IO-202 as Monotherapy in Patients in AML and CMML

Inclusion Criteria:

1. Patients must be ≥18.

2. For the Part 1 Dose-Escalation Phase, patients must be diagnosed with the following:

   1. Relapsed or refractory AML with myelomonocytic or monoblastic/monocytic differentiation according to the World Health Organization 2016 criteria and has failed treatment with available therapies known to be active for AML.
   2. Relapsed or refractory CMML and has failed treatment with available therapies known to be active for CMML

3. Part 2 Expansion Phase:

   a) Relapsed or refractory AML with myelomonocytic or monoblastic/monocytic differentiation and has failed treatment with available therapies known to be active for AML.

4. Patients must be amenable to serial BM aspirates/biopsies and peripheral blood sampling during the study.
5. Patients must be able to understand and willing to sign an informed consent. A legally authorized representative may consent on behalf of a patient who is otherwise unable to provide informed consent, if acceptable to and approved by the site and/or site's Institutional Review Board (IRB) or Ethics Committee.
6. Patients must have an ECOG performance status of 0 to 2
7. Patients must have adequate hepatic function
8. Patients must have adequate renal function
9. Patients must be recovered from any clinically relevant toxic effects of any prior surgery, radiotherapy, or other therapy intended for the treatment of cancer (patients with residual Grade 1 toxicity, or any grade of alopecia, are allowed; patients with peripheral neuropathy that is not more than Grade 2 and stable are allowed).
10. Patients must be off systemic calcineurin inhibitors (e.g., cyclosporine, tacrolimus) for at least 4 weeks prior to study drug treatment.
11. Female patients with reproductive potential must have a negative serum pregnancy test within 7 days prior to the start of therapy.

Exclusion Criteria:

1. Patients who have previously received IO-202.
2. Patients who have undergone HSCT within 60 days of the first dose of IO-202, or patients on immunosuppressive therapy post human stem cell transplantation (HSCT) at the time of screening, or with clinically significant graft-versus-host disease (GVHD) (the use of a stable dose of oral steroids post-HSCT of <10 mg prednisone/day or dose equivalent of other corticosteroid and/or topical steroids for ongoing skin GVHD is permitted with Medical Monitor approval).
3. Patients who received systemic anti-cancer therapy or radiotherapy <7 days prior to their first day of study drug administration (Hydroxyurea or leukapheresis is allowed up to 24 hours prior to the first dose. However, hydroxyurea must be ceased 24 hours prior to the first dose of IO-202 treatment in Cycle 1); it may be initiated again if necessary 24 hours after the first dose of IO-202 treatment in Cycle 1).
4. Patients who received an investigational agent <7 days prior to their first day of study drug administration. In addition, the first dose of IO-202 should not occur before a period ≥5 half-lives of the investigational agent has elapsed.
5. Patients for whom potentially curative anti-cancer therapy is available.
6. Patients who are pregnant or breast feeding.
7. Patients with uncontrolled, active infection.
8. Patients with known hypersensitivity to any of the components of the IO-202 formulation.

9. Active known malignancy with the exception of any of the following:

   1. Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer;
   2. Low-risk prostate cancer for which observation or hormonal therapy only is indicated;
   3. Any other malignancy treated with curative intent with the last treatment completed ≥6 months before study initiation (with the exception of hormonal therapies when indicated).
10. Patients with New York Heart Association (NYHA) Class III or IV congestive heart failure (CHF) or left ventricular ejection fraction (LVEF) <40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan ≤28 days prior to Cycle 1, Day 1.
11. Any of the following in the previous 6 months: myocardial infarction, congenital long QT syndrome, Torsades de pointes, clinically significant arrhythmias (including sustained ventricular tachyarrhythmia and ventricular fibrillation), and left anterior hemiblock (bifascicular block), unstable angina, coronary/peripheral artery bypass graft, symptomatic CHF (NYHA class III or IV), cerebrovascular accident, transient ischemic attack, or pulmonary embolism. Patients with asymptomatic right bundle branch block or controlled atrial fibrillation are allowed.
12. Ongoing cardiac dysrhythmias Grade 2 or higher per of NCI CTCAE, Version 5.0, Grade ≥2.
13. Known or suspected hypersensitivity to recombinant human proteins.
14. Known active bacterial, viral, and/or fungal infection including hepatitis B (HBV), hepatitis C, human immunodeficiency virus (HIV), acquired immunodeficiency syndrome (AIDS)-related illness, or active Covid-19 infection. . Hepatitis B and C and HIV testing are not required for asymptomatic patients; however, for patients who have previously tested positive or have a known history of hepatitis B and C, HIV, and/or tuberculosis, clinical laboratory assessments at screening will include repeat testing for the previous infection. A sample for SARS-CoV-2 should be obtained during the screening period, and results must be available prior to C1D1.
15. Patients with any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before trial entry.
16. Patients with clinical signs and/or symptoms suggesting active, uncontrolled central nervous system (CNS) leukemia or known active, uncontrolled CNS leukemia (a lumbar puncture is not required in patients without signs or symptoms that are suggestive of CNS leukemia). Note: Patients with controlled CNS leukemia (documented by 2 consecutive assessments of zero blast count in cerebrospinal fluid), and who are still receiving intrathecal (IT) therapy at study entry are considered eligible and will continue to receive IT therapy.
17. Patients with immediately life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, or disseminated intravascular coagulation.
18. Donor Lymphocyte Infusion within 30 days prior to first IO-202 administration.
19. Current active treatment in another interventional therapeutic clinical study.
20. Chronic systemic corticosteroid treatment with a dose of ≥10 mg prednisone/day or dose equivalent of another corticosteroid. Topical applications, inhaled sprays, eye drops, local injections of corticosteroids, and systemic steroids required for acute medical interventions are allowed.
21. Other severe acute or chronic medical or psychiatric condition 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.
22. Acute Promyelocytic Leukemia patients or patients with known Philadelphia chromosome (Ph+) positive AML or chronic myelogenous leukemia (CML) blast crisis.
23. Hyperleukocytosis (leukocytes ≥25 x 10e9/L) at first dose of IO-202. These patients may be treated with hydroxyurea or receive leukapheresis treatment according to routine practice, and enrolled in the study when the leukocyte count falls below 25 x 10e9/L.
24. Patients who are investigational site staff members or relatives of those site staff members or patients who are Immune-Onc employees directly involved in the conduct of the trial.