Clinical trial NCT04372433: IO-202 as Monotherapy and IO-202 Plus Azacitidine ± Venetoclax in Patients in AML and CMML
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: AML With Monocytic Differentiation
CMML
Keywords: Monocytic
Lead sponsor: Immune-Onc Therapeutics
Sponsor class: INDUSTRY
Collaborators: name: California Institute for Regenerative Medicine (CIRM)
First posted: 2020-05-04
Enrollment: 67
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Dose Escalation and Expansion
Primary purpose: TREATMENT

Brief summary: 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: 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

Eligibility criteria: 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:

   1. Relapsed or refractory LILRB4high AML with myelomonocytic or monoblastic/monocytic differentiation and has failed treatment with available therapies known to be active for AML.
   2. Hypomethylating-agent naive CMML regardless of LILRB4 expression levels.
   3. Newly diagnosed high LILRB4 expression monocytic AML patients considered to be ineligible for standard induction therapy.
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.
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.
10. Patients must be off systemic calcineurin inhibitors 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 a monoclonal antibody therapy targeting LILRB4.
2. Patients who have undergone HSCT within 60 days of the first dose of IO-202.
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.
4. Patients who received an investigational agent \<7 days prior to their first day of study drug administration.
5. Patients for whom potentially curative anti-cancer therapy is available.
6. Patients who are pregnant or breastfeeding.
7. Patients with uncontrolled, active infection.
8. Patients with known hypersensitivity to any of the components of the IO-202 formulation.
9. Patients with known pulmonary lesions and/or history of pneumonitis or interstitial lung disease.
10. Active known malignancy.
11. Patients with New York Heart Association (NYHA) Class III or IV congestive heart failure (CHF) or left ventricular ejection fraction (LVEF) \<40%.
12. Ongoing cardiac dysrhythmias Grade 2 or higher per of NCI CTCAE, Version 5.0, Grade ≥2.
13. Known or suspected hypersensitivity to recombinant proteins.
14. Known active bacterial, viral, and/or fungal infection.
15. Patients with any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol.
16. Patients with clinical signs and/or symptoms suggesting active, uncontrolled central nervous system (CNS) leukemia or known active, uncontrolled CNS leukemia.
17. Patients with immediately life-threatening, severe complications of leukemia.
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.
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.

Primary outcomes:
measure: Safety of IO-202 and IO-202 plus azacitidine ± venetoclax as measured by incidence of adverse events.
timeFrame: From first dose of IO-202 to 30 days following last study treatment
measure: Safety of IO-202 and IO-202 plus azacitidine ± venetoclax as measured by incidence of adverse events.
timeFrame: From first dose of IO-202 to 30 days following last study treatment
measure: 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.
timeFrame: From first dose of IO-202 to 30 days following last study treatment
Secondary outcomes:
measure: To characterize the pharmacokinetics (PK) of IO-202 and IO-202 plus azacitidine ± venetoclax and as defined by maximum plasma concentration (Cmax)
timeFrame: Through study completion, an average of 1 year
measure: To characterize the PK of IO-202 and IO-202 IO-202 plus azacitidine ± venetoclax as defined by area under the curve (AUC)
timeFrame: Through study completion, an average of 1 year
measure: To evaluate the incidence of anti-drug antibodies against IO-202
timeFrame: Through study completion, an average of 1 year
measure: To measure rates of response to IO-202 and IO-202 plus azacitidine ± venetoclax
timeFrame: Through study completion, an average of 1 year
Other outcomes:
measure: To correlate target expression with response rates
timeFrame: Through study completion, an average of 1 year
measure: To correlate target expression with rates of adverse events
timeFrame: Through study completion, an average of 1 year
measure: To evaluate immunophenotype of leukemic blasts after study treatment.
timeFrame: Through study completion, an average of 1 year
Locations:
city: Davis
country: United States
facility: University California, Davis (117)
state: California
city: Duarte
country: United States
facility: City of Hope (106)
state: California
city: Irvine
country: United States
facility: University of California, Irvine (107)
state: California
city: Los Angeles
country: United States
facility: UCLA, Medical Center Division of Hematology/Oncology (119)
state: California
city: Palo Alto
country: United States
facility: Stanford University (114)
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco (118)
state: California
city: Aurora
country: United States
facility: University of Colorado, Anschutz Medical Campus (103)
state: Colorado
city: Atlanta
country: United States
facility: Winship Cancer Institute of Emory University (105)
state: Georgia
city: Chicago
country: United States
facility: The University of Chicago (113)
state: Illinois
city: New York
country: United States
facility: Weill Cornell Medical College, New York Presbyterian Hospital (110)
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic, Taussig Cancer Institute (111)
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University, Center for Hematologic Malignancies (116)
state: Oregon
city: Dallas
country: United States
facility: University of Texas Southwestern, Simmons Comprehensive Cancer Center (104)
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center (101)
state: Texas
Study officials:
affiliation: Immune-Onc Therapeutics
name: Hong Xiang, PhD
role: STUDY_DIRECTOR
References: