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

NCT ID: NCT03962465

Last Updated: 2023-08-22

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE1
• Total Enrollment: 36 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-07-22
• Study Completion Date: 2026-07-31

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.

Conditions

B-cell Acute Lymphoblastic Leukemia

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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)

Group Type: EXPERIMENTAL

Inotuzumab ozogamicin

Intervention Type: DRUG

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

Prednisone Pill

Intervention Type: DRUG

Taken daily days 1-28 by mouth

Daunorubicin

Intervention Type: DRUG

By IV, given on days 1, 8, 15, and 22

Vincristine

Intervention Type: DRUG

By IV, given on days 1, 8, 15, and 22

Cytarabine

Intervention Type: DRUG

Intrathecal, administered on day 1 only

Methotrexate

Intervention Type: DRUG

Intrathecal, administered on days 8 and 29

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)

Group Type: EXPERIMENTAL

Inotuzumab ozogamicin

Intervention Type: DRUG

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

Prednisone Pill

Intervention Type: DRUG

Taken daily days 1-28 by mouth

Daunorubicin

Intervention Type: DRUG

By IV, given on days 1, 8, 15, and 22

Vincristine

Intervention Type: DRUG

By IV, given on days 1, 8, 15, and 22

Cytarabine

Intervention Type: DRUG

Intrathecal, administered on day 1 only

Methotrexate

Intervention Type: DRUG

Intrathecal, administered on days 8 and 29

Pegaspargase

Intervention Type: DRUG

By IV, given on day 4

Interventions

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

Intervention Type: DRUG

Prednisone Pill

Taken daily days 1-28 by mouth

Intervention Type: DRUG

Daunorubicin

By IV, given on days 1, 8, 15, and 22

Intervention Type: DRUG

Vincristine

By IV, given on days 1, 8, 15, and 22

Intervention Type: DRUG

Cytarabine

Intrathecal, administered on day 1 only

Intervention Type: DRUG

Methotrexate

Intrathecal, administered on days 8 and 29

Intervention Type: DRUG

Pegaspargase

By IV, given on day 4

Intervention Type: DRUG

Other Intervention Names

Besponsa; Deltasone; Cerubidine; daunomycin; rubidomycin; Oncovin; Vincasar; Leurocristine; Ara-C; Cytosar-U; Otrexup; Rasuvo; Rheumatrex; Trexall; MTX; Amethopterin; Oncospar

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 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

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

• Minimum Eligible Age: 16 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Pfizer

INDUSTRY

Sponsor Role: collaborator

Vanderbilt University

OTHER

Sponsor Role: collaborator

University of Wisconsin, Madison

OTHER

Sponsor Role: collaborator

Virginia Commonwealth University

OTHER

Sponsor Role: collaborator

University of Virginia

OTHER

Sponsor Role: lead

Responsible Party

Michael Douvas, MD

Associate Professor of Medicine and Pediatrics

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Michael Douvas, MD

Role: PRINCIPAL_INVESTIGATOR

University of Virginia

Locations

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, United States

University of Virginia

Charlottesville, Virginia, United States

VCU Massey Cancer Center

Richmond, Virginia, United States

University of Wisconsin

Madison, Wisconsin, United States

Countries

United States

Other Identifiers

21417

Identifier Type: -

Identifier Source: org_study_id