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ALL-001: Phase I Study of Inotuzumab With Augmented BFM Re-Induction for Patients With Relapsed/Refractory B-cell ALL

Sponsor
University of Virginia (Other)
Overall Status
Recruiting
CT.gov ID
NCT03962465
Collaborator
Pfizer (Industry), Vanderbilt University (Other), University of Wisconsin, Madison (Other), Virginia Commonwealth University (Other)
36
Enrollment
4
Locations
2
Arms
72.3
Anticipated Duration (Months)
9
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

In the proposed study, escalating doses of inotuzumab ozogamicin will be added to a standard pediatric inspired re-induction regimen and administered to patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). Two re-induction regimens will be tested (one without pegaspargase and one including pegaspargase) and participants will be followed for disease status, allogeneic hematopoietic cell transplant (allo HCT), veno-occlusive disease following allo HCT, and overall survival.

Condition or Disease Intervention/Treatment Phase
Phase 1

Detailed Description

Inotuzumab ozogamicin has been studied as a single agent in refractory and relapsed ALL. In the relapsed setting, inotuzumab ozogamicin has been shown to achieve complete remission (CR) in 81% of patients and minimal residual disease (MRD) negativity in 78% of patients who achieve CR. In the proposed study, escalating doses of inotuzumab ozogamicin will be added to a standard pediatric inspired re-induction regimen and administered to patients with relapsed or refractory B-cell ALL. Two re-induction regimens will be tested. The first regimen is a 3-drug regimen comprised of prednisone, vincristine, and daunorubicin. The second is a 4-drug regimen comprised of prednisone, vincristine, daunorubicin, and pegaspargase. Intrathecal methotrexate (IT-methotrexate) and intrathecal cytarabine (IT-ARA-C) will be included for central nervous system (CNS) prophylaxis with both the 3-drug and 4-drug regimens. We hypothesize that combining inotuzumab ozogamicin with these regimens is safe and will improve CR rates, successful transition to allo HCT, and overall survival in patients with relapsed or refractory B-ALL.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
36 participants
Allocation:
Non-Randomized
Intervention Model:
Single Group Assignment
Intervention Model Description:
This is an early-phase study evaluating the safety of inotuzumab ozogamicin administered in combination with a 3-drug and 4-drug re-induction regimen in participants with relapsed or refractory B-ALL. The trial is planned to first determine the maximum tolerated dose (MTD) of the 3-drug re-induction regimen in Part 1 and then to determine the MTD of the 4-drug re-induction regimen (including pegaspargase) in Part 2.This is an early-phase study evaluating the safety of inotuzumab ozogamicin administered in combination with a 3-drug and 4-drug re-induction regimen in participants with relapsed or refractory B-ALL. The trial is planned to first determine the maximum tolerated dose (MTD) of the 3-drug re-induction regimen in Part 1 and then to determine the MTD of the 4-drug re-induction regimen (including pegaspargase) in Part 2.
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Phase I Study of Inotuzumab Ozogamicin With 3 and 4 Drug Augmented Berlin-Frankfurt-Münster (BFM) Re-Induction for Patients With Relapsed or Refractory B-cell Acute Lymphoblastic Leukemia (B-ALL)
Actual Study Start Date :
Jul 22, 2022
Anticipated Primary Completion Date :
Jul 30, 2024
Anticipated Study Completion Date :
Jul 30, 2028

Arms and Interventions

Arm Intervention/Treatment
Experimental: 3-drug re-induction regimen with inotuzumab

One cycle of a 3-drug regimen comprised of standard doses of prednisone, vincristine, and daunorubicin with inotuzumab ozogamicin at a reduced dose. Intrathecal methotrexate (IT-methotrexate) and intrathecal cytarabine (IT-Ara-C) will be included for CNS prophylaxis. IV inotuzumab ozogamicin will be given at a reduced dose (may vary from a total cycle dose of 0.4 mg/m^2 to 0.9 mg/m^2)

Drug: Inotuzumab ozogamicin
By IV, given on days 12 and 19 Inotuzumab ozogamicin is approved as a single-agent in this population (patients with B-ALL) but adding it to these drug combinations has not been tested in humans
Other Names:
  • Besponsa

    • Drug: Prednisone Pill
    Taken daily days 1-28 by mouth
    Other Names:
  • Deltasone

    • Drug: Daunorubicin
    By IV, given on days 1, 8, 15, and 22
    Other Names:
  • Cerubidine
  • daunomycin
  • rubidomycin

    • Drug: Vincristine
    By IV, given on days 1, 8, 15, and 22
    Other Names:
  • Oncovin
  • Vincasar
  • Leurocristine

    • Drug: Cytarabine
    Intrathecal, administered on day 1 only
    Other Names:
  • Ara-C
  • Cytosar-U

    • Drug: Methotrexate
    Intrathecal, administered on days 8 and 29
    Other Names:
  • Otrexup
  • Rasuvo
  • Rheumatrex
  • Trexall
  • MTX
  • Amethopterin

    		•
    Experimental: 4-drug re-induction regimen with inotuzumab

    One cycle of a 4-drug regimen comprised of standard doses of prednisone, vincristine, daunorubicin, and pegaspargase with inotuzumab ozogamicin at a reduced dose. Intrathecal methotrexate (IT-methotrexate) and intrathecal cytarabine (IT-Ara-C) will be included for CNS prophylaxis. IV inotuzumab ozogamicin will be given at a reduced dose (may vary from a total cycle dose of 0.4 mg/m^2 to 0.9 mg/m^2)

    Drug: Inotuzumab ozogamicin
    By IV, given on days 12 and 19 Inotuzumab ozogamicin is approved as a single-agent in this population (patients with B-ALL) but adding it to these drug combinations has not been tested in humans
    Other Names:
  • Besponsa

    • Drug: Prednisone Pill
    Taken daily days 1-28 by mouth
    Other Names:
  • Deltasone

    • Drug: Daunorubicin
    By IV, given on days 1, 8, 15, and 22
    Other Names:
  • Cerubidine
  • daunomycin
  • rubidomycin

    • Drug: Vincristine
    By IV, given on days 1, 8, 15, and 22
    Other Names:
  • Oncovin
  • Vincasar
  • Leurocristine

    • Drug: Cytarabine
    Intrathecal, administered on day 1 only
    Other Names:
  • Ara-C
  • Cytosar-U

    • Drug: Methotrexate
    Intrathecal, administered on days 8 and 29
    Other Names:
  • Otrexup
  • Rasuvo
  • Rheumatrex
  • Trexall
  • MTX
  • Amethopterin

    • Drug: Pegaspargase
    By IV, given on day 4
    Other Names:
  • Oncospar

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Characterization of Adverse Events (CTCAE version 5) [All adverse events occurring through 30 days following last dose of inotuzumab ozogamicin.]

      A characterization of all adverse events experienced by patients receiving these drug combinations. Also, any SAEs deemed related to study treatment, including veno-occlusive disease, will be captured at any time while the participant is on-study.

    2. Dose-limiting toxicities [From initiation of inotuzumab ozogamicin through 30 days following the last dose of inotuzumab ozogamicin]

      The number of dose-limiting toxicities will be used to determine the maximum tolerated dose combination for these combinations of drugs

    3. Informative course of treatment [For each participant, up to the 29 days of study treatment]

      Percent of patients that receive enough treatment to be informative to the study

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    16 Years to 60 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    1. Provision of signed and dated informed consent form

    2. Stated willingness to comply with all study procedures and availability for the duration of the study

    3. Diagnosed with CD-22 positive* B-cell Acute Lymphoblastic Leukemia or B-cell Lymphoblastic Lymphoma (Philadelphia chromosome negative) * For the purposes of this study, CD-22 positive will be defined based on the analysis completed for diagnostic purposes.

    4. Male or female, aged 16-60 years

    5. ECOG performance status of 0-2

    6. Left ventricular ejection fraction ≥ 50% measured by echocardiogram or MUGA

    7. Either relapsed following remission after initial induction therapy or refractory to induction therapy

    8. Adequate organ function, including serum creatinine ≤ 1.6 mg/dL OR creatinine clearance >50 ml/min by Cockgroft-Gault formula, bilirubin ≤ 1.5 mg/dL (except in patients with Gilbert's disease), AST, ALT and alkaline phosphatase ≤ 3 x upper limit of normal (elevation exceeding this threshold of either AST OR ALT would not meet eligibility)

    9. For females of reproductive potential: negative pregnancy test

    10. For females and males of reproductive potential: agreement to use adequate contraception during study participation and for an additional 1 year after the end of study treatment

    11. Agreement to adhere to Lifestyle Considerations throughout study duration and for 1 year following last study treatment.

    Exclusion Criteria:

    1. Past receipt of a total of ≥ 300 mg/m2 doxorubicin equivalents (600 mg/m2 daunorubicin, 60 mg/m2 idarubicin, 75 mg/m2 mitoxantrone)

    2. Current or past history of pancreatitis

    3. QT interval on electrocardiogram (ECG) > 0.45 by Framingham formula

    4. Known congestive heart failure

    5. Known allergy to asparaginase (only an exclusion criteria for participants enrolling in part 2)

    6. Presence of central nervous system (CNS) disease

    7. Pregnancy or lactation

    8. Chronic liver disease including chronic active hepatitis and/or cirrhosis

    9. Active Hepatitis B virus (HBV) by core antibody, surface antigen (HBsAg) or viral load

    10. Active Hepatitis C virus (HCV) (positive antibody test confirmed by viral load if antibody test is positive)

    11. Known history of infection with Human Immunodeficiency Virus (HIV)

    12. Active or uncontrolled infections

    13. Abnormal baseline hepatic ultrasound (including Dopplers)

    14. Prior allogeneic stem cell transplant

    15. Prior use of inotuzumab ozogamicin

    16. Known diagnosis of hemochromatosis with iron overload

    17. Treatment with steroids or hydroxyurea for more than 7 days with each within the 2 weeks prior to registration -that is, each is allowed for up to 7 days

    18. Gastrointestinal tract disease causing the inability to take oral medication, malabsorption syndrome, a requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease, or inability to swallow medications.

    19. Philadelphia chromosome positive B-cell ALL

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Vanderbilt-Ingram Cancer Center Nashville Tennessee United States 37232
    2 University of Virginia Charlottesville Virginia United States 22908
    3 VCU Massey Cancer Center Richmond Virginia United States 23298
    4 University of Wisconsin Madison Wisconsin United States 53792

    Sponsors and Collaborators

    • University of Virginia
    • Pfizer
    • Vanderbilt University
    • University of Wisconsin, Madison
    • Virginia Commonwealth University

    Investigators

    • Principal Investigator: Michael Douvas, MD, University of Virginia

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Michael Douvas, MD, Associate Professor of Medicine and Pediatrics, University of Virginia
    ClinicalTrials.gov Identifier:
    NCT03962465
    Other Study ID Numbers:
    • 21417
    First Posted:
    May 24, 2019
    Last Update Posted:
    Aug 16, 2022
    Last Verified:
    Aug 1, 2022
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:
    Leukemia
    Precursor Cell Lymphoblastic Leukemia-Lymphoma
    Leukemia, Lymphoid
    Cytarabine
    Prednisone
    Methotrexate
    Vincristine
    Daunorubicin
    Pegaspargase
    Inotuzumab Ozogamicin

    Study Results

    No Results Posted as of Aug 16, 2022