Hematopoietic and Lymphoid Cell Neoplasm
Conditions
Brief summary
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
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.
Interventions
PROCEDUREAllogeneic Bone Marrow Transplantation
Undergo allogeneic BM transplant
PROCEDUREAllogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic PBSC or BM transplant
BIOLOGICALAnti-Thymocyte Globulin
Given IV
DRUGBendamustine Hydrochloride
Given IV
DRUGFludarabine Phosphate
Given IV
BIOLOGICALInotuzumab Ozogamicin
Given IV
DRUGMethotrexate
Given IV
PROCEDUREPeripheral Blood Stem Cell Transplantation
Undergo allogeneic PBSC transplant
BIOLOGICALRituximab
Given IV
DRUGTacrolimus
Given IV or PO
Sponsors
National Cancer Institute (NCI)
M.D. Anderson Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum-tolerated Dose (MTD) of Inotuzumab Without DLT | Up to 30 days | Number of participants received inotuzumab in each cohort without DLT |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response | Up to 3 years | Overall response (CR+PR) with estimated with a 95% confidence interval in the dose that is declared the MTD. Complete Response is no clinical or radiological evidence of disease. Partial remission is equal to or more than 50% reduction in lymphadenopathy, liver and or spleen if abnormal at pre-treatment. |
| Overall Survival (OS) | Up to 3 years | Participants are disease free and alive at 3 years post transplant. |
Countries
United States
Participant flow
Recruitment details
All recruitment done at the University of Texas MD Anderson Cancer Center.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1:Allogeneic TP for CD22(+) Lymphoid Malignancy Conditioned w/ Flu/Ben/Rit/CMC544(0.6 mg/m2) 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.
Allogeneic Bone Marrow Transplantation: Undergo allogeneic BM transplant
Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic PBSC or BM transplant
Anti-Thymocyte Globulin: Given IV
Bendamustine Hydrochloride: Given IV
Fludarabine Phosphate: Given IV
Inotuzumab Ozogamicin: Given IV at 0.6 mg/m2
Methotrexate: Given IV
Peripheral Blood Stem Cell Transplantation: Undergo allogeneic PBSC transplant
Rituximab: Given IV
Tacrolimus: Given IV or PO | 4 |
| Cohort 2:Allogeneic TP for CD22(+) Lymphoid Malignancy Conditioned w/ Flu/Ben/Rit/CMC544(1.2 mg/m2) 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.
Allogeneic Bone Marrow Transplantation: Undergo allogeneic BM transplant
Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic PBSC or BM transplant
Anti-Thymocyte Globulin: Given IV
Bendamustine Hydrochloride: Given IV
Fludarabine Phosphate: Given IV
Inotuzumab Ozogamicin: Given IV at 1.2 mg/m2
Methotrexate: Given IV
Peripheral Blood Stem Cell Transplantation: Undergo allogeneic PBSC transplant
Rituximab: Given IV
Tacrolimus: Given IV or PO | 2 |
| Cohort 3:Allogeneic TP for CD22(+) Lymphoid Malignancy Conditioned w/ Flu/Ben/Rit/CMC544(1.8 mg/m2) 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.
Allogeneic Bone Marrow Transplantation: Undergo allogeneic BM transplant
Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic PBSC or BM transplant
Anti-Thymocyte Globulin: Given IV
Bendamustine Hydrochloride: Given IV
Fludarabine Phosphate: Given IV
Inotuzumab Ozogamicin: Given IV at 1.8 mg/m2
Methotrexate: Given IV
Peripheral Blood Stem Cell Transplantation: Undergo allogeneic PBSC transplant
Rituximab: Given IV
Tacrolimus: Given IV or PO | 21 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Cohort 1:Allogeneic TP for CD22(+) Lymphoid Malignancy Conditioned w/ Flu/Ben/Rit/CMC544(0.6 mg/m2) | Cohort 2:Allogeneic TP for CD22(+) Lymphoid Malignancy Conditioned w/ Flu/Ben/Rit/CMC544(1.2 mg/m2) | Cohort 3:Allogeneic TP for CD22(+) Lymphoid Malignancy Conditioned w/ Flu/Ben/Rit/CMC544(1.8 mg/m2) | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 4 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 2 Participants | 17 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 2 Participants | 19 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 4 participants | 2 participants | 21 participants | 27 participants |
| Sex: Female, Male Female | 4 Participants | 0 Participants | 8 Participants | 12 Participants |
| Sex: Female, Male Male | 0 Participants | 2 Participants | 13 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 2 | 7 / 21 |
| other Total, other adverse events | 4 / 4 | 2 / 2 | 16 / 21 |
| serious Total, serious adverse events | 0 / 4 | 0 / 2 | 2 / 21 |
Outcome results
Primary
Maximum-tolerated Dose (MTD) of Inotuzumab Without DLT
Number of participants received inotuzumab in each cohort without DLT
Time frame: Up to 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1:Allogeneic TP for CD22(+) Lymphoid Malignancy Conditioned w/ Flu/Ben/Rit/CMC544(0.6 mg/m2) | Maximum-tolerated Dose (MTD) of Inotuzumab Without DLT | 4 Participants |
| Cohort 2:Allogeneic TP for CD22(+) Lymphoid Malignancy Conditioned w/ Flu/Ben/Rit/CMC544(1.2 mg/m2) | Maximum-tolerated Dose (MTD) of Inotuzumab Without DLT | 2 Participants |
| Cohort 3:Allogeneic TP for CD22(+) Lymphoid Malignancy Conditioned w/ Flu/Ben/Rit/CMC544(1.8 mg/m2) | Maximum-tolerated Dose (MTD) of Inotuzumab Without DLT | 20 Participants |
Secondary
Overall Response
Overall response (CR+PR) with estimated with a 95% confidence interval in the dose that is declared the MTD. Complete Response is no clinical or radiological evidence of disease. Partial remission is equal to or more than 50% reduction in lymphadenopathy, liver and or spleen if abnormal at pre-treatment.
Time frame: Up to 3 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1:Allogeneic TP for CD22(+) Lymphoid Malignancy Conditioned w/ Flu/Ben/Rit/CMC544(0.6 mg/m2) | Overall Response | Not Evaluable | 0 Participants |
| Cohort 1:Allogeneic TP for CD22(+) Lymphoid Malignancy Conditioned w/ Flu/Ben/Rit/CMC544(0.6 mg/m2) | Overall Response | Complete Response | 4 Participants |
| Cohort 1:Allogeneic TP for CD22(+) Lymphoid Malignancy Conditioned w/ Flu/Ben/Rit/CMC544(0.6 mg/m2) | Overall Response | Partial Response | 0 Participants |
| Cohort 2:Allogeneic TP for CD22(+) Lymphoid Malignancy Conditioned w/ Flu/Ben/Rit/CMC544(1.2 mg/m2) | Overall Response | Not Evaluable | 0 Participants |
| Cohort 2:Allogeneic TP for CD22(+) Lymphoid Malignancy Conditioned w/ Flu/Ben/Rit/CMC544(1.2 mg/m2) | Overall Response | Partial Response | 0 Participants |
| Cohort 2:Allogeneic TP for CD22(+) Lymphoid Malignancy Conditioned w/ Flu/Ben/Rit/CMC544(1.2 mg/m2) | Overall Response | Complete Response | 2 Participants |
| Cohort 3:Allogeneic TP for CD22(+) Lymphoid Malignancy Conditioned w/ Flu/Ben/Rit/CMC544(1.8 mg/m2) | Overall Response | Not Evaluable | 1 Participants |
| Cohort 3:Allogeneic TP for CD22(+) Lymphoid Malignancy Conditioned w/ Flu/Ben/Rit/CMC544(1.8 mg/m2) | Overall Response | Partial Response | 1 Participants |
| Cohort 3:Allogeneic TP for CD22(+) Lymphoid Malignancy Conditioned w/ Flu/Ben/Rit/CMC544(1.8 mg/m2) | Overall Response | Complete Response | 19 Participants |
Secondary
Overall Survival (OS)
Participants are disease free and alive at 3 years post transplant.
Time frame: Up to 3 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1:Allogeneic TP for CD22(+) Lymphoid Malignancy Conditioned w/ Flu/Ben/Rit/CMC544(0.6 mg/m2) | Overall Survival (OS) | 4 Participants |
| Cohort 2:Allogeneic TP for CD22(+) Lymphoid Malignancy Conditioned w/ Flu/Ben/Rit/CMC544(1.2 mg/m2) | Overall Survival (OS) | 2 Participants |
| Cohort 3:Allogeneic TP for CD22(+) Lymphoid Malignancy Conditioned w/ Flu/Ben/Rit/CMC544(1.8 mg/m2) | Overall Survival (OS) | 14 Participants |