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

Primary Purpose

B-cell Acute Lymphoblastic Leukemia

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Inotuzumab ozogamicin
Prednisone Pill
Daunorubicin
Vincristine
Cytarabine
Methotrexate
Pegaspargase
Sponsored by
University of Virginia
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for B-cell Acute Lymphoblastic Leukemia

Eligibility Criteria

16 Years - 60 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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/m^2 doxorubicin equivalents (600 mg/m^2 daunorubicin, 60 mg/m^2 idarubicin, 75 mg/m^2 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

Sites / Locations

  • Vanderbilt-Ingram Cancer Center
  • University of Virginia
  • VCU Massey Cancer Center
  • University of Wisconsin

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

3-drug re-induction regimen with inotuzumab

4-drug re-induction regimen with inotuzumab

Arm Description

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)

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)

Outcomes

Primary Outcome Measures

Characterization of Adverse Events (CTCAE version 5)
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.
Dose-limiting toxicities
The number of dose-limiting toxicities will be used to determine the maximum tolerated dose combination for these combinations of drugs
Informative course of treatment
Percent of patients that receive enough treatment to be informative to the study

Secondary Outcome Measures

Full Information

First Posted
May 22, 2019
Last Updated
August 18, 2023
Sponsor
University of Virginia
Collaborators
Pfizer, Vanderbilt University, University of Wisconsin, Madison, Virginia Commonwealth University
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1. Study Identification

Unique Protocol Identification Number
NCT03962465
Brief Title
Phase I Study of Inotuzumab With Augmented BFM Re-Induction for Patients With Relapsed/Refractory B-cell ALL
Acronym
ALL-001
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)
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
July 22, 2022 (Actual)
Primary Completion Date
July 15, 2023 (Actual)
Study Completion Date
July 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Virginia
Collaborators
Pfizer, Vanderbilt University, University of Wisconsin, Madison, Virginia Commonwealth University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
B-cell Acute Lymphoblastic Leukemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
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.
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
36 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
3-drug re-induction regimen with inotuzumab
Arm Type
Experimental
Arm Description
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)
Arm Title
4-drug re-induction regimen with inotuzumab
Arm Type
Experimental
Arm Description
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)
Intervention Type
Drug
Intervention Name(s)
Inotuzumab ozogamicin
Other Intervention Name(s)
Besponsa
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Prednisone Pill
Other Intervention Name(s)
Deltasone
Intervention Description
Taken daily days 1-28 by mouth
Intervention Type
Drug
Intervention Name(s)
Daunorubicin
Other Intervention Name(s)
Cerubidine, daunomycin, rubidomycin
Intervention Description
By IV, given on days 1, 8, 15, and 22
Intervention Type
Drug
Intervention Name(s)
Vincristine
Other Intervention Name(s)
Oncovin, Vincasar, Leurocristine
Intervention Description
By IV, given on days 1, 8, 15, and 22
Intervention Type
Drug
Intervention Name(s)
Cytarabine
Other Intervention Name(s)
Ara-C, Cytosar-U
Intervention Description
Intrathecal, administered on day 1 only
Intervention Type
Drug
Intervention Name(s)
Methotrexate
Other Intervention Name(s)
Otrexup, Rasuvo, Rheumatrex, Trexall, MTX, Amethopterin
Intervention Description
Intrathecal, administered on days 8 and 29
Intervention Type
Drug
Intervention Name(s)
Pegaspargase
Other Intervention Name(s)
Oncospar
Intervention Description
By IV, given on day 4
Primary Outcome Measure Information:
Title
Characterization of Adverse Events (CTCAE version 5)
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.
Time Frame
All adverse events occurring through 30 days following last dose of inotuzumab ozogamicin.
Title
Dose-limiting toxicities
Description
The number of dose-limiting toxicities will be used to determine the maximum tolerated dose combination for these combinations of drugs
Time Frame
From initiation of inotuzumab ozogamicin through 30 days following the last dose of inotuzumab ozogamicin
Title
Informative course of treatment
Description
Percent of patients that receive enough treatment to be informative to the study
Time Frame
For each participant, up to the 29 days of study treatment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
16 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Provision of signed and dated informed consent form Stated willingness to comply with all study procedures and availability for the duration of the study 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. Male or female, aged 16-60 years ECOG performance status of 0-2 Left ventricular ejection fraction ≥ 50% measured by echocardiogram or MUGA Either relapsed following remission after initial induction therapy or refractory to induction therapy 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) For females of reproductive potential: negative pregnancy test 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 Agreement to adhere to Lifestyle Considerations throughout study duration and for 1 year following last study treatment. Exclusion Criteria: 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) Current or past history of pancreatitis QT interval on electrocardiogram (ECG) > 0.45 by Framingham formula Known congestive heart failure Known allergy to asparaginase (only an exclusion criteria for participants enrolling in part 2) Presence of central nervous system (CNS) disease Pregnancy or lactation Chronic liver disease including chronic active hepatitis and/or cirrhosis Active Hepatitis B virus (HBV) by core antibody, surface antigen (HBsAg) or viral load Active Hepatitis C virus (HCV) (positive antibody test confirmed by viral load if antibody test is positive) Known history of infection with Human Immunodeficiency Virus (HIV) Active or uncontrolled infections Abnormal baseline hepatic ultrasound (including Dopplers) Prior allogeneic stem cell transplant Prior use of inotuzumab ozogamicin Known diagnosis of hemochromatosis with iron overload 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 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. Philadelphia chromosome positive B-cell ALL
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michael Douvas, MD
Organizational Affiliation
University of Virginia
Official's Role
Principal Investigator
Facility Information:
Facility Name
Vanderbilt-Ingram Cancer Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
Facility Name
University of Virginia
City
Charlottesville
State/Province
Virginia
ZIP/Postal Code
22908
Country
United States
Facility Name
VCU Massey Cancer Center
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23298
Country
United States
Facility Name
University of Wisconsin
City
Madison
State/Province
Wisconsin
ZIP/Postal Code
53792
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

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