements
  10. Resolution of all treatment-related, non-hematological toxicities, except alopecia, from any previous cancer therapy to < Grade 1 prior to the first dose of study treatment
  11. Female patients of childbearing potential must have a negative serum or urine pregnancy test within 3 days of the first dose of study drug and agree to use dual methods of contraception during the study and for a minimum of 3 months following the last dose of study drug. Post-menopausal females (>/= 45 years old and without menses for >/= 1 year) and surgically sterilized females are exempt from these requirements. Male patients must use an effective barrier method of contraception during the study and for a minimum of 3 months following the last dose of study drug if sexually active with a female of childbearing potential.
  Exclusion Criteria:
  1. Any prior or coexisting medical condition that in the investigator's judgment will substantially increase the risk associated with the subject's participation in the study.
  2. Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary study procedures
  3. Active uncontrolled infection at study enrollment including known diagnosis of human immunodeficiency virus or chronic active Hepatitis B or C infection.
  4. Clinically significant gastrointestinal conditions or disorders that may interfere with study drug absorption, including prior gastrectomy.
  5. Patients with known active CNS disease, including leptomeningeal involvement.
  6. Impaired cardiac function, uncontrolled cardiac arrhythmia, or clinically significant cardiac disease including the following: a) New York Heart Association Grade III or IV congestive heart failure, b) myocardial infarction within the last 6 months
  7. Subjects with a QTc > 480 ms (QTc > 510 msec for subjects with a bundle branch block at baseline).
  8. Nursing or pregnant women.
  9. Subjects with known hypersensitivity to study drugs or their excipients.

Relevance to patient case: not relevant