Study of Escalating Doses of INA03 Administered Intravenously as Single Agent in Adult Patients With Relapse/Refractory Acute Leukemia

Study Overview
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Brief Summary
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This Phase 1 Study is an open-label, non-randomized, dose escalation, safety, efficacy, pharmacokinetic, and pharmacodynamic evaluation study of INA03 administered as a single agent IV infusion every 2 weeks to patients ≥18 years of age with R/R AML, MLL, or ALL. The study will be performed in 2 parts: a Dose Titration for Day 1 study (Part 1) followed by a Dose Escalation Part (Part 2) of INA03 used as monotherapy.

Detailed Description
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This Phase 1 Study is an open-label, non-randomized, dose escalation, safety, efficacy, pharmacokinetic, and pharmacodynamic evaluation study of INA03 administered as a single agent IV infusion every 2 weeks to patients ≥18 years of age with R/R AML, MLL, or ALL. The study will be performed in 2 parts: a Dose Titration for Day 1 study (Part 1) followed by a Dose Escalation Part (Part 2) of INA03 used as monotherapy.

Official Title
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A Phase I, First in Human, Open-label Study of Escalating Doses of INA03 Administered Intravenously as Single Agent in Adult Patients With Relapse/Refractory Acute Leukemia

Conditions
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Acute Lymphoblastic Leukemia Recurrent, Acute Lymphoblastic Leukemia, in Relapse, Acute Myeloid Leukemia, in Relapse, Acute Myeloid Leukaemia Recurrent, Mixed Phenotype Acute Leukemia

Intervention / Treatment
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* Drug: INA03 administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: . Patient with cytologically confirmed and documented B-cell or T-cell ALL or de novo, secondary or therapy-related AML or Mixed Phenotype Acute Leukemia (MPAL) defined according to World Health Organization (WHO) 2016 classification28 AND with 20% or more CD71 positive blast cells in relapse after- or refractory to registered therapies or ineligible to standard treatments with circulating blasts ≤ 20 000/mm3. For eligible patients with AML/ALL with blasts > 20000/mm3, a treatment with hydroxyurea is allowed to maintain tumor cells ≤ 20000/mm3 2. Male or female age ≥ 18 years 3. WHO performance status 0-2 4. Following laboratory values unless considered due to the leukemia: AST and or ALT ≤ 2.5 ULN Total bilirubin level < 1.5 ULN (except Gilbert disease) Serum creatinine ≤ 1.5 ULN LDH < 3-5 ULN Uric acid ≤8 mg/dl Electrolyte panel within normal range Urine Dipstick Reading negative for proteinuria or, if documentation of +1 results for protein on dipstick reading, then total urinary protein ≤ 500 mg and measured creatinine clearance ≥50mL/min/1.73m2 from a 24-hour urine collection Patients who have recovered at least CTCAE grade <2 5. Life expectancy greater than 3 months 6. Women of child bearing potential must be willing to use birth control method during the study duration (W4 or early termination) plus 30 days. Male partner of women must use condom; in case of male patient, he must agree to use condom during the study duration (W4 or early termination) plus 30 days; 7. Pregnancy test (females of childbearing potential): negative 8. Signed informed consent indicating that they have been informed of the procedures to be followed, an is willing and able to comply the experimental nature of the therapy, alternatives, potential benefits, side effects, risks, and discomforts 9. Patient affiliated to the national Social Security regimen or beneficiary of this regi-men Exclusion Criteria: Patients with acute promyelocytic leukemia Patients with more than 30% marrow erythroid cells Patients who have been treated with any anti-TfR antibody Allogeneic stem cell transplantation in the last 6 months or with persistent active GVHD. Autologous bone marrow transplant in the last 3 months Last dose of prior chemotherapy, immunotherapy or investigational agent within 14 days or within 5 half-lives before baseline receipt of study medication, except for hydroxyurea and corticosteroids 7. Patients who have had a prior anaphylactic or other severe infusion reaction such that the patient is unable to tolerate human immunoglobulin or monoclonal antibody administration 8. Patients who have history or clinical evidence of central nervous system (CNS), meningeal, or epidural disease from any cause and/or peripheral neuropathy 9. Impaired cardiac function or clinically significant cardiac disease, including any one of the following: a. New York Heart Association Class III or IV cardiac disease, including preexisting clinically significant arrhythmia, congestive heart failure, or cardiomyopathy b. Angina pectoris ≤ 3 months prior to starting study drug c. Acute myocardial infarction ≤ 3 months prior to starting study drug d. Other clinically significant heart disease (e.g., uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen) e. Left ventricular Ejection Fraction <45% 11. Uncontrolled infection 12. Acute and chronic liver disease 13. Other severe, acute, or chronic medical or psychiatric condition or laboratory abnor-mality that may increase the risk associated with study participation or study drug administra-tion or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for this study. 14. Patients with prior radiation therapy ≤12 weeks for cranial radiation therapy ≤ 4 weeks for wide field radiation therapy ≤2 weeks for involved field radiation therapy 15. Major surgery ≤ 4weeks prior to starting study drug or who have not recovered from side effects of such therapy 16. Known diagnosis of HIV infection (HIV testing is not mandatory). 17. History of another primary malignancy that is currently clinically significant or currently requires active intervention 18. Pregnant or breastfeeding patient; 19. Active drug or alcohol dependence; 20. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

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
Intervention Model: Sequential Assignment
Interventional Model Description: This Phase 1 Study is an open-label, non-randomized, dose escalation, safety, efficacy, pharmacokinetic, and pharmacodynamic evaluation study of INA03 administered as a single agent IV infusion every 2 weeks to patients ≥18 years of age with R/R AML, MLL, or ALL. The study will be performed in 2 parts: a Dose Titration for Day 1 study (Part 1) followed by a Dose Escalation Part (Part 2) of INA03 used as monotherapy.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: INA03<br>INA03 administration | Drug: INA03 administration<br>* INA03 will be administered IV on Day 1, Day 14 of 28-day cycles. The administration of INA03 will begin at 0.02 mg/kg. Study Part I is a titration study to determine the dose for the first INA03 infusion. Patients will be enrolled in sequential cohorts of 2 patients to receive ascending starting doses of INA03, starting from the lowest starting dose (0.02 mg/kg), and followed by subsequent administrations of INA03 (D14 and beyond) at a fixed dose of 0.1 mg/kg. The starting dose will be increased every cohort of 2 patients until evidence of absence of marrow residual erythroblasts by D14 myelogram. This dose is referred to as the MEID and will be selected as the D1 dose for the study Part 2. Patient accumulation in Part I of the study will continue until no evidence of non-hematological DLT within 28 days post dosing<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of the minimal erythroblastopenia-inducing dose (MEID) for INA03 in adults with refractory/relapsed acute leukemia | MEID defined as the lowest dose associated with the risks of residual erythroblasts in the bone marrow at 2 weeks from initial dosing or grade 2 or above non hematologic toxicity within 2 weeks from initial dosing | within 2 weeks from initial dosing | 
| Determination of the maximum tolerated dose (MTD) for subsequent administrations (D15 from initial dosing and beyond) for INA03 in adults with refractory/relapsed acute leukemia | the maximum tolerated dose (MTD) for subsequent administrations (D15 from initial dosing and beyond) | 28 days from the first administration of INA03 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of INA03: NCI-CTCAE v5.0 | Safety from the findings of reports of adverse events based on incidence, severity (as graded by the NCI-CTCAE v5.0), cumulative nature of treatment-emergent adverse event (TEAEs) | Until 30 days after last dose | 
| pharmacokinetic (PK) profile of INA03 | Peak Plasma Concentration (Cmax) will be calculated, as appropriate | From initial dosing day to Day 42 | 
| pharmacokinetic (PK) profile of INA03 | Area under the plasma concentration versus time curve (AUC) will be calculated, as appropriate | From initial dosing day to Day 42 | 
| pharmacokinetic (PK) profile of INA03 | The terminal half-life will be calculated, as appropriate | From initial dosing day to Day 42 | 
| pharmacodynamics (PD) profile of INA03 | PD according to variation of erythroblast and blasts decrease using bone marrow as-pirate (BMA), and blood samples before and under treatment | From screening to end of study visit (maximum 182 days) | 
| Concentration of anti-INA03 antibodies | Serum concentration of anti-INA03 antibodies in micrograms per milliliter | From screening to end of study visit (maximum 182 days) | 
| Preliminary clinical response of INA03 | Clinical response as defined by European LeukemiaNet (ELN) 2017 recommendations | from the date of treatment initiation (Day-1) to the date of relapse, progression or death, whichever comes first (a maximum 182 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute leukemia, refractory, in relapse, antibody drug conjugate, first in human, escalating doses, INA03