Clinical trial NCT03957915: Study of Escalating Doses of INA03 Administered Intravenously as Single Agent in Adult Patients With Relapse/Refractory Acute Leukemia
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: EARLY_PHASE1
Conditions: Acute Lymphoblastic Leukemia Recurrent
Acute Lymphoblastic Leukemia, in Relapse
Acute Myeloid Leukemia, in Relapse
Acute Myeloid Leukaemia Recurrent
Mixed Phenotype Acute Leukemia
Keywords: acute leukemia
refractory
in relapse
antibody drug conjugate
first in human
escalating doses
INA03
Lead sponsor: Institut Paoli-Calmettes
Sponsor class: OTHER
Collaborators: name: INATHERYS
First posted: 2019-05-21
Enrollment: 33
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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:

  1. AST and or ALT ≤ 2.5 ULN
  2. Total bilirubin level \< 1.5 ULN (except Gilbert disease)
  3. Serum creatinine ≤ 1.5 ULN
  4. LDH \< 3-5 ULN
  5. Uric acid ≤8 mg/dl
  6. Electrolyte panel within normal range
  7. 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
  8. 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:
     1. Patients with acute promyelocytic leukemia
     2. Patients with more than 30% marrow erythroid cells
     3. Patients who have been treated with any anti-TfR antibody
     4. Allogeneic stem cell transplantation in the last 6 months or with persistent active GVHD. Autologous bone marrow transplant in the last 3 months
     5. 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
  1. ≤12 weeks for cranial radiation therapy
  2. ≤ 4 weeks for wide field radiation therapy
  3. ≤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.

Primary outcomes:
measure: Determination of the minimal erythroblastopenia-inducing dose (MEID) for INA03 in adults with refractory/relapsed acute leukemia
timeFrame: within 2 weeks from initial dosing
measure: 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
timeFrame: 28 days from the first administration of INA03
Secondary outcomes:
measure: Safety of INA03: NCI-CTCAE v5.0
timeFrame: Until 30 days after last dose
measure: pharmacokinetic (PK) profile of INA03
timeFrame: From initial dosing day to Day 42
measure: pharmacokinetic (PK) profile of INA03
timeFrame: From initial dosing day to Day 42
measure: pharmacokinetic (PK) profile of INA03
timeFrame: From initial dosing day to Day 42
measure: pharmacodynamics (PD) profile of INA03
timeFrame: From screening to end of study visit (maximum 182 days)
measure: Concentration of anti-INA03 antibodies
timeFrame: From screening to end of study visit (maximum 182 days)
measure: Preliminary clinical response of INA03
timeFrame: from the date of treatment initiation (Day-1) to the date of relapse, progression or death, whichever comes first (a maximum 182 days)
Other outcomes:
Locations:
city: Marseille
country: France
facility: Institut Paoli-Calmettes
state: Bouches-du Rhône
city: Pessac
country: France
facility: Chu Bordeaux Hopital Haut Leveque
city: Toulouse
country: France
facility: IUCT
Study officials:
affiliation: Institut Paoli-Calmettes
name: Norbert VEY, Pr
role: PRINCIPAL_INVESTIGATOR
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