Randomized, Sequential, Open-Label Study to Evaluate the Efficacy of IDH Targeted/Non- Targeted Versus Non-targeted/IDH-targeted Approaches in the Treatment of Newly Diagnosed IDH Mutated AML Patients Not Candidates for Intensive Induction Therapy (I- DATA Study)
This phase II study compares the order of treatment with ivosidenib or enasidenib and azacitidine plus venetoclax in treating older patients with acute myeloid leukemia with genetic changes in the IDH1 or IDH2 genes (IDH mutated). Ivosidenib is in a class of medications called isocitrate dehydrogenase-1 (IDH1) inhibitors. It works by slowing or stopping the growth of cancer cells. Enasidenib is in a class of medications called an IDH2 inhibitor. It also works by slowing or stopping the growth of cancer cells. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Azacitidine is in a class of medications called demethylation agents. It works by helping the bone marrow to produce normal blood cells and by killing abnormal cells. This study may help researchers determine which treatment order is best for older patients with IDH mutated acute myeloid leukemia: 1) ivosidenib or enasidenib followed by azacitidine plus venetoclax; or 2) azacitidine plus venetoclax followed by ivosidenib or enasidenib.
• Patients with newly diagnosed IDH1 or IDH2 mutated AML
• Not a candidate for or refuses intensive induction therapy
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Creatinine clearance \> 40 ml/min
• Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) \< 5 x upper limit of normal
• Total bilirubin \< 1.5 x upper limit of normal (except for patients with Gilbert's disease)
• At the time of Venetoclax initiation, white blood cells (WBC) needs to be \< 25 × 103 microliter: Hydroxyurea can be used to achieve that level.
• For female patients of childbearing potential, willingness to abstain from heterosexual intercourse or use a protocol-recommended method of contraception from the screening visit throughout the study treatment period and for 30 days following the last dose of either study drug. A serum pregnancy test will be done at screening. A serum or urine pregnancy test will be done on Day 1 of each cycle for women of childbearing potential. If the urine pregnancy test is positive, a serum pregnancy test must be performed per institutional standards.
∙ The following methods are acceptable methods of contraception for the purpose of this study:
• Highly Effective Contraception Methods that can achieve a failure rate of less than 1% per year when used consistently and correctly are considered as highly effective birth control methods (Clinical Trials Facilitation Group 2014):
‣ Combined (estrogen and progestin containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal).
⁃ Progestin-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable).
⁃ Intrauterine device.
⁃ Intrauterine hormone-releasing system.
⁃ Bilateral tubal occlusion.
⁃ Vasectomized partner, provided that partner is the sole sexual partner of the female study participant and that the vasectomized partner has received medical assessment of the surgical success.
⁃ Sexual abstinence- only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient.
• Acceptable Birth Control Methods that are not Highly Effective Contraception Acceptable birth control methods that result in a failure rate of more than 1% per year:
‣ Progestin-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of action.
⁃ Male or female condom with or without spermicide.
⁃ Cap, diaphragm, or sponge with spermicide. A combination of male condom with either cap, diaphragm, or sponge with spermicide (double barrier methods) are also acceptable, but not highly effective, birth control methods.
• The following methods are NOT acceptable methods of contraception for the purpose of this study:
‣ Periodic abstinence (calendar, symptothermal, postovulation methods).
⁃ Withdrawal (coitus interruptus).
⁃ Spermicides only.
⁃ Lactational amenorrhea method.
⁃ Combination of male and female condom
• For male patients of childbearing potential having intercourse with females of childbearing potential, the willingness to abstain from heterosexual intercourse or use a protocol recommended method of contraception from the start of study treatment throughout the study treatment period and for 90 days following the last dose of either study drug. Males must also refrain from sperm donation from the start of study treatment throughout the study treatment period and for 90 days following the last dose of either dose of study drug
‣ Willingness to comply with scheduled visits, drug administration plan, imaging studies, laboratory tests, other study procedures and study restrictions