IO-202 as Monotherapy and IO-202 Plus Azacitidine ± Venetoclax in Patients in AML and CMML

Study Overview
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Brief Summary
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To assess safety and tolerability at increasing dose levels of IO-202 in successive cohorts of participants with AML with monocytic differentiation and CMML in order to estimate the maximum tolerated dose (MTD) or maximum administered dose (MAD) and select the recommended Phase 2 dose (RP2D)

Detailed Description
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This is a Phase 1, Multicenter, Open-Label, Dose-Escalation and Expansion, Safety, Pharmacokinetic, Pharmacodynamic, and Clinical Activity Study of Intravenously Administered IO-202 and IO-202 + Azacitidine ± Venetoclax in Acute Myeloid Leukemia (AML) Patients with Monocytic Differentiation and in Chronic Myelomonocytic Leukemia (CMML) Patients

Official Title
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A Phase 1, Multicenter, Open-Label, Dose-Escalation and Expansion, Safety, Pharmacokinetic, Pharmacodynamic, and Clinical Activity Study of Intravenously Administered IO-202 and IO-202 + Azacitidine ± Venetoclax in Acute Myeloid Leukemia (AML) Patients With Monocytic Differentiation and in Chronic Myelomonocytic Leukemia (CMML) Patients

Conditions
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AML With Monocytic Differentiation, CMML

Intervention / Treatment
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* Biological: IO-202
* Biological: IO-202 and Azacitidine
* Biological: IO-202 and Azacitidine + Venetoclax
* Biological: IO-202 and Azacitidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be ≥18. For the Part 1 Dose-Escalation Phase, patients must be diagnosed with the following: 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. Relapsed or refractory CMML and has failed treatment with available therapies known to be active for CMML Part 2 Expansion Phase: Relapsed or refractory LILRB4high AML with myelomonocytic or monoblastic/monocytic differentiation and has failed treatment with available therapies known to be active for AML. Hypomethylating-agent naive CMML regardless of LILRB4 expression levels. Newly diagnosed high LILRB4 expression monocytic AML patients considered to be ineligible for standard induction therapy. Patients must be amenable to serial BM aspirates/biopsies and peripheral blood sampling during the study. Patients must be able to understand and willing to sign an informed consent. A legally authorized representative may consent. Patients must have an ECOG performance status of 0 to 2 Patients must have adequate hepatic function Patients must have adequate renal function 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 must be off systemic calcineurin inhibitors for at least 4 weeks prior to study drug treatment. Female patients with reproductive potential must have a negative serum pregnancy test within 7 days prior to the start of therapy. Exclusion Criteria: Patients who have previously received a monoclonal antibody therapy targeting LILRB4. Patients who have undergone HSCT within 60 days of the first dose of IO-202. 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. Patients who received an investigational agent <7 days prior to their first day of study drug administration. Patients for whom potentially curative anti-cancer therapy is available. Patients who are pregnant or breastfeeding. Patients with uncontrolled, active infection. Patients with known hypersensitivity to any of the components of the IO-202 formulation. Patients with known pulmonary lesions and/or history of pneumonitis or interstitial lung disease. Active known malignancy. Patients with New York Heart Association (NYHA) Class III or IV congestive heart failure (CHF) or left ventricular ejection fraction (LVEF) <40%. Ongoing cardiac dysrhythmias Grade 2 or higher per of NCI CTCAE, Version 5.0, Grade ≥2. Known or suspected hypersensitivity to recombinant proteins. Known active bacterial, viral, and/or fungal infection. Patients with any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol. Patients with clinical signs and/or symptoms suggesting active, uncontrolled central nervous system (CNS) leukemia or known active, uncontrolled CNS leukemia. Patients with immediately life-threatening, severe complications of leukemia. Donor Lymphocyte Infusion within 30 days prior to first IO-202 administration. Current active treatment in another interventional therapeutic clinical study. Chronic systemic corticosteroid treatment with a dose of >10 mg prednisone/day or dose equivalent. 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. Acute Promyelocytic Leukemia patients or patients with known Philadelphia chromosome (Ph+) positive AML or chronic myelogenous leukemia (CML) blast crisis. Hyperleukocytosis (leukocytes ≥25 x 10e9/L) at first dose of IO-202.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Dose Escalation and Expansion
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation of IO-202<br>Dose cohorts treated with intravenous (IV) IO-202 monotherapy in ascending doses. | Biological: IO-202<br>* IO-202 as monotherapy<br>|
| Experimental: Dose Escalation of IO-202 Plus Azacitidine<br>AZA Dose cohorts treated with intravenous (IV) IO-202 in ascending doses plus Azacitidine (IV or SC) on days 1-7 of each 28-day cycle. | Biological: IO-202 and Azacitidine<br>* IO-202 and azacitidine combination therapy<br>* Other names: IO-202 and AZA;|
| Experimental: Dose Expansion of IO-202 plus Azacitidine AML<br>To enroll high LILRB4 expression monocytic AML patients refractory to or relapsed after available therapies known to be active in AML. | Biological: IO-202 and Azacitidine<br>* IO-202 and azacitidine combination therapy<br>* Other names: IO-202 and AZA;|
| Experimental: Dose Expansion of IO-202 plus Azacitidine CMML<br>To enroll hypomethylating-agent naive CMML patients. | Biological: IO-202 and Azacitidine<br>* IO-202 and azacitidine combination therapy<br>* Other names: IO-202 and AZA;|
| Experimental: Dose Expansion of IO-202 plus Azacitidine + Venetoclax (Ven)<br>To enroll newly diagnosed high LILRB4 expression AML patients who are unfit for intensive induction chemotherapy. | Biological: IO-202 and Azacitidine + Venetoclax<br>* IO-202 and azacitidine + venetoclax combination therapy<br>* Other names: IO-202 and AZA + Ven;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of IO-202 and IO-202 plus azacitidine ± venetoclax as measured by incidence of adverse events. | Incidence of adverse events | From first dose of IO-202 to 30 days following last study treatment | 
| Safety of IO-202 and IO-202 plus azacitidine ± venetoclax as measured by incidence of adverse events. | Severity of adverse events | From first dose of IO-202 to 30 days following last study treatment | 
| Tolerability of IO-202 and IO-202 plus azacitidine ± venetoclax as measured by incidence and duration of dose interruptions and dose reductions of study treatment. | Incidence dose interruptions and dose reductions | From first dose of IO-202 to 30 days following last study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To characterize the pharmacokinetics (PK) of IO-202 and IO-202 plus azacitidine ± venetoclax and as defined by maximum plasma concentration (Cmax) | Maximum concentration (Cmax) of IO-202 | Through study completion, an average of 1 year | 
| To characterize the PK of IO-202 and IO-202 IO-202 plus azacitidine ± venetoclax as defined by area under the curve (AUC) | measure area under the curve (AUC) of IO-202 | Through study completion, an average of 1 year | 
| To evaluate the incidence of anti-drug antibodies against IO-202 | Measure anti-drug antibodies in plasma. | Through study completion, an average of 1 year | 
| To measure rates of response to IO-202 and IO-202 plus azacitidine ± venetoclax | Measure response rates in patients with anti-drug antibodies. | Through study completion, an average of 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Monocytic