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

• ClinicalTrials.gov Identifier: NCT03962465
• Recruitment Status: Recruiting
• First Posted: May 24, 2019
• Last Update Posted: September 11, 2020
• Sponsor: University of Virginia
• Collaborators: Pfizer; Vanderbilt University; University of Wisconsin, Madison; Virginia Commonwealth University
• Information provided by (Responsible Party): Michael Douvas, MD, University of Virginia

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 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.

Condition or disease	Intervention/treatment	Phase
B-cell Acute Lymphoblastic Leukemia	Drug: Inotuzumab ozogamicin; Drug: Prednisone Pill; Drug: Daunorubicin; Drug: Vincristine; Drug: Cytarabine; Drug: Methotrexate; Drug: Pegaspargase	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 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated 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.
• 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 Younger Adults Ages 18-55 With Relapsed or Refractory B-cell Acute Lymphoblastic Leukemia (B-ALL)
• Actual Study Start Date: November 22, 2019
• Estimated Primary Completion Date: January 30, 2022
• Estimated Study Completion Date: November 30, 2025

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 Name: Besponsa; Drug: Prednisone Pill; Taken daily days 1-28 by mouth; Other Name: 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 Name: Besponsa; Drug: Prednisone Pill; Taken daily days 1-28 by mouth; Other Name: 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 Name: Oncospar

Outcome Measures

Primary Outcome Measures :

1. Characterization of Adverse Events (CTCAE version 5) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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

• Ages Eligible for Study: 18 Years to 55 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 registration
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

Contacts and Locations

Contacts

Contact: Katie Rea, RN; 434-924-8574; KAW3J@hscmail.mcc.virginia.edu

Contact: April Muniz; 434 243 5350; am4pf@virginia.edu

Locations

United States, Virginia

University of Virginia; Recruiting

Charlottesville, Virginia, United States, 22908

Contact: Cory Caldwell 434-297-4182 CJC2P@virginia.edu

Contact: Jungeun Kim 434 982 3365 JK9TE@virginia.edu

Principal Investigator: Michael Douvas, MD

Sub-Investigator: Karen Ballen, MD

Sub-Investigator: Michael Keng, MD

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

More Information

• 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: September 11, 2020
• Last Verified: September 2020

• 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; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Cytarabine; Prednisone; Methotrexate; Vincristine; Daunorubicin; Pegaspargase; Inotuzumab Ozogamicin; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Reproductive Control Agents; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Dermatologic Agents