CMC-544 and Allogeneic Transplantation for CD22 Positive-Lymphoid Malignancies

Study Overview
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Brief Summary
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This phase I/II trial studies the side effects and the best dose of inotuzumab ozogamicin when given together with fludarabine phosphate, bendamustine hydrochloride, and rituximab before donor stem cell transplant in treating patients with lymphoid malignancies. Giving chemotherapy drugs, such as fludarabine phosphate and bendamustine hydrochloride, before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells or abnormal cell and helps stop the patient's immune system from rejecting the donor's stem cells. Immunotherapy with monoclonal antibodies, such as inotuzumab ozogamicin and rituximab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cell from a donor can make an immune system response against the body's normal cells. Giving fludarabine phosphate and bendamustine hydrochloride before the transplant together with anti-thymocyte globulin and tacrolimus may stop this from happening.

Detailed Description
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PRIMARY OBJECTIVES: I. To characterize the safety of anti-cluster of differentiation (CD) 22 immunoconjugate inotuzumab ozogamicin (CMC-544), when administered in conjunction with fludarabine (fludarabine phosphate), bendamustine (bendamustine hydrochloride), and rituximab as non-myeloablative preparative regimen for allogeneic stem cell transplantation for CD22-positive lymphoid malignancies. SECONDARY OBJECTIVES: I. To estimate tumor response. II. To determine overall and event-free survival rates by histology subtype. OUTLINE: This is a dose-escalation study of inotuzumab ozogamicin. Patients receive inotuzumab ozogamicin intravenously (IV) over 1 hour on day -13, and fludarabine phosphate IV over 1 hour and bendamustine hydrochloride IV over 30 minutes to 1 hour on days -5 to -3. Patients with CD20-positive disease also receive rituximab IV over 4-6 hours on days -6, 1, and 8 and patients with matched unrelated donors (MUD) receive anti-thymocyte globulin IV over 3-4 hours on days -2 to -1. All patients also receive tacrolimus IV over 24 hours continuously or orally (PO) daily beginning on days -2 to 180 followed by taper in the absence of graft-versus-host disease (GVHD) and methotrexate IV over 30 minutes on days 1, 3, and 6 (1, 3, 6, and 11 in patients with MUD). Patients undergo allogeneic bone marrow (BM) or peripheral blood stem cell (PBSC) transplant on day 0. After completion of study treatment, patients are followed up periodically.

Official Title
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Anti-CD22 Immunoconjugate Inotuzumab Ozogamicin (CMC-544) Added to Fludarabine, Bendamustine and Rituximab and Allogeneic Transplantation for CD22 Positive-Lymphoid Malignancies

Conditions
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Hematopoietic and Lymphoid Cell Neoplasm

Intervention / Treatment
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* Procedure: Allogeneic Bone Marrow Transplantation
* Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
* Biological: Anti-Thymocyte Globulin
* Drug: Bendamustine Hydrochloride
* Drug: Fludarabine Phosphate
* Biological: Inotuzumab Ozogamicin
* 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: Patients with B-cell hematological malignancies who are eligible for allogeneic transplantation Patients must have a fully-matched sibling donor or a matched unrelated donor identified Performance score of at least 80% by Karnofsky or 0 to 2 Eastern Cooperative Oncology Group (ECOG) Left ventricular ejection fraction (EF) >= 45% with no uncontrolled arrhythmias or symptomatic heart disease Forced expiratory volume in one second (FEV1) >= 50% Forced vital capacity (FVC) >= 50% Corrected diffusion capacity of the lung for carbon monoxide (DLCO) >= 50% Serum creatinine < 1.6 mg/dL Serum bilirubin < 2 mg/dL upper limit of normal (unless due to Gilbert's disease; patient with this disease should have a right upper quadrant ultrasound evaluation before treatment) Serum glutamate pyruvate transaminase (SGPT) < 2 x upper limit of normal Men and women of reproductive potential must agree to follow accepted birth control methods (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study 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: Patient with active central nervous system (CNS) involvement Known infection with human immunodeficiency virus (HIV), human T-cell lymphotropic virus (HTLV)-I, hepatitis B, or hepatitis C Patients with other malignancies diagnosed within 2 years prior to study registration; skin squamous or basal cell carcinoma are exceptions Active bacterial, viral or fungal infections History of stroke within 6 months History of biliary colic attack A prior autologous transplant within 3 months of study entry or allogeneic stem cell transplant Serious medical or psychiatric illness likely to interfere with participation in this clinical study Patient has received other investigational drugs within 3 weeks before study registration Serious nonmalignant disease which, in the opinion of the investigator would compromise protocol objectives Prior exposure to CMC-544 within past 6 months Established refractoriness to CMC-544

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (transplant)<br>Patients receive inotuzumab ozogamicin IV over 1 hour on day -13, and fludarabine phosphate IV over 1 hour and bendamustine hydrochloride IV over 30 minutes to 1 hour on days -5 to -3. Patients with CD20-positive disease also receive rituximab IV over 4-6 hours on days -6, 1, and 8 and patients with MUD receive anti-thymocyte globulin IV over 3-4 hours on days -2 to -1. All patients also receive tacrolimus IV over 24 hours continuously or PO daily beginning on days -2 to 180 followed by taper in the absence of GVHD and methotrexate IV over 30 minutes on days 1, 3, and 6 (1, 3, 6, and 11 in patients with MUD). Patients undergo allogeneic BM or PBSC transplant on day 0. | Procedure: Allogeneic Bone Marrow Transplantation<br>* Undergo allogeneic BM transplant<br>* Other names: Allogeneic BMT;Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo allogeneic PBSC or BM transplant<br>* Other names: HSCT;Biological: Anti-Thymocyte Globulin<br>* Given IV<br>* Other names: Thymoglobulin;Drug: Bendamustine Hydrochloride<br>* Given IV<br>* Other names: Treanda;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;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>* Undergo allogeneic PBSC transplant<br>* Other names: Peripheral Stem Cell Transplantation;Biological: Rituximab<br>* Given IV<br>* Other names: RTXM83;Drug: Tacrolimus<br>* Given IV or PO<br>* Other names: Protopic;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum-tolerated dose (MTD) of inotuzumab ozogamicin | Defined as the highest dose for which the probability of toxicity is closest to 30%. | Up to 30 days | 
| Incidence of dose-limiting toxicity | Defined as grade III or IV renal, hepatic, intestinal, neurologic, pulmonary or cardiac adverse events, as well as graft failure or death at any time. | Up to 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective overall response (complete remission and partial remission) | Estimated with a 95% confidence interval in the dose that is declared the MTD. Logistic regression will be used to assess the association between response and disease and clinical characteristics of interest. | Up to 3 years | 
| Overall survival (OS) | Kaplan-Meier survival curves will be used to estimate OS. Cox proportional hazards regression methodology will be used to assess the association between disease and clinical characteristics and the survival outcomes. | Up to 3 years | 
| Recurrence-free survival | Kaplan-Meier survival curves will be used to estimate recurrence-free survival. Cox proportional hazards regression methodology will be used to assess the association between disease and clinical characteristics and the survival outcomes. | Up to 3 years | 
| Cumulative incidence of acute and chronic graft versus host disease (GVHD) | The method of Gooley et al will be used to estimate the cumulative incidence of acute and chronic GVHD. | Up to 3 years |