Study of NMS-03597812 in Adult Patients With Relapsed/Refractory Acute Myeloid Leukemia

Inclusion Criteria:

• Confirmed diagnosis of refractory/relapsed (R/R) AML according to 2022 ELNrecommendation:

Phase Ia

• single agent dose escalation of NMS-03597812: R/R AML patients who have exhaustedstandard therapy: a) prior fit patients to intensive chemotherapy (IC): failed atleast one cycle of IC in front-line therapy or b) prior unfit to IC: failed at least 2 cycles of hypomethylating agents (HMA)/venetoclax combination therapy, or at least 4 cycles of HMA monotherapy; c) patients must have failed all other approvedtherapies for which they are eligible, including FLT3 inhibitors, IDH1/2 inhibitors,and CD33 directed therapy

Phase Ib

• Cohort A: single agent in R/R AML TP53mt patients who have exhausted standardtherapy: a) prior unfit to intensive chemotherapy (IC): failed at least 2 cycles ofHMA/venetoclax combination therapy, or at least 4 cycles of HMA monotherapy; b)patients must have failed all other approved therapies for which they are eligible,including FLT3 inhibitors, IDH1/2 inhibitors, and CD33 directed therapy

• Cohort B: single agent in R/R AML TP53wt patients who have exhausted standardtherapy: a) prior fit patients to intensive chemotherapy (IC): failed at least onecycle of IC in front-line therapy or b) prior unfit to IC: failed at least 2 cyclesof HMA/venetoclax combination therapy, or at least 4 cycles of HMA monotherapy; c)patients must have failed all other approved therapies for which they are eligible,including FLT3 inhibitors, IDH1/2 inhibitors, and CD33 directed therapy

• Adult (age ≥ 18 years) patients

• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

• Unless agreed with sponsor, the interval from prior antitumor treatment should be atleast 2 weeks or 5 half-lives, whichever is longer, other than hydroxyurea

• All acute toxic effects (excluding alopecia) of any prior therapy must have resolvedto NCI CTCAE version 5.0 Grade≤ 1

• Adequate organ function

• Must use highly effective contraception or true abstinence. Female patients must besurgically sterile or, if patient is of childbearing potential, must agree to useeffective contraception of therapy and in the following 210 days afterdiscontinuation of study treatment. Since NMS-03597812 has potential induction ofCYP3A4, women of childbearing potential must be advised that hormonal contraceptivesmight lose efficacy and must use alternate form of highly effective contraception.Male patients must be surgically sterile or must agree to use highly effectivecontraception or true abstinence during the period of therapy and in the following 120 days for male patients who must refrain from donating sperm during this periodafter discontinuation of study treatment.

• Capability to swallow capsules intact (without chewing, crushing, or opening)

• Willingness and ability to comply with scheduled visits, treatment plan, laboratorytests and other study indications or procedures

• Signed and dated Independent Ethics Committee (IEC) or Institutional Review Board (IRB)-approved informed consent form indicating that the patient is aware of theneoplastic nature of his/her disease and has been informed of the procedures to befollowed, the investigational nature of the therapy, potential benefits, sideeffects, discomforts, risks, and alternative treatments.

Exclusion Criteria:

• Current enrollment in another interventional clinical study unless onlyparticipating in survival follow up

• White blood cells (WBC) count >20×10^3/microliter (μL). However, patients can betreated with hydroxyurea and/or leukapheresis prior to study treatment start toreduce the WBC to ≤ 20×10^3/μL to enable eligibility for study drug dosing.

• Diagnosis of acute promyelocytic leukemia or BCR-ABL-positive leukemia

• Currently active second malignancy, except for adequately treated basal or squamouscell skin cancer and/or cone biopsied in situ carcinoma of the cervix uteri and/orsuperficial bladder cancer.

• Patients with known leukemia involvement of central nervous system (CNS).

• Hematopoietic stem cell transplantation (HSCT) within 3 months of treatment startand/or persistent non- hematologic toxicities of Grade ≥2 related to the transplant

• Active acute or chronic graft versus host disease (GVHD) requiring immunosuppressivetreatment

• Patients with QTcF interval ≥ 470 milliseconds or with risk factors for torsade depointes (e.g., uncontrolled heart failure, uncontrolled hypokalemia, history ofprolonged QTc interval or family history of long QT syndrome). For patientsreceiving treatment with concomitant medications known to prolong the QTc interval,replacement with another treatment needs to be considered. If replacement ordiscontinuation is not clinically feasible, a careful risk/benefit evaluation shouldbe performed prior to enrollment.

• Pregnancy. All female patients with reproductive potential must have a negativepregnancy test (serum or urine) within the screening period prior to start of studydrug.

• Breast-feeding or planning to breast feed during the study or within 90 days afterstudy treatment.

• Known active gastrointestinal disease (eg, gastro-duodenal ulcer, gastrectomy,Crohn's disease, ulcerative colitis, or short gut syndrome) or other malabsorptionsyndromes that would impact on drug absorption.

• Patient who are receiving concomitant medications with antacids (proton pumpinhibitors are strictly prohibited; calcium carbonate antacids are only allowed 6hours prior to a dose or 1 hour after). Note: exclusion criterion not applicable tooptional backfill cohort for investigation of drug-drug interaction with antiacids.

• Patient who are receiving concomitant medications that are strong inducers orinhibitors of CYP3A4 (with the exception of azole antifungals) and CYP2C9 thatcannot be replaced with alternative therapy.

• Patients who are receiving concomitant medications that are sensitive substrates ofCYP3A4,CYP2D6, CYP1A2 and CYP2B6 with narrow therapeutic window that cannot bereplaced with alternative therapy. Drugs with broad therapeutic indices may still beacceptable.

• Patients who are receiving concomitant medications that are strong or moderate P-gpinhibitors that cannot be replaced with alternative therapy.

• Major surgery within 4 weeks before study treatment start.

• Radiotherapy within 4 weeks before study treatment start. However, if the radiationportal covered ≤5 % of the bone marrow reserve, the patient may be enrolledirrespective of the end date of radiotherapy.

• History of necrotic pancreatitis or acute severe pancreatitis, requiring medicalintervention and/or hospitalization, in the previous 6 months before study treatmentstart.

NOTE: Other protocol defined inclusion/exclusion criteria may apply.