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

Inclusion Criteria:

1. Patient with newly diagnosed IDH1-mutated AML, or IDH1-mutated MDS/AML according tothe 2022 International Consensus Classification (Appendix A). Patients with AML withboth IDH1 and IDH2 mutation are eligible as well. Of note: in case both NPM1 andIDH1 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 patientscan only be included in the EVOLVE-1 trial (HO173)

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

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

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

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

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

• DLCO ≤ 65% or FEV1 ≤ 65%.

• Creatinine clearance ≥ 30 mL/min to <45 ml/min calculated by the CockcroftGault formula.

• Moderate hepatic impairment with total bilirubin > 1.5 to < 3.0 x upperlimit of normal (ULN).

• Any other comorbidity that the local physician assesses to be incompatiblewith intensive chemotherapy. If a patient meets this criterion, sponsormust be informed via HO173@erasmusmc.nl

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

6. Patient must have a white cell blood (WBC) count of < 25 x 109/L. Hydroxyurea can beused 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 ofnormal (ULN) or creatinine clearance >30 mL/min based on the Cockcroft-Gaultglomerular 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 beinformed 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 alkalinephosphatase (ALP) ≤ 3.0 × ULN, unless considered due to leukemic involvement.If a patient meets this criterion, sponsor must be informed viaHO173@erasmusmc.nl

9. Female patients :

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

• of childbearing potential (not surgically sterile and not postmenopausal) mustagree to avoid pregnancy during the study and for 6 months after the finalstudy drug administration o and have a negative urine or serum pregnancy testat screening.o and, if heterosexually active, agree to consistently apply one highlyeffective* method of birth control in combination to a barrier method for theduration of the study and for 6 months after the final study drugadministration.

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

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

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

11. Male patient must not donate sperm starting at screening and throughout the studyperiod 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 informedconsent and privacy language as per national regulations must be obtained from theparticipant prior to any study-related procedures (including consent for withdrawalof prohibited medication, if applicable).

Exclusion Criteria:

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

2. Acute promyelocytic leukemia (APL) with t(15;17)(q24.1;q21.2); PML-RARA; or one ofthe 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 studytreatment, 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 orknown CNS leukemia. Evaluation of cerebrospinal fluid (CSF) during screening is onlyrequired if there is a clinical suspicion of CNS involvement by leukemia duringscreening.

9. Active infection, including hepatitis B or hepatitis C or Human ImmunodeficiencyVirus (HIV) infection, that is uncontrolled prior to first dose of study treatmentand may interfere with the study objectives or which could expose the patient toundue risk through the participation in the clinical trial; an infection controlledwith an approved antibiotic/ antiviral/ antifungal treatment that is not a strong ormoderate 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 toinclusion in the trial.

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

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

12. Patient with a currently active second malignancy. Patients are not considered tohave a currently active malignancy, if they have completed therapy and areconsidered 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 anduntil 6 months after the therapy).

14. Severe neurological or psychiatric disorder interfering with ability to give aninformed 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 investigationalagents.

16. Patient taking Dabigatran unless they can be transferred to other medications within ≥5 half-lives prior to dosing. Patients taking other P-gP transporter-sensitivemedications (see Appendix J) should be properly monitored during the study if theycannot be transferred to other medications." 18. Patients taking known strongcytochrome P450 (CYP) 3A4 inducers (see Appendix H), unless they can be transferredto other medications within ≥5 half-lives prior to dosing.

17. The patient is a pregnant or lactating woman, or plans to become pregnant during thestudy.

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