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出境医 / 临床实验 / Study of Escalating Doses of INA03 Administered Intravenously as Single Agent in Adult Patients With Relapse/Refractory Acute Leukemia (INA03)

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

Study Description
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.


Condition or disease Intervention/treatment Phase
Acute Lymphoblastic Leukemia Recurrent Acute Lymphoblastic Leukemia, in Relapse Acute Myeloid Leukemia, in Relapse Acute Myeloid Leukaemia Recurrent Mixed Phenotype Acute Leukemia Drug: INA03 administration Early Phase 1

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.

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 34 participants
Intervention Model: Sequential Assignment
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.
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : January 27, 2020
Estimated Primary Completion Date : January 27, 2022
Estimated Study Completion Date : February 28, 2022
Arms and Interventions
Arm Intervention/treatment
Experimental: INA03
INA03 administration
 Drug: INA03 administration
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
Outcome Measures
Primary Outcome Measures :
  1. Determination of the minimal erythroblastopenia-inducing dose (MEID) for INA03 in adults with refractory/relapsed acute leukemia [ Time Frame: within 2 weeks from initial dosing ]
    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

  2. 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 [ Time Frame: 28 days from the first administration of INA03 ]
    the maximum tolerated dose (MTD) for subsequent administrations (D15 from initial dosing and beyond)


Secondary Outcome Measures :
  1. Safety of INA03: NCI-CTCAE v5.0 [ Time Frame: Until 30 days after last dose ]
    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)

  2. pharmacokinetic (PK) profile of INA03 [ Time Frame: From initial dosing day to Day 42 ]
    Peak Plasma Concentration (Cmax) will be calculated, as appropriate

  3. pharmacokinetic (PK) profile of INA03 [ Time Frame: From initial dosing day to Day 42 ]
    Area under the plasma concentration versus time curve (AUC) will be calculated, as appropriate

  4. pharmacokinetic (PK) profile of INA03 [ Time Frame: From initial dosing day to Day 42 ]
    The terminal half-life will be calculated, as appropriate

  5. pharmacodynamics (PD) profile of INA03 [ Time Frame: From screening to end of study visit (maximum 182 days) ]
    PD according to variation of erythroblast and blasts decrease using bone marrow as-pirate (BMA), and blood samples before and under treatment

  6. Concentration of anti-INA03 antibodies [ Time Frame: From screening to end of study visit (maximum 182 days) ]
    Serum concentration of anti-INA03 antibodies in micrograms per milliliter

  7. Preliminary clinical response of INA03 [ Time Frame: from the date of treatment initiation (Day-1) to the date of relapse, progression or death, whichever comes first (a maximum 182 days) ]
    Clinical response as defined by European LeukemiaNet (ELN) 2017 recommendations


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Dominique Genre, Dr (00) 4 91 22 37 78 drci.up@ipc.unicancer.fr
Contact: Margot Berline, MSc, MBA 04 91 22 33 14 BERLINEM@ipc.unicancer.fr

Locations
Layout table for location information
France
Institut Paoli-Calmettes Recruiting
Marseille, Bouches-du Rhône, France, 13009
Contact: Dominique GENRE, MD    +33 4 91 22 37 78    drci.up@ipc.unicancer.fr   
Principal Investigator: Norbert VEY         
IUCT Not yet recruiting
Toulouse, France
Principal Investigator: Christian RECHER         
Sponsors and Collaborators
Institut Paoli-Calmettes
INATHERYS
Investigators
Layout table for investigator information
Principal Investigator: Norbert VEY, Pr Institut Paoli-Calmettes
Tracking Information
First Submitted Date  ICMJE May 6, 2019
First Posted Date  ICMJE May 21, 2019
Last Update Posted Date February 6, 2020
Actual Study Start Date  ICMJE January 27, 2020
Estimated Primary Completion Date January 27, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 20, 2019)
  • Determination of the minimal erythroblastopenia-inducing dose (MEID) for INA03 in adults with refractory/relapsed acute leukemia [ Time Frame: within 2 weeks from initial dosing ]
    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
  • 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 [ Time Frame: 28 days from the first administration of INA03 ]
    the maximum tolerated dose (MTD) for subsequent administrations (D15 from initial dosing and beyond)
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 20, 2019)
  • Safety of INA03: NCI-CTCAE v5.0 [ Time Frame: Until 30 days after last dose ]
    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)
  • pharmacokinetic (PK) profile of INA03 [ Time Frame: From initial dosing day to Day 42 ]
    Peak Plasma Concentration (Cmax) will be calculated, as appropriate
  • pharmacokinetic (PK) profile of INA03 [ Time Frame: From initial dosing day to Day 42 ]
    Area under the plasma concentration versus time curve (AUC) will be calculated, as appropriate
  • pharmacokinetic (PK) profile of INA03 [ Time Frame: From initial dosing day to Day 42 ]
    The terminal half-life will be calculated, as appropriate
  • pharmacodynamics (PD) profile of INA03 [ Time Frame: From screening to end of study visit (maximum 182 days) ]
    PD according to variation of erythroblast and blasts decrease using bone marrow as-pirate (BMA), and blood samples before and under treatment
  • Concentration of anti-INA03 antibodies [ Time Frame: From screening to end of study visit (maximum 182 days) ]
    Serum concentration of anti-INA03 antibodies in micrograms per milliliter
  • Preliminary clinical response of INA03 [ Time Frame: from the date of treatment initiation (Day-1) to the date of relapse, progression or death, whichever comes first (a maximum 182 days) ]
    Clinical response as defined by European LeukemiaNet (ELN) 2017 recommendations
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Escalating Doses of INA03 Administered Intravenously as Single Agent in Adult Patients With Relapse/Refractory Acute Leukemia
Official Title  ICMJE 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
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Early Phase 1
Study Design  ICMJE Intervention Model: Sequential Assignment
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.

Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Acute Lymphoblastic Leukemia Recurrent
  • Acute Lymphoblastic Leukemia, in Relapse
  • Acute Myeloid Leukemia, in Relapse
  • Acute Myeloid Leukaemia Recurrent
  • Mixed Phenotype Acute Leukemia
Intervention  ICMJE Drug: INA03 administration
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
Study Arms  ICMJE Experimental: INA03
INA03 administration
Intervention: Drug: INA03 administration
Publications *
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*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 17, 2020) 		34
Original Estimated Enrollment  ICMJE
 (submitted: May 20, 2019) 		30
Estimated Study Completion Date  ICMJE February 28, 2022
Estimated Primary Completion Date January 27, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Dominique Genre, Dr (00) 4 91 22 37 78 drci.up@ipc.unicancer.fr
Contact: Margot Berline, MSc, MBA 04 91 22 33 14 BERLINEM@ipc.unicancer.fr
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03957915
Other Study ID Numbers  ICMJE INA03-IPC 2018-008
2019-000814-13 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Institut Paoli-Calmettes
Study Sponsor  ICMJE Institut Paoli-Calmettes
Collaborators  ICMJE INATHERYS
Investigators  ICMJE
Principal Investigator: Norbert VEY, Pr Institut Paoli-Calmettes
PRS Account Institut Paoli-Calmettes
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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