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

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)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: B-cell Acute Lymphoblastic Leukemia
• Intervention / Treatment: Drug: Inotuzumab ozogamicin; Drug: Prednisone Pill; Drug: Daunorubicin; Drug: Vincristine; Drug: Cytarabine; Drug: Methotrexate; Drug: Pegaspargase

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 Type: Interventional
• Enrollment (Estimated): 36
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Amy Smith, BS; Phone Number: 434-243-2270; Email: AJB6BB@hscmail.mcc.virginia.edu

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt-Ingram Cancer Center
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia
    • Richmond, Virginia, United States, 23298
      • VCU Massey Cancer Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 58 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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: MTX; Amethopterin; Rheumatrex; Trexall; Otrexup; Rasuvo
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: MTX; Amethopterin; Rheumatrex; Trexall; Otrexup; Rasuvo; Drug: Pegaspargase; By IV, given on day 4; Other Names: Oncospar

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	All adverse events occurring through 30 days following last dose of inotuzumab ozogamicin.
Dose-limiting toxicities	The number of dose-limiting toxicities will be used to determine the maximum tolerated dose combination for these combinations of drugs	From initiation of inotuzumab ozogamicin through 30 days following the last dose of inotuzumab ozogamicin
Informative course of treatment	Percent of patients that receive enough treatment to be informative to the study	For each participant, up to the 29 days of study treatment

Collaborators and Investigators

• Sponsor: University of Virginia
• Collaborators: Pfizer; University of Wisconsin, Madison; Vanderbilt University; Virginia Commonwealth University
• Investigators: Principal Investigator: Michael Douvas, MD, University of Virginia

Study record dates

Study Major Dates

• Study Start (Actual): July 22, 2022
• Primary Completion (Actual): July 15, 2023
• Study Completion (Estimated): July 1, 2026

Study Registration Dates

• First Submitted: May 22, 2019
• First Submitted That Met QC Criteria: May 23, 2019
• First Posted (Actual): May 24, 2019

Study Record Updates

• Last Update Posted (Actual): August 22, 2023
• Last Update Submitted That Met QC Criteria: August 18, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Dermatologic Agents; Antibiotics, Antineoplastic; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Immunoconjugates; Immunotoxins; Prednisone; Cytarabine; Methotrexate; Vincristine; Daunorubicin; Pegaspargase; Inotuzumab Ozogamicin
• Other Study ID Numbers: 21417

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No