Patient case: 14-year-old female with Li-Fraumeni syndrome; genetic feature: TP53

Clinical trial: Targeted Therapy With the IDH2-Inhibitor Enasidenib (AG221) for High-Risk IDH2-Mutant Myelodysplastic Syndrome

Summary: The goal of this clinical research study is to learn if enasidenib (AG-221) alone or in combination with azacitidine can help to control myelodysplastic syndrome (MDS). The safety of this drug will also be studied.
  If you are reading and signing this form on behalf of a potential participant, please note: Any time the words "you," "your," "I," or "me" appear, it is meant to apply to the potential participant.
  This is an investigational study. Enasidenib 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. It is considered investigational to give enasidenib and azacitidine in combination for the treatment of MDS. The study doctor can explain how the study drug(s) are designed to work.
  Up to 105 participants will be enrolled in this multicenter study. Up to 75 will take part at MD Anderson.

Detailed description: Study Groups:
  If you are found to be eligible to take part in this study, you will be assigned to 1 of 2 study groups based on the status of your disease and the treatment you may have received in the past.
  -  If you have never received a hypomethylating drug (such as azacitidine or decitabine), you will be assigned to Arm A.
  -  If you have received a hypomethylating drug (such as azacitidine or decitabine) and you have relapsed (has come back) or refractory (has not responded to treatment) MDS, you will be assigned to Arm B.
  Participants in Arm A will receive azacitidine and enasidenib.
  Participants in Arm B will receive enasidenib alone.
  Study Drug Administration:
  Each study cycle is 28 days.
  If you are in Arm A, you will receive azacitidine by vein over about 30-60 minutes on Days 1-7 of every cycle. If needed, you may be given azacitidine as an injection under the skin. If you are receiving azacitidine at a clinic that closes over the weekend, alternate dosing schedules (such as receiving azacitidine on Days 1-5 and 8-9 of each cycle) are possible.
  All participants will take enasidenib tablets by mouth with a cup (about 8 ounces) of water at the same time every day. You should swallow the tablets whole without chewing them. You should fast (not have anything to eat or drink except water) for 2 hours before and 1 hour after each dose.
  If you miss your dose, you can still take it as long as it is within 6 hours of your scheduled dose time. If more than 6 hours have passed, you should skip that dose and wait to take the next dose at the normal time the next day.
  Length of Treatment:
  You may continue taking the study drug(s) for as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drug(s) 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 follow-up visits.
  Study Visits:
  On Day 1 of Cycle 1, you will have the following procedures. You should fast before this visit, so do not eat breakfast until the study staff tells you that you can eat. You may have water during this time. You will take your dose of enasidenib during your clinic visit:
  -  You will have a physical exam.
  -  Blood (about 4 teaspoons) will be drawn for routine, pharmacokinetic (PK), and biomarker testing, which may include genetic biomarkers. Biomarkers are found in the blood/tissue and may be related to your reaction to the study drug. PK testing measures the amount of study drug in the body at different time points.
  -  You will have a bone marrow aspirate/biopsy for biomarker testing.
  On Days 8, 15, and 22 (+/- 3 days) of Cycle 1:
  -  You will have a physical exam.
  -  Blood (about 3 teaspoons) will be drawn for routine tests.
  On Day 1 (+/- 5 days) of Cycle 2 and beyond, you will have the following procedures. During Cycles 2 and 3 only, you should take your dose of enasidenib during your clinic visit:
  -  You will have a physical exam.
  -  Blood (about 4 teaspoons) will be drawn for routine and biomarker testing.
  -  During Cycle 2 only, you will have a bone marrow biopsy/aspirate to check the status of the disease and for biomarker and pharmacodynamic (PD) testing. PD testing measures how the level of study drug in your body may affect the disease.
  -  During Cycles 2 and 3 only, blood (about 2 tablespoons) will be drawn for PK testing before your dose of study drug. During Cycle 2, blood will also be drawn 4 times over the 8 hours after the dose. During Cycle 3, blood will also be drawn about 4 hours after the dose.
  On Day 1 (+/- 5 days) of Cycle 4, 6, and every 3 cycles after that (Cycle 9, 12, 15, and so on), you will have a bone marrow biopsy/aspirate for biomarker testing, PD testing, and to check the status of the disease.
  End-of-Study Visit:
  Within 28 days of your last dose of study drug(s):
  -  You will have a physical exam.
  -  Blood (about 4 teaspoons) will be drawn for routine testing.
  -  You will have an EKG.
  -  If the disease appears to be getting worse or returns, you will have a bone marrow aspirate/biopsy for biomarker and PD testing.
  -  If you are able to become pregnant, blood (about 1 tablespoon) or urine will be collected for a pregnancy test.
  Long-Term Follow-Up:
  Every 3 months for up to 3 years after the last patient enrolls on this study, a member of the study staff will call and ask you how you are doing and if you have started any new anti-cancer treatments. This phone call should last about 5 minutes.
  Additional Information:
  Your body may not show a response to enasidenib and azacitidine until after you've received 6 cycles.

Eligibility: Inclusion Criteria:
  1. Signed, informed consent must be obtained prior to any study specific procedures.
  2. Subjects must be >/= 12 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 must have an IDH2 gene mutation (IDH2-R140 or R172) as determined by local laboratory result.
  5. (Arm A only): Subject must be hypomethylating agent naïve (i.e. prior azacitidine, decitabine, SGI-110 is exclusionary). Receipt of other MDS-directed therapy such as lenalidomide is allowed
  6. (Arm A only): 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 with high-risk molecular features including TP53, ASXL1, EZH2, and/or RUNX1 mutations are also eligible.
  7. (Arm B only): Subject must be relapsed or refractory to prior hypomethylating agent therapy, defined as prior receipt of 6 cycles of HMA therapy with failure to attain a response, or relapse after prior response to HMA therapy
  8. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2
  9. Adequate liver function, as evidenced by a serum bilirubin </= 2x the ULN (except for patients with Gilbert's disease), ALT and/or AST </= 3x the laboratory ULN
  10. Serum creatinine </= 2x the ULN
  11. Able to understand and voluntarily sign a written informed consent, and willing and able to comply with protocol requirements
  12. Resolution of all clinically significant treatment-related, non-hematological toxicities, except alopecia, from any previous cancer therapy to </= Grade 1 prior to the first dose of study treatment
  13. Female patients of childbearing potential must have a negative serum or urine pregnancy test within 7 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. Subject has received a prior targeted IDH2 inhibitor
  3. Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary study procedures
  4. Active uncontrolled infection at study enrollment including known diagnosis of human immunodeficiency virus or chronic active Hepatitis B or C infection
  5. Clinically significant gastrointestinal conditions or disorders that may interfere with study drug absorption, including prior gastrectomy
  6. Patients with known active CNS disease, including leptomeningeal involvement
  7. 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
  8. Subjects with a QTc > 480 ms (QTc > 510 msec for subjects with a bundle branch block at baseline
  9. Nursing or pregnant women
  10. Subjects with known hypersensitivity to study drugs or their excipients

Relevance to patient case: not relevant