A PHASE 1/2 STUDY OF ALX148 IN COMBINATION WITH AZACITIDINE IN PATIENTS WITH HIGHER RISK MYELODYSPLASTIC SYNDROME (MDS) (ASPEN-02)

Prior treatment

• Prior treatment with myeloid growth factors and erythropoiesis stimulating agents (ESAs) must be discontinued a minimum of 4-5 half-lives prior to initiation of study treatment.
• Any experimental antibodies or live vaccines in the last 28 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed.
• Any of the following in the previous 6 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, NYHA Class II or greater congestive heart failure, uncontrolled hypertension, cerebrovascular accident, transient ischemic attack, deep venous thrombosis (except for thrombi considered device-associated and not clinically significant), arterial thrombosis, symptomatic pulmonary embolism, or any other significant thromboembolism. Any major surgery, within 28 days prior to enrollment.
• Previous allogeneic hematopoietic stem cell transplant (allo-HSCT) for MDS or AML. If allo-HSCT was performed for another disease, patient must be at least a year post-HSCT, off all treatment for graft-versus-host disease (GVHD), and without any active GVHD.
• Prior treatment with any anti-CD47 or anti-SIRPalpha agent.
• Phase 1 dose escalation only: prior cytotoxic chemotherapy, CAR-T, or other cellular or experimental therapy within 4 weeks of starting study treatment. If any of these therapies (except hydroxyurea up to day -1 of study) was given within 4 weeks, patient may be included if at least 4 times the elimination half-life of the drug has passed Phase 1 dose expansion part and Phase 2: Prior treatment with any hypomethylating agents or cytotoxic chemotherapy for MDS (except hydroxyurea up to day -1 of study and lenalidomide for low or intermediate-1 risk MDS with deletion 5q abnormality).

Other illness

• Patients with a history of autoimmune hemolytic anemia, autoimmune thrombocytopenia, or hemolytic transfusion reaction secondary to an acquired allo-antibody
• Patients with intolerance to or who have had a severe allergic or anaphylactic reaction to antibodies or infused therapeutic proteins or patients who have had a severe allergic or anaphylactic reaction to any of the substances included in the study drug (including excipients).
• Known active viral infections, including hepatitis B (HBV), hepatitis C (HCV), human immunodeficiency virus (HIV), acquired immunodeficiency syndrome (AIDS) related illness, or known active infection with SARS-CoV-2 (testing to be performed per local criteria).
• Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, prostate/breast/other cancer under control with hormone therapy alone, or other cancer from which the subject has been disease free for at least 2 years and felt to be at low risk for recurrence by the treating physician.
• Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
• Phase 1 dose expansion part and Phase 2: Patients with MPN/MDS overlap syndromes, including CMML.

Lab values

• Other severe acute or chronic medical or psychiatric condition, including uncontrolled systemic infection, recent (within the past year) or active suicidal ideation or behavior, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study. Please refer to section 4.2 of the protocol for exclusion criteria 15 and 16.

Other

• Current active treatment in another interventional therapeutic clinical study.

• Phase 1 dose escalation part: Adult patients with documented diagnosis of relapsed/refractory MDS or higher risk MDS (IPSS-R score >3.5) that is previously untreated. For patients with relapsed/refractory MDS, prior exposure to hypomethylating agents is allowed. Patients with previously untreated disease must have had no prior exposure to hypomethylating agents or cytotoxic chemotherapy (prior use of single agent lenalidomide for low or intermediate-1 risk MDS with deletion 5q abnormality is allowed) for the treatment of MDS and be appropriate candidates for single-agent AZA. Phase 1 dose expansion part and phase II: Adult patients with documented diagnosis of higher risk MDS (IPSS-R score >3.5) who have had no prior exposure to hypomethylating agents or cytotoxic chemotherapy (prior use of single agent lenalidomide for low or intermediate-1 risk MDS with deletion 5q abnormality is allowed) for the treatment of MDS, and are considered appropriate candidates for single-agent AZA.
• Serum pregnancy test (for females of childbearing potential) negative at screening.
• Male and female patients of childbearing potential must agree to use a highly effective method of contraception throughout the study and for at least 120 days after the last dose of assigned treatment. A patient is of childbearing potential if, in the opinion of the Investigator, he/she is biologically capable of having children and is sexually active.
• Evidence of a personally signed and dated informed consent document indicating that the patient (or legal representative) has been informed of all pertinent aspects of the study before any study-specific activity is performed.
• Patients who are willing and able to comply with scheduled visits, treatment plans, laboratory, tests and other procedures.
• Phase 1 dose expansion part and phase II: Bone marrow with <20% myeloblasts.
• Adequate Renal Function with estimated creatinine clearance > or =30 mL/min as calculated using the method standard for the institution.
• Adequate Liver Function, including: a. Total serum bilirubin < or =1.5 x ULN (< or =3.0 x ULN if the patient has documented Gilbert syndrome); b. Aspartate and alanine transaminase (AST and ALT) < or =3.0 x ULN; < or =5.0 x ULN if due to leukemic organ involvement; c. Alkaline phosphatase < or =2.5 x ULN; (< or =5.0 x ULN if bone or liver metastasis).
• WBC < 20,000/microL. Administration of hydroxyurea for WBC control is permitted during the screening period up to and including treatment day -1 of the study (ie, one day prior to starting study treatment).
• QTcF interval of < or =480 msec (Based upon mean value from triplicate ECGs).
• Age > or = 18 years because MDS is extremely rare in the pediatric (<18 yrs) population.
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) must be 0, 1 or 2.
• Resolved acute effects of any prior therapy to baseline severity or Grade < or =1 NCI CTCAE v.5.0 except for AEs not constituting a safety risk by Investigator judgment.