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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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B-cell Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: Inotuzumab ozogamicin
* Drug: Prednisone Pill
* Drug: Daunorubicin
* Drug: Vincristine
* Drug: Cytarabine
* Drug: Methotrexate
* Drug: Pegaspargase


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 3-drug re-induction regimen with inotuzumab<br>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<br>* 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<br>* Other names: Besponsa;Drug: Prednisone Pill<br>* Taken daily days 1-28 by mouth<br>* Other names: Deltasone;Drug: Daunorubicin<br>* By IV, given on days 1, 8, 15, and 22<br>* Other names: rubidomycin;Drug: Vincristine<br>* By IV, given on days 1, 8, 15, and 22<br>* Other names: Leurocristine;Drug: Cytarabine<br>* Intrathecal, administered on day 1 only<br>* Other names: Cytosar-U;Drug: Methotrexate<br>* Intrathecal, administered on days 8 and 29<br>* Other names: Amethopterin;|
| Experimental: 4-drug re-induction regimen with inotuzumab<br>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<br>* 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<br>* Other names: Besponsa;Drug: Prednisone Pill<br>* Taken daily days 1-28 by mouth<br>* Other names: Deltasone;Drug: Daunorubicin<br>* By IV, given on days 1, 8, 15, and 22<br>* Other names: rubidomycin;Drug: Vincristine<br>* By IV, given on days 1, 8, 15, and 22<br>* Other names: Leurocristine;Drug: Cytarabine<br>* Intrathecal, administered on day 1 only<br>* Other names: Cytosar-U;Drug: Methotrexate<br>* Intrathecal, administered on days 8 and 29<br>* Other names: Amethopterin;Drug: Pegaspargase<br>* By IV, given on day 4<br>* Other names: Oncospar;|

What is the study measuring?
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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 |