Clinical Trials /

Phase I Study of Inotuzumab With Augmented BFM Re-Induction for Younger Adults With Relapsed/Refractory B-cell ALL

NCT03962465

Description:

In the proposed study, escalating doses of inotuzumab ozogamicin will be added to a standard pediatric inspired re-induction regimen and administered to younger adults 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.

Related Conditions:
  • B-Cell Acute Lymphoblastic Leukemia
  • B-Cell Lymphoblastic Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Phase I Study of Inotuzumab With Augmented BFM Re-Induction for Younger Adults With Relapsed/Refractory B-cell ALL
  • Official Title: Phase I Study of Inotuzumab Ozogamicin With 3 and 4 Drug Augmented Berlin-Frankfurt-Münster (BFM) Re-Induction for Younger Adults Ages 18-55 With Relapsed or Refractory B-cell Acute Lymphoblastic Leukemia (B-ALL)

Clinical Trial IDs

  • ORG STUDY ID: 21417
  • NCT ID: NCT03962465

Conditions

  • B-cell Acute Lymphoblastic Leukemia

Interventions

DrugSynonymsArms
Inotuzumab ozogamicinBesponsa3-drug re-induction regimen with inotuzumab
Prednisone PillDeltasone3-drug re-induction regimen with inotuzumab
DaunorubicinCerubidine, daunomycin, rubidomycin3-drug re-induction regimen with inotuzumab
VincristineOncovin, Vincasar, Leurocristine3-drug re-induction regimen with inotuzumab
CytarabineAra-C, Cytosar-U3-drug re-induction regimen with inotuzumab
MethotrexateOtrexup, Rasuvo, Rheumatrex, Trexall, MTX, Amethopterin3-drug re-induction regimen with inotuzumab
PegaspargaseOncospar4-drug re-induction regimen with inotuzumab

Purpose

In the proposed study, escalating doses of inotuzumab ozogamicin will be added to a standard pediatric inspired re-induction regimen and administered to younger adults 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.

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 younger adults 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
      younger adults with relapsed or refractory B-ALL.
    

Trial Arms

NameTypeDescriptionInterventions
3-drug re-induction regimen with inotuzumabExperimentalOne 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)
  • Inotuzumab ozogamicin
  • Prednisone Pill
  • Daunorubicin
  • Vincristine
  • Cytarabine
  • Methotrexate
4-drug re-induction regimen with inotuzumabExperimentalOne 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)
  • Inotuzumab ozogamicin
  • Prednisone Pill
  • Daunorubicin
  • Vincristine
  • Cytarabine
  • Methotrexate
  • Pegaspargase

Eligibility Criteria

        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 is defined as at least 60% positive by flow cytometry or
             immunohistochemistry.

          4. Body mass index (BMI) < 35 (BMI = weight in kg/(height in meters)^2)

          5. Male or female, aged 18-55 years

          6. ECOG performance status of 0-2

          7. Left ventricular ejection fraction > 45% measured by echocardiogram or MUGA

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

          9. 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

         10. For females of reproductive potential: negative pregnancy test

         11. 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

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

        Exclusion Criteria:

          1. Requires concomitant therapeutic anticoagulation (e.g. warfarin, low molecular weight
             heparin, direct oral anticoagulant) or any medication included in the restricted
             concomitant medications

          2. Past receipt of a total of ≥ 300 mg/m^2 doxorubicin equivalents (600 mg/m^2
             daunorubicin, 60 mg/m^2 idarubicin, 75 mg/m^2 mitoxantrone)

          3. Current or past history of pancreatitis

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

          5. Known congestive heart failure

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

          7. Presence of central nervous system (CNS) disease

          8. Pregnancy or lactation

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

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

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

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

         13. Active or uncontrolled infections

         14. Abnormal baseline hepatic ultrasound (including Dopplers)

         15. Prior allogeneic stem cell transplant

         16. Prior use of inotuzumab ozogamicin

         17. Known diagnosis of hemochromatosis with iron overload

         18. Prior CAR-T cell therapy

         19. Treatment with steroids or hydroxyurea for more than 7 days within the 2 weeks prior
             to enrollment

         20. 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.

         21. Philadelphia chromosome positive B-cell ALL
      
Maximum Eligible Age:55 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Characterization of Adverse Events (CTCAE version 5)
Time Frame:All adverse events occurring through 30 days following last dose of inotuzumab ozogamicin.
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of Virginia

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