Inotuzumab Ozogamicin and Chemotherapy in Treating Patients With Leukemia or Lymphoma Undergoing Stem Cell Transplantation

Study Overview
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Brief Summary
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The goal of this phase II clinical study is to learn about the safety of inotuzumab ozogamicin when given with fludarabine, with or without bendamustine, melphalan, and rituximab before and after a stem cell transplant. Researchers also want to learn if inotuzumab ozogamicin when given after a stem cell transplant can help control leukemia and lymphoma. Inotuzumab ozogamicin is a monoclonal antibody, called inotuzumab, linked to a chemotherapy drug called ozogamicin. Inotuzumab attaches to CD22-positive cancer cells in a targeted way and delivers ozogamicin to kill them. Giving chemotherapy before a bone marrow or peripheral blood stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. Sometimes the transplanted cells from a donor attack the body's normal cells (called graft-versus-host disease). Giving tacrolimus and filgrastim before or after the transplant may stop this from happening. Fludarabine, bendamustine, melphalan, and rituximab are commonly given before stem cell transplants. Giving inotuzumab ozogamicin with chemotherapy may work better in treating patients with leukemia or lymphoma undergoing stem cell transplantation.

Detailed Description
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PRIMARY OBJECTIVE: I. To assess the safety of the addition of inotuzumab ozogamicin (IO) pre- and post-allogeneic transplantation in patients with CD22-positive hematological malignancies. SECONDARY OBJECTIVES: I. Overall survival, progression-free survival and relapse rates. II. Treatment-related mortality. III. Cumulative incidence of acute and chronic graft-versus-host disease (GVHD). OUTLINE: Patients are assigned to 1 of 2 groups. GROUP I: Patients with acute lymphoblastic leukemia (ALL) receive inotuzumab ozogamicin intravenously (IV) over 1 hour on day -13, fludarabine IV over 1 hour on days -5 to -2, melphalan IV over 30 minutes on day -2, and tacrolimus IV continuously beginning on day -2 then orally (PO) once daily (QD) or twice daily (BID) for about 6 months. Patients receiving stem cells from a matched unrelated donor (MUD), receive anti-thymocyte globulin IV over 3-4 hours on days -2 to -1 and not receive chemotherapy drugs. Patients also receive bone marrow or peripheral blood progenitor cells IV on day 0. Patients then receive methotrexate IV over 30 minutes on days 1, 3, 6, and 11 and filgrastim-sndz subcutaneously (SC) QD beginning 1 week after the transplant until blood cell levels return to normal. Patients with CD22-positive cancer, receive rituximab IV over 4-6 hours on days 1 and 8. GROUP II: Patients with lymphoma receive inotuzumab ozogamicin IV over 1 hour on day -13, fludarabine IV over 1 hour and bendamustine IV over 30 minutes to 1 hour on days -5 to -3, and tacrolimus IV continuously beginning on day -2 then PO QD or BID for about 6 months. Patients receiving stem cells from a MUD, receive anti-thymocyte globulin IV over 3-4 hours on days -2 to -1 and not receive chemotherapy drugs. Patients also receive bone marrow or peripheral blood progenitor cells IV on day 0. Patients then receive rituximab IV over 4-6 hours on days 1 and 8, methotrexate IV over 30 minutes on days 1, 3, and 6, and filgrastim-sndz SC once a day beginning 1 week after the transplant. Patients who received a stem cell transplant from a MUD also receive methotrexate IV over 30 minutes on day 11. MAINTENANCE: Between 45 and 100 days after stem cell transplantation, all patients receive inotuzumab ozogamicin IV over 1 hour on days 1 and 2. Beginning 28 to 100 days after start of first cycle, patients receive inotuzumab ozogamicin IV over 1 hour on days 1 and 2 in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically.

Official Title
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Addition of Inotuzumab Ozogamicin Pre- and Post-Allogeneic Transplantation

Conditions
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Acute Lymphoblastic Leukemia, B Acute Lymphoblastic Leukemia, Lymphocytic Neoplasm, Lymphoma

Intervention / Treatment
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* Procedure: Allogeneic Bone Marrow Transplantation
* Biological: Anti-Thymocyte Globulin
* Drug: Bendamustine
* Biological: Filgrastim-sndz
* Drug: Fludarabine
* Biological: Inotuzumab Ozogamicin
* Drug: Melphalan
* Drug: Methotrexate
* Procedure: Peripheral Blood Stem Cell Transplantation
* Biological: Rituximab
* Drug: Tacrolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Young adults (age 18-35) with ALL will be included only if they are not eligible for myeloablative transplants. CD22+ lymphoid malignancies including B acute lymphoblastic leukemia (B-ALL). Eligible to receive a reduced-intensity allogeneic hematopoietic stem cell transplantation (alloSCT). Donor: HLA compatible related or matched unrelated donor (HLA-A, B, C, DRB1). Performance status of 0 to 2. Creatinine less than or equal to 1.6 mg/dL (at time of study entry). Bilirubin less than 1.6 mg/dL (at time of study entry). Serum glutamate pyruvate transaminase (SGPT) < 2 x upper limit of normal (ULN) (at time of study entry). Ejection fraction >= 40% (at time of study entry). Forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and diffusion capacity of the lung for carbon monoxide (DLCO) >= 40% (at time of study entry). Negative beta human chorionic gonadotropin (HCG) test in a woman with child bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization) or currently breast-feeding. Pregnancy testing is not required for post menopausal or surgically sterilized women. Exclusion Criteria: Human immunodeficiency virus (HIV) positive. Philadelphia chromosome (Ph)-positive ALL. Active and uncontrolled disease/infection. Unable or unwilling to sign consent. Current active hepatic or biliary disease (with exception of Gilbert's syndrome). Active hepatitis B or C. Recent chemotherapy or radiation within 3 weeks of study entry. Exception: ibrutinib and venetoclax are allowed to within 3 days. Prior inotuzumab ozogamicin within 3 weeks of study entry. Peripheral blast count of greater than 10 K/microL. Corrected QT using Fridericia's formula (QTcF) interval > 470 ms.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group I (inotuzumab ozogamicin, chemotherapy, transplant)<br>See Detailed Description. | Procedure: Allogeneic Bone Marrow Transplantation<br>* Given IV<br>* Other names: Allogeneic BMT;Biological: Anti-Thymocyte Globulin<br>* Given IV<br>* Other names: ATS;Biological: Filgrastim-sndz<br>* Given IV<br>* Other names: Zarxio;Drug: Fludarabine<br>* Given IV<br>* Other names: Fluradosa;Biological: Inotuzumab Ozogamicin<br>* Given IV<br>* Other names: WAY-207294;Drug: Melphalan<br>* Given IV<br>* Other names: WR-19813;Drug: Methotrexate<br>* Given IV<br>* Other names: WR-19039;Procedure: Peripheral Blood Stem Cell Transplantation<br>* Given IV<br>* Other names: Peripheral Stem Cell Transplantation;Biological: Rituximab<br>* Given IV<br>* Other names: Truxima;Drug: Tacrolimus<br>* Given IV and PO<br>* Other names: Protopic;|
| Experimental: Group II (inotuzumab ozogamicin, chemotherapy, transplant)<br>See Detailed Description. | Procedure: Allogeneic Bone Marrow Transplantation<br>* Given IV<br>* Other names: Allogeneic BMT;Biological: Anti-Thymocyte Globulin<br>* Given IV<br>* Other names: ATS;Drug: Bendamustine<br>* Given IV<br>* Other names: SDX-105;Biological: Filgrastim-sndz<br>* Given IV<br>* Other names: Zarxio;Drug: Fludarabine<br>* Given IV<br>* Other names: Fluradosa;Biological: Inotuzumab Ozogamicin<br>* Given IV<br>* Other names: WAY-207294;Drug: Methotrexate<br>* Given IV<br>* Other names: WR-19039;Procedure: Peripheral Blood Stem Cell Transplantation<br>* Given IV<br>* Other names: Peripheral Stem Cell Transplantation;Biological: Rituximab<br>* Given IV<br>* Other names: Truxima;Drug: Tacrolimus<br>* Given IV and PO<br>* Other names: Protopic;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of grade 3 or higher renal, hepatic, cardiac, pulmonary, or neurologic toxicity | Will be assessed using the Bayesian method of Thall, Simon, and Estey. At the end of the trial, the rates of severe toxicity will be summarized, and analyses will be performed to assess the relationship between each toxicity endpoint and covariates of interest using logistic regression. | Up to 30 days after cycle 1 of maintenance therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-related mortality (TRM) | The cumulative incidence of TRM will be assessed in a competing risks framework with the competing risk of disease relapse. Regression models will be fit to assess the relationship between each and covariates of interest using the method of Fine and Gray. | Up to 2 years | 
| Relapse |  | Up to 2 years | 
| Overall survival (OS) | The distribution of OS will be assessed using the Kaplan-Meier method, and distributions will be compared using the log-rank test. Cox proportional hazards regression models will be fit to assess the relationship between OS and covariates of interest. | Up to 2 years | 
| Progression-free survival (PFS) | The distribution of PFS will be assessed using the Kaplan-Meier method, and distributions will be compared using the log-rank test. Cox proportional hazards regression models will be fit to assess the relationship between PFS and covariates of interest. | Up to 2 years | 
| Acute graft versus host disease (GVHD) | The cumulative incidence of acute GvHD will be assessed in a competing risks framework with competing risks of death without relapse and disease relapse. The method of Fine and Gray will be used to assess the association between GvHD and covariates of interest. | Up to 2 years | 
| Chronic GVHD | The cumulative incidence of chronic GvHD will be assessed in a competing risks framework with competing risks of death without relapse and disease relapse. The method of Fine and Gray will be used to assess the association between GvHD and covariates of interest. | Up to 2 years |