Ivosidenib or Enasidenib plus Azacitidine followed by Venetoclax plus Azacitidine compared to Venetoclax plus Azacitidine followed by Ivosidenib or Enasidenib plus Azacitidine for the Treatment of IDH Mutated Acute Myeloid Leukemia, I-DATA Trial
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. 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. 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. This study may help researchers determine which treatment order is best for patients with IDH mutated acute myeloid leukemia: 1) ivosidenib or enasidenib and azacitidine followed by azacitidine plus venetoclax; or 2) azacitidine plus venetoclax followed by ivosidenib or enasidenib and azacitidine.
Inclusion Criteria
- Patients ≥ 18 years 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 × 10^3 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. 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
Exclusion Criteria
- Patients with acute promyelocytic leukemia
- Known active central nervous system involvement of leukemia
- History of active non-myeloid malignancy except for the following: adequately treated local basal cell carcinoma or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease, patients receiving tamoxifen/aromatase inhibitors for non-metastatic breast cancer, or any other cancer that has been in complete remission without treatment for >= 5 years prior to enrollment
- Evidence of ongoing uncontrolled systemic bacterial, fungal or viral infection at the time of start of study treatment
- Uncontrolled infection with hepatitis C, hepatitis B, or human immunodeficiency virus (HIV)
- Pregnancy or breast feeding
- Concurrent participation in an investigational drug trial with therapeutic intent defined as prior study therapy within 14 days prior to study treatment
- Inability to tolerate oral medications including symptomatic disease significantly affecting gastrointestinal function such as inflammatory bowel disease or resection of stomach or small bowel
Additional locations may be listed on ClinicalTrials.gov for NCT05401097.
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PRIMARY OBJECTIVE:
I. To compare overall treatment failure at 24 months in newly diagnosed IDH1 or IDH2 mutated acute myeloid leukemia (AML) patients ≥ 18 years not candidates for intensive induction therapy randomized to either sequential treatment with an IDH inhibitor in combination with azacitidine followed by venetoclax in combination with azacitidine (Arm A) or sequential treatment with venetoclax in combination with azacitidine followed by an IDH inhibitor in combination with azacitidine (Arm B).
SECONDARY OBJECTIVES:
I. To compare overall survival at 24 months between patients treated on the two sequential treatment arms.
II. To compare time to overall treatment failure and time-to-event overall survival between patients treated on the two sequential treatment arms.
III. To determine the degree of response and compare complete remission (CR) rates, CR/complete remission with hematologic improvement (CRh)/complete remission with incomplete blood count recovery (CRi) rates, and overall response rates (CR/CRh/CRi/morphologic leukemia free state [MLFS]) for first-line therapy and second-line therapy between patients treated on the two sequential treatment arms.
IV. To compare the duration of response (CR/CRh/CRi) to first-line therapy and second-line therapy between patients treated on the two sequential treatment arms.
V. To determine toxicity profiles for patients treated on the two sequential treatment arms, overall and by first-line treatment and by second-line treatment.
VI. To determine causes that would not allow patients that first line treatment fails to go on to second line treatment.
VII. To determine the number and proportion of patients who are able to go onto allogeneic transplantation in both treatment arms.
EXPLORATORY OBJECTIVES:
I. To assess the clonal, biochemical and differentiation changes in AML cells during IDH-inhibitor and venetoclax treatment using flow cytometry and serial next generation sequencing on bone marrow specimens before and during treatment to assess for potential resistance mutations or clonal evolution that may be predictors of relapse.
II. To examine molecular properties of AML cells associated with primary and secondary resistance to each treatment arm to determine if particular subtypes of AML may be more or less likely to respond to a certain treatment modality.
III. To perform minimal residual disease (MRD) monitoring via liquid biopsy via our custom-designed 30-gene mutation ArcherPlex panel to monitor clonal dynamics during both sequential treatment arms.
IV. To determine the feasibility of longitudinal sociodemographic and social determinants of health (SDOH) data collection for adults with AML on a clinical trial.
V. To determine the acceptability of longitudinal sociodemographic/SDOH data collection for adults with AML on a clinical trial.
VI. To describe changes in SDOH for adults with AML on a clinical trial.
VII. To describe associations between SDOH measures and trial outcomes for adults with AML on a clinical trial.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM A:
FIRST-LINE THERAPY (IDH INHIBITOR [IDHi] + AZACITIDINE [AZA]): Patients with IDH1 mutated AML receive ivosidenib orally (PO) once daily (QD) on days 1-28 of each cycle, and patients with IDH2 mutated AML receive enasidenib PO QD on days 1-28 of each cycle. All patients also receive azacitidine intravenously (IV) or subcutaneously (SC) QD on days 1-7 or 1-5 and 8-9 of each cycle. Cycles repeat every 28 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity. Patients who achieve CR/CRh/CRi continue receiving ivosidenib with azacitidine or enasidenib with azacitidine in the absence of unacceptable toxicity, relapse, or death. Patients whose disease progresses during the first 5 cycles of therapy, does not attain CR/CRh/CRi by the end of 5 cycles of therapy, attains CR/CRh/CRi by the end of 5 cycles of therapy and subsequently relapses, or has unacceptable toxicity discontinue IDHi + AZA therapy and proceed to second-line therapy within 28 days.
SECOND-LINE THERAPY (VENETOCLAX [VEN] + AZA): Patients receive venetoclax PO QD on days 1-28 of each cycle and azacitidine IV or SC QD on days 1-7 or 1-5 and 8-9 of each cycle. Cycles repeat every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients who achieve CR/CRh/CRi continue receiving venetoclax with azacitidine in the absence of unacceptable toxicity, relapse, or death. Patients whose disease progresses during the first 3 cycles of therapy, does not attain CR/CRh/CRi by the end of 3 cycles of therapy, attains CR/CRh/CRi by the end of 3 cycles of therapy and subsequently relapses, or has unacceptable toxicity discontinue study treatment.
ARM B:
FIRST-LINE THERAPY (VEN + AZA): Patients receive venetoclax PO QD on days 1-28 of each cycle and azacitidine IV or SC QD on days 1-7 or 1-5 and 8-9 of each cycle. Cycles repeat every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients who achieve CR/CRh/CRi continue receiving venetoclax with azacitidine in the absence of unacceptable toxicity, relapse, or death. Patients whose disease progresses during the first 3 cycles of therapy, does not attain CR/CRh/CRi by the end of 3 cycles of therapy, attains CR/CRh/CRi by the end of 3 cycles of therapy and subsequently relapses, or has unacceptable toxicity discontinue VEN + AZA therapy and proceed to second-line therapy within 28 days.
SECOND-LINE THERAPY (IDHi + AZA): Patients with IDH1 mutated AML receive ivosidenib PO QD on days 1-28 of each cycle, and patients with IDH2 mutated AML receive enasidenib PO QD on days 1-28 of each cycle. All patients also receive azacitidine IV or SC QD on days 1-7 or 1-5 and 8-9 of each cycle. Cycles repeat every 28 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity. Patients who achieve CR/CRh/CRi continue receiving ivosidenib with azacitidine or enasidenib with azacitidine in the absence of unacceptable toxicity, relapse, or death. Patients whose disease progresses during the first 5 cycles of therapy, does not attain CR/CRh/CRi by the end of 5 cycles of therapy, attains CR/CRh/CRi by the end of 5 cycles of therapy and subsequently relapses, or has unacceptable toxicity discontinue study treatment.
All patients also undergo blood sample collection as well as bone marrow biopsy and aspiration throughout the trial.
After completion of the study treatment, patients are followed up at 30 days and then every 3 months for 5 years from registration, until death, or withdrawal of consent from study assessments and all further follow-up.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationOhio State University Comprehensive Cancer Center
Principal InvestigatorAlice Scott Mims
- Primary IDOSU-21330
- Secondary IDsNCI-2022-01324, 2022C0009
- ClinicalTrials.gov IDNCT05401097