BAL0891 in Patients With Advanced Solid Tumors or Relapsed or Refractory Acute Myeloid Leukemia

1.1. Inclusion criteria: Substudy 1, 2, 3 and Dose expansion Each patient must meet all the following inclusion criteria.

1. Informed consent signed by the patient prior to any study-related procedure indicating that they understand the purpose of, and procedures required for, the study, and are willing to participate in the study.

2. Male or female aged ≥18 years (or ≥ 19 years according to local regulatory guidelines) at the time of screening.

3. Patients with incurable advanced/metastatic solid tumor disease refractory to or intolerant of existing therapy known to provide clinical benefit for their condition.

   Note: Patients with non-CNS tumors participating during dose escalation may have inactive CNS metastasis, defined as 4 weeks after either brain metastasis resection or radiation, and a) all residual neurological symptoms resolved to grade ≤ 2; b) on stable doses of dexamethasone, if applicable; and c) follow-up imaging shows no new lesions appearing.

4. Patients enrolled in Dose Expansion only

   • TNBC cohorts i. Must have histologically confirmed breast adenocarcinoma that is unresectable, loco-regional, or metastatic.

   ii. Must have source data documented pathologically confirmed triple negative breast cancer, defined as both of the following.

   1. Estrogen receptor (ER) and progesterone receptor (PgR) negative: <1% of tumor cell nuclei are immunoreactive in the presence of evidence that the sample can express ER or PgR (positive intrinsic controls)

   2. Human epidermal growth factor receptor 2 (HER2) negative as per American Society of Clinical Oncology/College of American Pathologists guidelines

      • IHC 0 or 1 fluorescence in situ hybridization (FISH) negative (or equivalent negative test)
      • Patients with IHC 2 must have a negative by FISH (or equivalent negative test) iii. Patients with a history of different breast cancer phenotypes (i.e., ER/PgR/HER2 Positive) must obtain pathological confirmation of triple-negative disease in at least one of the current sites of metastasis.

   iv. Must have progression on or after therapy containing anthracycline and/or a taxane. Subjects must have received anthracycline and/or a taxane based regimen or other chemotherapy / targeted therapy regimen if anthracycline or taxane was contraindicated or another available approved targeted agent was contraindicated. At time of enrolment, patients must have progressed on, be intolerant of, or be ineligible for, all available standard of care therapies with proven benefit.

   • GC cohort i. Must have a histologically or cytologically confirmed diagnosis of gastric or gastroesophageal junction adenocarcinoma.

   ii. Must have progression on or after therapy containing platinum/fluoropyrimidine. Subjects must have received platinum-based chemotherapy or other chemotherapy regimen if platinum-based chemotherapy was contraindicated or another available approved targeted agent unless the targeted agent was contraindicated. At time of enrolment, patients must have progressed on, be intolerant of, or be ineligible for, all available standard of care therapies with proven benefit.

   iii. Documentation of HER2/neu status. Patients who are HER2/neu-positive must be treated with a HER2/neu inhibitor, and subjects should have progressed on or be intolerant to the targeted therapy or subjects must have received other chemotherapy regimen if HER2/neu inhibitor was contraindicated or another available approved targeted agent unless the targeted agent was contraindicated. At time of enrolment, patients must have progressed on, be intolerant of, or be ineligible for, all available standard of care therapies with proven benefit.

   iv. Subjects must/should have received no more than 3 lines of prior therapy for the advanced disease (if a subject progressed within 6 months of completing adjuvant therapy, this would count as a prior line of therapy).

5. For patients enrolled in Substudy 3 or cohort 3 and 4, if a taxane (i.e., paclitaxel or docetaxel) was administered as part of the previous regimen, PD must have occurred > 12 months from the end of the previous treatment. (Patients who received a taxane in previous treatments without reaching PD may enroll without the 12-month waiting period.)

6. Patients enrolled in Dose Expansion only, patient must have undergone a minimum of 1 prior systemic regimen for advanced or metastatic disease. (Korea only, patients must have received the second line standard of care treatment as per the regulations of the respective country. Patients who are unsuitable to receive the standard of care second line treatment will be eligible for enrollment)

7. Eastern Cooperative Oncology Group performance status (ECOG PS) 0or-1

8. For patients enrolled from DL1.4 of Substudy 1 onwards and for all patients in Substudies 2 and 3 and all four dose expansion cohorts, measurable tumor disease per Response Evaluation Criteria in Solid Tumors 1.1 criteria (RECIST 1.1), i.e., a minimum of one target lesion.

9. Adequate organ functions as indicated by the following Screening visit local laboratory values:

   1. Hemoglobin ≥ 9 g/dL (criterion must be met without erythropoietin dependency and without packed red blood cell transfusion within the last 4 weeks)
   2. ANC ≥ 2.0 × 109/L; criterion must be met without growth factor (e.g., G-CSF, GM CSF, etc.) administration within the last 2 weeks
   3. Platelets ≥ 100 × 109/L
   4. Total bilirubin ≤ 1.5 × ULN
   5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) baseline levels ≤ 1.5 × ULN, with the option for AST/ALT ≤ 3.0 × ULN, or ≤ 5.0 × ULN for patients with liver metastasis, upon accumulating evidence for the absence of liver toxicity in biologically active DLs
   6. Albumin ≥ 2.8 g/dL
   7. CLCR ≥ 50 mL/min (as calculated by the Cockcroft-Gault formula), or eGFR ≥ 50 mL/min/1.73 m² (MDRD equation or CKD-EPI equation)
   8. For women of childbearing potential, negative serum human chorionic gonadotropin (hCG)

10. Men/women of child-producing/bearing potential must agree to: avoid impregnating a partner or becoming pregnant, respectively, during the study, and for at least 6 months after the last dose of either investigational drug, and comply with the contraception requirements.

1.2. Inclusion criteria: Substudy 4 Each patient must meet all the following inclusion criteria.

1. Informed consent signed by the patient prior to any study-related procedure indicating that they understand the purpose of, and procedures required for, the study, and are willing to participate in the study.

2. Male or female aged ≥18 years (or ≥ 19 years according to local regulatory guidelines) at the time of screening.

3. Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2.

4. Estimated life expectancy of at least 8 weeks

5. AML either de novo or secondary as any subtype diagnosed according to the WHO 2022 classification system [except acute promyelocytic leukemia (APL)] who either:

   Relapse/refractory (R/R) acute myeloid leukemia (AML) defined as those who have also failed or are not appropriate for any approved standard-of-care (SOC) therapies, or hematopoietic stem cell transplant (HSCT) with reappearance of ≥ 5% blasts in the bone marrow.

6. Relapsed AML is defined as having 5% or more leukemic blasts in the bone marrow, reappearance of leukemic blasts in peripheral blood (in at least two peripheral blood samples taken at least one week apart), or the development of new extramedullary disease.

7. WBC, peripheral blood leukocyte count≤ 25,000/µL and blast count ≤ 25,000/µL prior to initiation of therapy

   1. Hydroxyurea is allowed during screening and prior to day 1 of study treatment to keep the blast count ≤25,000/µL; hydroxyurea is to be ceased 24 hours prior to study therapy.
   2. Hydroxyurea may be used for up to 28 days in the initial treatment cycle if needed, to keep the white blood cell (WBC) count ≤25,000/µL. However, no other anti-leukemic treatments, apart from the study drug, are allowed during this period.
   3. Leukapheresis is allowed to maintain blast count ≤25,000/µL

8. Adequate organ functions as indicated by the following Screening visit local laboratory values:

   1. CLCR ≥ 60 mL/min (as calculated by the Cockcroft-Gault formula), or eGFR ≥ 60 mL/min/1.73 m² (MDRD equation or CKD-EPI equation)
   2. Total bilirubin ≤ 1.5 × ULN (unless considered due to leukemic organ involvement), or, Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN
   3. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) baseline levels ≤ 3.0 × ULN
   4. Albumin ≥ 2.5 g/dL
   5. International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
   6. Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

9. Men/women of child-producing/bearing potential must agree to: avoid impregnating a partner or becoming pregnant, respectively, during the study, and for at least 6 months after the last dose of either investigational drug, and comply with the contraception requirements.