Ivosidenib and Azacitidine With or Without Venetoclax in Adult Patients With Newly Diagnosed IDH1-Mutated AML or MDS/AML Considered Ineligible for Intensive Chemotherapy

Ivosidenib and Azacitidine With or Without Venetoclax in Adult Patients With Newly Diagnosed IDH1-Mutated AML or MDS/AML Considered Ineligible for Intensive Chemotherapy

The standard treatment for patients with acute myeloid leukemia (AML) with an abnormality in the IDH1 gene, who are not eligible for intensive chemotherapy, is a combination of ivosidenib and azacitidine. In this study it is investigated whether adding venetoclax to the standard treatment can improve the outcome of the treatment of this specific form of AML. The safety is investigated and how well it works. In order to properly assess the value of venetoclax, the effect of venetoclax is compared with the effect of a placebo. A placebo is a product without an active ingredient, a 'fake medicinal product'.

Inclusion Criteria:

1. Patient with newly diagnosed IDH1-mutated AML, or IDH1-mutated MDS/AML according to the 2022 International Consensus Classification (Appendix A). Patients with AML with both IDH1 and IDH2 mutation are eligible as well. Of note: in case both NPM1 and IDH1 are mutated and both EVOLVE-1 (HO173/AMLSG 3423/ACT-HOV-AML-001) and EVOLVE-2 (HO177/AMLSG 35-24/ACT-HOV-AML-002are open for inclusion at your site, then patients can only be included in the EVOLVE-1 trial (HO173)

2. Central confirmation of IDH1 mutation in one of the dedicated central genetic laboratories.

3. Age ≥ 18 years, no upper age limit.

4. Patient is ineligible for intensive induction chemotherapy by meeting at least 1 of the following criteria:

   • older than or equal to 75 years of age ineligible for intensive chemotherapy per physician's discretion (with an ECOG performance status 0-2; Appendix C).

   • 18-74 years: patient is not eligible for standard chemotherapy because of any of the following co-morbidities: o ECOG performance status 2 or 3 (Appendix C). o Cardiac history of chronic heart failure requiring treatment; or with an ejection fraction ≤50%; or chronic stable angina.

     • DLCO ≤ 65% or FEV1 ≤ 65%.
     • Creatinine clearance ≥ 30 mL/min to <45 ml/min calculated by the Cockcroft Gault formula.
     • Moderate hepatic impairment with total bilirubin > 1.5 to < 3.0 x upper limit of normal (ULN).
     • Any other comorbidity that the local physician assesses to be incompatible with intensive chemotherapy. If a patient meets this criterion, sponsor must be informed via HO173@erasmusmc.nl

5. Patient must have a projected life expectancy of at least 12 weeks (as assessed by the treating physician).

6. Patient must have a white cell blood (WBC) count of < 25 x 109/L. Hydroxyurea can be used prior to study enrollment to reduce the WBC count to meet this criterion.

7. Adequate renal function as evidenced by serum creatinine ≤ 2.0 × upper limit of normal (ULN) or creatinine clearance >30 mL/min based on the Cockcroft-Gault glomerular filtration rate (GFR).

8. Adequate hepatic function as evidenced by:

   • Serum total bilirubin ≤ 3.0 × ULN unless considered due to Gilbert's disease, or leukemic involvement. If a patient meets this criterion, sponsor must be informed via HO173@erasmusmc.nl Page 30 of 117 HOVON 173 AML / AMLSG 34-23 / ACT-HOV-AML-001 Version 1.1, UK 11 FEB 2025
   • Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 3.0 × ULN, unless considered due to leukemic involvement. If a patient meets this criterion, sponsor must be informed via HO173@erasmusmc.nl

9. Female patients :

   • of nonchildbearing potential must be: o postmenopausal (defined as at least 1 year without any menses). o documented surgically sterile (e.g. documented hysterectomy, bilateral oophorectomy or bilateral salpingectomy) or status posthysterectomy (at least 1 month prior to screening).

   • of childbearing potential (not surgically sterile and not postmenopausal) must agree to avoid pregnancy during the study and for 6 months after the final study drug administration o and have a negative urine or serum pregnancy test at screening.

     o and, if heterosexually active, agree to consistently apply one highly effective* method of birth control in combination to a barrier method for the duration of the study and for 6 months after the final study drug administration.

   • must agree not to breastfeed starting at screening and throughout the study period, and for 1 month after the final study drug administration.

   • must agree not to donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration.

10. Men must use a latex condom during any sexual contact with women of childbearing potential (WOCBP), even if they have undergone a successful vasectomy and must agree to avoid to father a child (while on therapy and for 6 months after the final study drug administration). In addition, their female partners of childbearing potential must use a highly effective method of birth control.

11. Male patient must not donate sperm starting at screening and throughout the study period and for 6 months after the final study drug administration.

12. Able to understand and willing to sign an informed consent form (ICF).

13. Institutional Review Board/Independent Ethics Committee-approved written informed consent and privacy language as per national regulations must be obtained from the participant prior to any study-related procedures (including consent for withdrawal of prohibited medication, if applicable).

Exclusion Criteria:

1. Subject has previously been treated for AML; a treatment period with hydroxyurea to control WBC counts is allowed; prior treatment with a hypomethylating agent for MDS-EB is not allowed; prior treatment with erythropoiesis-stimulating agents or luspatercept for MDS is allowed.

2. Acute promyelocytic leukemia (APL) with t(15;17)(q24.1;q21.2); PML-RARA; or one of the other pathognomonic variant chromosomal translocations / fusion genes.

3. AML with BCR-ABL1; or myeloid blast crisis of CML

4. Significant active cardiac disease within 3 months prior to the start of study treatment, including:

   - New York Heart Association (NYHA) class III or IV congestive heart failure (Appendix F)

   - Myocardial infarction

   - Unstable angina

   • Severe cardiac arrhythmias
   • Congenital long QT syndrome of family member with this condition
   • QTcF >480 msec on screening electrogram (mean of triplicate recordings).

5. Familial history of sudden death or polymorphic ventricular arrhythmia.

6. Severe obstructive or restrictive ventilation disorder.

7. History of stroke or intracranial hemorrhage within 6 months prior to randomization.

8. Clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid (CSF) during screening is only required if there is a clinical suspicion of CNS involvement by leukemia during screening.

9. Active infection, including hepatitis B or hepatitis C or Human Immunodeficiency Virus (HIV) infection, that is uncontrolled prior to first dose of study treatment and may interfere with the study objectives or which could expose the patient to undue risk through the participation in the clinical trial; an infection controlled with an approved antibiotic/ antiviral/ antifungal treatment that is not a strong or moderate CYP3A inducer is allowed. Patients with COVID-19 infection can be enrolled, if the patient has no symptoms and was tested negative twice by PCR test prior to inclusion in the trial.

10. Immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding and/or disseminated intravascular coagulation.

11. Conditions that limit the ingestion or gastrointestinal absorption of orally administered drugs

12. Patient with a currently active second malignancy. Patients are not considered to have a currently active malignancy, if they have completed therapy and are considered by their physician to be at < 30% risk of relapse within one year. However, patients with the following history/concurrent conditions are allowed:

    • Basal or squamous cell carcinoma of the skin;
    • Carcinoma in situ of the cervix;
    • Carcinoma in situ of the breast;
    • Incidental histologic finding of prostate cancer.

13. Receipt of live, attenuated vaccine within 30 days prior to the study inclusion (NOTE: patient, if enrolled, should not receive live vaccine during the study and until 6 months after the therapy).

14. Severe neurological or psychiatric disorder interfering with ability to give an informed consent.

15. Contraindication to any of the anti-leukemic agents used (as per SmPC). 16. Participation in other prospective studies with anti-leukemic and/or investigational agents.

17. Patient taking Dabigatran unless they can be transferred to other medications within ≥5 half-lives prior to dosing. Patients taking other P-gP transporter-sensitive medications (see Appendix J) should be properly monitored during the study if they cannot be transferred to other medications." 18. Patients taking known strong cytochrome P450 (CYP) 3A4 inducers (see Appendix H), unless they can be transferred to other medications within ≥5 half-lives prior to dosing.

19. The patient is a pregnant or lactating woman, or plans to become pregnant during the study.

20. Patient who has once been screened and randomized into this HO173 trial but was considered ineligible cannot re-enter this trial at a later date.

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