Hematologic Malignancy, Bone Marrow Transplant
Conditions
Keywords
Tocilizumab, Haplo-Cord Transplant, Allogeneic Transplant, Hematologic Malignancies
Brief summary
The purpose of this study is to evaluate the safety of reducing and ultimately eliminating anti-thymocyte globulin (ATG) from the haplo-cord transplant conditioning regimen and replacing it with tocilizumab, an IL-6 receptor monoclonal antibody, to improve immune reconstitution and reduce relapse while preserving low rates of graft failure and graft versus host disease (GVHD).
Detailed description
This study is a prospective phase II non-inferiority study investigating tocilizumab as a potential alternative to anti-thymocyte globulin (ATG) in haplo-cord transplantation. It is a single-center study based at Weill Cornell Medicine/NewYork Presbyterian Hospital. The hypothesis is that tocilizumab is a safe and effective alternative to ATG in haplo-cord transplantation, facilitating transient engraftment of the haplo-identical stem cell graft without prolonged neutropenia or second nadir prior to durable cord engraftment while also preventing graft versus host disease (GVHD). This study plans to enroll patients with hematologic malignancies in need of alternate donor transplant. All subjects will be conditioned with fludarabine, melphalan and total body irradiation (TBI), followed by a single dose of tocilizumab 8 mg/kg on Day -1. Patients will be enrolled into 4 successive cohorts, initially administering the current standard 3 doses of ATG 1.5 mg/kg (total 4.5 mg/kg). In the absence of safety signals, we will drop one dose of ATG in successive cohorts until the drug ultimately has been eliminated. The primary endpoint of the study is successful haplo-derived neutrophil engraftment. Treatment will only be of interest if there is evidence that this rate is greater than 60%. If there are 4 or fewer successes, that dose group will be deemed unacceptable and the next higher ATG dose for which there were 5 or more success will be expanded.
Interventions
DRUGTocilizumab
Tocilizumab 8 mg/kg intravenously administered as a single dose on Day -1 of transplant conditioning regimen
DRUGFludarabine
Fludarabine 30 mg/m2 intravenously administered on Day -7, Day -6, Day -5, Day -4, Day -3 of transplant conditioning regimen if under the age of 60. If over the age of 60, Fludarabine 30 mg/m2 intravenously administered on Day -5, Day -4 and Day -3 of transplant conditioning regimen.
DRUGMelphalan
Melphalan 140 mg/m2 intravenously administered on Day -2 of transplant conditioning regimen.
Anti-thymocyte globulin (ATG) 1.5 mg/kg
RADIATIONTotal Body Irradiation
Total Body Irradiation (TBI) 2 Gray, administered on Day -4 and Day -3 of transplant conditioning regimen
Sponsors
Weill Medical College of Cornell University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Subject must have a confirmed diagnosis of one of the following: 1. Relapsed or refractory acute leukemia (myeloid or lymphoid) 2. Acute leukemia in first remission at high-risk for recurrence 3. Chronic myelogenous leukemia in chronic, accelerated phase or blast-crisis 4. Myelodysplastic syndromes 5. Chronic myeloproliferative disease 6. Recurrent, refractory or high-risk malignant lymphoma 7. Chronic lymphocytic leukemia, relapsed or with poor prognostic features 8. Multiple myeloma 9. Other hematological disorder in need of allogeneic transplant (e.g. blastoid dendritic cell neoplasm) 2. Age ≥ 18 years. 3. Likely to benefit from allogeneic transplant in the opinion of the transplant physician. 4. An HLA-identical related or unrelated donor cannot be identified within an appropriate time frame. 5. Karnofsky Performance Status (KPS) of ≥ 70%. 6. Acceptable organ function as defined below: 1. Serum bilirubin: \<2.0 mg/dL 2. ALT (SGPT) \<3x upper limit of normal (ULN) 3. Creatinine Clearance: \>50 mL/min/1.73m2 (eGFR as estimated by the modified MDRD equation) 4. Left ventricular ejection fraction \>40% 5. Pulmonary diffusion capacity \>40% predicted 7. Ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
1. Life expectancy is severely limited by concomitant illness or uncontrolled infection. 2. Evidence of chronic active hepatitis or cirrhosis 3. Uncontrolled HIV disease. 4. Pregnancy or lactation. 5. History of complicated diverticulitis, including fistulae, abscess formation or gastrointestinal perforation 6. History of allergic reactions attributed to compounds of similar chemical or biological composition as tocilizumab, including known allergies to Chinese hamster ovary cell products or other recombinant human or humanized antibodies.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects With Successful Haplo-derived Neutrophil Engraftment | 21 days post-transplant | This is defined as: 1. Achieve an absolute neutrophil count (ANC) of 500 cells/microL for three consecutive days with the first on or prior to Day +21 post-transplant, AND 2. Absence of a second nadir - a drop in the ANC to \<300 cells/microL for five consecutive days - after initial neutrophil recovery. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 5 years post-transplant | Time elapsed between Day 0 and death from any cause, assessed up to 5 years post-transplant. |
| Transplant-Related Mortality | 5 years post-transplant | Proportion of deaths which cannot be explained by persistence, relapse or progression of the underlying malignancy once the preparative regimen starts, assessed up to 5 years post-transplant. |
| Proportion of Platelet Engraftment Success | 6 months post-transplant | Proportion of patients who successfully achieve platelet engraftment, defined as a platelet count of \>20k/microL for three consecutive days without transfusion support for seven consecutive days. |
| Progression-Free Survival | 5 years post-transplant | Time elapsed between Day 0 and progression of the underlying malignancy for which the transplant was performed, assessed up to 5 years post-transplant. |
| Proportion of Acute Graft-versus-Host Disease | 1 year post-transplant | Proportion of patients who develop acute graft-versus-host disease |
| Percentage of Chronic Graft-versus-Host Disease | 5 years post-transplant | Percentage of patients who develop chronic graft-versus-host disease |
| Proportion of Failure of the Haplo-Graft | 21 days post-transplant | Proportion of patients with a failed haplo-graft, defined as the absence of neutrophil engraftment by Day +21 or a drop in the absolute neutrophil count to \<0.3 cells/microL for five consecutive days occurring after initial neutrophil engraftment within the first 3 weeks post-transplantation (second nadir) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ATG Group I Anti-thymocyte Globulin (ATG) 1.5 mg/kg administered on Day -5, Day -3 and Day -1 of the transplant conditioning regimen.
* Fludarabine 30mg/m2 administered on Day -7 through Day -3 of transplant conditioning regimen (if under 60 years old), or on Day -5 through Day -3 of transplant conditioning regimen (if over 60 years old)
* Melphalan 140 mg/m2 administered on Day -2 of transplant conditioning regimen.
* Total Body Irradiation 2 Gray administered on Day -4, Day -3 of transplant conditioning regimen.
* Tocilizumab 8 mg/kg administered on Day -1 of transplant conditioning regimen.
Tocilizumab: Tocilizumab 8 mg/kg intravenously administered as a single dose on Day -1 of transplant conditioning regimen
Fludarabine: Fludarabine 30 mg/m2 intravenously administered on Day -7, Day -6, Day -5, Day -4, Day -3 of transplant conditioning regimen if under the age of 60. If over the age of 60, Fludarabine 30 mg/m2 intravenously administered on Day -5, Day -4 and Day -3 of transplant conditioning regimen.
Melphalan: Melphalan 140 mg/m2 intravenously administered on Day -2 of transplant conditioning regimen.
Anti-thymocyte globulin (rabbit): Anti-thymocyte globulin (ATG) 1.5 mg/kg
Total Body Irradiation: Total Body Irradiation (TBI) 2 Gray, administered on Day -4 and Day -3 of transplant conditioning regimen | 10 |
| ATG Group II Anti-thymocyte Globulin (ATG) 1.5 mg/kg administered on Day -5, and Day -3 of the transplant conditioning regimen.
* Fludarabine 30mg/m2 administered on Day -7 through Day -3 of transplant conditioning regimen (if under 60 years old), or on Day -5 through Day -3 of transplant conditioning regimen (if over 60 years old)
* Melphalan 140 mg/m2 administered on Day -2 of transplant conditioning regimen.
* Total Body Irradiation 2 Gray administered on Day -4, Day -3 of transplant conditioning regimen.
* Tocilizumab 8 mg/kg administered on Day -1 of transplant conditioning regimen.
Tocilizumab: Tocilizumab 8 mg/kg intravenously administered as a single dose on Day -1 of transplant conditioning regimen
Fludarabine: Fludarabine 30 mg/m2 intravenously administered on Day -7, Day -6, Day -5, Day -4, Day -3 of transplant conditioning regimen if under the age of 60. If over the age of 60, Fludarabine 30 mg/m2 intravenously administered on Day -5, Day -4 and Day -3 of transplant conditioning regimen.
Melphalan: Melphalan 140 mg/m2 intravenously administered on Day -2 of transplant conditioning regimen.
Anti-thymocyte globulin (rabbit): Anti-thymocyte globulin (ATG) 1.5 mg/kg
Total Body Irradiation: Total Body Irradiation (TBI) 2 Gray, administered on Day -4 and Day -3 of transplant conditioning regimen | 10 |
| ATG Group III Anti-thymocyte Globulin (ATG) 1.5 mg/kg administered on Day -5 of the transplant conditioning regimen.
* Fludarabine 30mg/m2 administered on Day -7 through Day -3 of transplant conditioning regimen (if under 60 years old), or on Day -5 through Day -3 of transplant conditioning regimen (if over 60 years old)
* Melphalan 140 mg/m2 administered on Day -2 of transplant conditioning regimen.
* Total Body Irradiation 2 Gray administered on Day -4, Day -3 of transplant conditioning regimen.
* Tocilizumab 8 mg/kg administered on Day -1 of transplant conditioning regimen.
Tocilizumab: Tocilizumab 8 mg/kg intravenously administered as a single dose on Day -1 of transplant conditioning regimen
Fludarabine: Fludarabine 30 mg/m2 intravenously administered on Day -7, Day -6, Day -5, Day -4, Day -3 of transplant conditioning regimen if under the age of 60. If over the age of 60, Fludarabine 30 mg/m2 intravenously administered on Day -5, Day -4 and Day -3 of transplant conditioning regimen.
Melphalan: Melphalan 140 mg/m2 intravenously administered on Day -2 of transplant conditioning regimen.
Anti-thymocyte globulin (rabbit): Anti-thymocyte globulin (ATG) 1.5 mg/kg
Total Body Irradiation: Total Body Irradiation (TBI) 2 Gray, administered on Day -4 and Day -3 of transplant conditioning regimen | 1 |
| ATG Group IV * Fludarabine 30mg/m2 administered on Day -7 through Day -3 of transplant conditioning regimen (if under 60 years old), or on Day -5 through Day -3 of transplant conditioning regimen (if over 60 years old)
* Melphalan 140 mg/m2 administered on Day -2 of transplant conditioning regimen.
* Total Body Irradiation 2 Gray administered on Day -4, Day -3 of transplant conditioning regimen.
* Tocilizumab 8 mg/kg administered on Day -1 of transplant conditioning regimen.
Tocilizumab: Tocilizumab 8 mg/kg intravenously administered as a single dose on Day -1 of transplant conditioning regimen
Fludarabine: Fludarabine 30 mg/m2 intravenously administered on Day -7, Day -6, Day -5, Day -4, Day -3 of transplant conditioning regimen if under the age of 60. If over the age of 60, Fludarabine 30 mg/m2 intravenously administered on Day -5, Day -4 and Day -3 of transplant conditioning regimen.
Melphalan: Melphalan 140 mg/m2 intravenously administered on Day -2 of transplant conditioning regimen.
Total Body Irradiation: Total Body Irradiation (TBI) 2 Gray, administered on Day -4 and Day -3 of transplant conditioning regimen | 0 |
| Total | 21 |
Baseline characteristics
| Characteristic | ATG Group I | ATG Group II | ATG Group III | ATG Group IV | Total |
|---|---|---|---|---|---|
| Age, Customized 18-29 years | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 3 Participants |
| Age, Customized 30-39 years | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 3 Participants |
| Age, Customized 40-49 years | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 3 Participants |
| Age, Customized 50-59 years | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Age, Customized 60-69 years | 7 Participants | 3 Participants | 1 Participants | 0 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 3 Participants | 0 Participants | 0 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 7 Participants | 1 Participants | 0 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Primary Malignancy Acute Myeloid Leukemia | 5 Participants | 5 Participants | 0 Participants | 0 Participants | 10 Participants |
| Primary Malignancy Myelodysplastic Syndrome | 1 Participants | 3 Participants | 1 Participants | 0 Participants | 5 Participants |
| Primary Malignancy Myeloproliferative Neoplasm | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Primary Malignancy Non-Hodgkin Lymphoma | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 3 Participants |
| Primary Malignancy Other Acute Leukemia | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 8 Participants | 6 Participants | 1 Participants | 0 Participants | 15 Participants |
| Region of Enrollment United States | 10 participants | 10 participants | 1 participants | — | 21 participants |
| Sex: Female, Male Female | 5 Participants | 5 Participants | 1 Participants | 0 Participants | 11 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 0 Participants | 0 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 10 | 1 / 10 | 1 / 1 | 0 / 0 |
| other Total, other adverse events | 10 / 10 | 10 / 10 | 1 / 1 | 0 / 0 |
| serious Total, serious adverse events | 8 / 10 | 9 / 10 | 1 / 1 | 0 / 0 |
Outcome results
Primary
Percentage of Subjects With Successful Haplo-derived Neutrophil Engraftment
This is defined as: 1. Achieve an absolute neutrophil count (ANC) of 500 cells/microL for three consecutive days with the first on or prior to Day +21 post-transplant, AND 2. Absence of a second nadir - a drop in the ANC to \<300 cells/microL for five consecutive days - after initial neutrophil recovery.
Time frame: 21 days post-transplant
Population: No subjects were enrolled to ATG Group IV; study enrollment was stopped before accrual reached that cohort.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ATG Group I | Percentage of Subjects With Successful Haplo-derived Neutrophil Engraftment | 80 percentage of participants |
| ATG Group II | Percentage of Subjects With Successful Haplo-derived Neutrophil Engraftment | 50 percentage of participants |
| ATG Group III | Percentage of Subjects With Successful Haplo-derived Neutrophil Engraftment | 0 percentage of participants |
Secondary
Overall Survival
Time elapsed between Day 0 and death from any cause, assessed up to 5 years post-transplant.
Time frame: 5 years post-transplant
Secondary
Percentage of Chronic Graft-versus-Host Disease
Percentage of patients who develop chronic graft-versus-host disease
Time frame: 5 years post-transplant
Secondary
Progression-Free Survival
Time elapsed between Day 0 and progression of the underlying malignancy for which the transplant was performed, assessed up to 5 years post-transplant.
Time frame: 5 years post-transplant
Secondary
Proportion of Acute Graft-versus-Host Disease
Proportion of patients who develop acute graft-versus-host disease
Time frame: 1 year post-transplant
Population: No subjects were enrolled to ATG Group IV, study enrollment was stopped before accrual reached that cohort.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ATG Group I | Proportion of Acute Graft-versus-Host Disease | 2 Participants |
| ATG Group II | Proportion of Acute Graft-versus-Host Disease | 1 Participants |
| ATG Group III | Proportion of Acute Graft-versus-Host Disease | 1 Participants |
| ATG Group IV | Proportion of Acute Graft-versus-Host Disease | 0 Participants |
Secondary
Proportion of Failure of the Haplo-Graft
Proportion of patients with a failed haplo-graft, defined as the absence of neutrophil engraftment by Day +21 or a drop in the absolute neutrophil count to \<0.3 cells/microL for five consecutive days occurring after initial neutrophil engraftment within the first 3 weeks post-transplantation (second nadir)
Time frame: 21 days post-transplant
Population: No subjects were enrolled to ATG Group IV; study enrollment was stopped before accrual reached that cohort.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ATG Group I | Proportion of Failure of the Haplo-Graft | 2 Participants |
| ATG Group II | Proportion of Failure of the Haplo-Graft | 5 Participants |
| ATG Group III | Proportion of Failure of the Haplo-Graft | 1 Participants |
Secondary
Proportion of Platelet Engraftment Success
Proportion of patients who successfully achieve platelet engraftment, defined as a platelet count of \>20k/microL for three consecutive days without transfusion support for seven consecutive days.
Time frame: 6 months post-transplant
Population: No subjects were enrolled to ATG Group IV, study enrollment was stopped before accrual reached that cohort.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ATG Group I | Proportion of Platelet Engraftment Success | 10 Participants |
| ATG Group II | Proportion of Platelet Engraftment Success | 10 Participants |
| ATG Group III | Proportion of Platelet Engraftment Success | 0 Participants |
| ATG Group IV | Proportion of Platelet Engraftment Success | 0 Participants |
Secondary
Transplant-Related Mortality
Proportion of deaths which cannot be explained by persistence, relapse or progression of the underlying malignancy once the preparative regimen starts, assessed up to 5 years post-transplant.
Time frame: 5 years post-transplant