Tocilizumab for the Prevention of Graft Failure and GVHD in Haplo-Cord Transplantation

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Prospective Study of Tocilizumab for the Prevention of Graft Failure and Graft-versus-Host Disease in Haplo-Cord Transplantation

Conditions
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Hematologic Malignancy, Bone Marrow Transplant

Intervention / Treatment
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* Drug: Tocilizumab
* Drug: Fludarabine
* Drug: Melphalan
* Drug: Anti-thymocyte globulin (rabbit)
* Radiation: Total Body Irradiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must have a confirmed diagnosis of one of the following: Relapsed or refractory acute leukemia (myeloid or lymphoid) Acute leukemia in first remission at high-risk for recurrence Chronic myelogenous leukemia in chronic, accelerated phase or blast-crisis Myelodysplastic syndromes Chronic myeloproliferative disease Recurrent, refractory or high-risk malignant lymphoma Chronic lymphocytic leukemia, relapsed or with poor prognostic features Multiple myeloma Other hematological disorder in need of allogeneic transplant (e.g. blastoid dendritic cell neoplasm) Age ≥ 18 years. Likely to benefit from allogeneic transplant in the opinion of the transplant physician. An HLA-identical related or unrelated donor cannot be identified within an appropriate time frame. Karnofsky Performance Status (KPS) of ≥ 70%. Acceptable organ function as defined below: Serum bilirubin: <2.0 mg/dL ALT (SGPT) <3x upper limit of normal (ULN) Creatinine Clearance: >50 mL/min/1.73m2 (eGFR as estimated by the modified MDRD equation) Left ventricular ejection fraction >40% Pulmonary diffusion capacity >40% predicted Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Life expectancy is severely limited by concomitant illness or uncontrolled infection. Evidence of chronic active hepatitis or cirrhosis Uncontrolled HIV disease. Pregnancy or lactation. History of complicated diverticulitis, including fistulae, abscess formation or gastrointestinal perforation 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.

Ages Eligible for Study
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Minimum Age: 18 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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ATG Group I<br>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. | Drug: Tocilizumab<br>* Tocilizumab 8 mg/kg intravenously administered as a single dose on Day -1 of transplant conditioning regimen<br>* Other names: Actemra;Drug: Fludarabine<br>* 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.<br>* Other names: Fludara;Drug: Melphalan<br>* Melphalan 140 mg/m2 intravenously administered on Day -2 of transplant conditioning regimen.<br>* Other names: Alkeran;Drug: Anti-thymocyte globulin (rabbit)<br>* Anti-thymocyte globulin (ATG) 1.5 mg/kg<br>* Other names: Thymoglobulin;Radiation: Total Body Irradiation<br>* Total Body Irradiation (TBI) 2 Gray, administered on Day -4 and Day -3 of transplant conditioning regimen<br>|
| Experimental: ATG Group II<br>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. | Drug: Tocilizumab<br>* Tocilizumab 8 mg/kg intravenously administered as a single dose on Day -1 of transplant conditioning regimen<br>* Other names: Actemra;Drug: Fludarabine<br>* 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.<br>* Other names: Fludara;Drug: Melphalan<br>* Melphalan 140 mg/m2 intravenously administered on Day -2 of transplant conditioning regimen.<br>* Other names: Alkeran;Drug: Anti-thymocyte globulin (rabbit)<br>* Anti-thymocyte globulin (ATG) 1.5 mg/kg<br>* Other names: Thymoglobulin;Radiation: Total Body Irradiation<br>* Total Body Irradiation (TBI) 2 Gray, administered on Day -4 and Day -3 of transplant conditioning regimen<br>|
| Experimental: ATG Group III<br>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. | Drug: Tocilizumab<br>* Tocilizumab 8 mg/kg intravenously administered as a single dose on Day -1 of transplant conditioning regimen<br>* Other names: Actemra;Drug: Fludarabine<br>* 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.<br>* Other names: Fludara;Drug: Melphalan<br>* Melphalan 140 mg/m2 intravenously administered on Day -2 of transplant conditioning regimen.<br>* Other names: Alkeran;Drug: Anti-thymocyte globulin (rabbit)<br>* Anti-thymocyte globulin (ATG) 1.5 mg/kg<br>* Other names: Thymoglobulin;Radiation: Total Body Irradiation<br>* Total Body Irradiation (TBI) 2 Gray, administered on Day -4 and Day -3 of transplant conditioning regimen<br>|
| Experimental: ATG Group IV<br>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. | Drug: Tocilizumab<br>* Tocilizumab 8 mg/kg intravenously administered as a single dose on Day -1 of transplant conditioning regimen<br>* Other names: Actemra;Drug: Fludarabine<br>* 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.<br>* Other names: Fludara;Drug: Melphalan<br>* Melphalan 140 mg/m2 intravenously administered on Day -2 of transplant conditioning regimen.<br>* Other names: Alkeran;Radiation: Total Body Irradiation<br>* Total Body Irradiation (TBI) 2 Gray, administered on Day -4 and Day -3 of transplant conditioning regimen<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects With Successful Haplo-derived Neutrophil Engraftment | This is defined as: 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 Absence of a second nadir - a drop in the ANC to <300 cells/microL for five consecutive days - after initial neutrophil recovery. | 21 days post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 5 years post-transplant | 
| Overall Survival | Time elapsed between Day 0 and death from any cause, assessed up to 5 years post-transplant. | 5 years post-transplant | 
| 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. | 5 years post-transplant | 
| 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. | 6 months post-transplant | 
| 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) | 21 days post-transplant | 
| Proportion of Acute Graft-versus-Host Disease | Proportion of patients who develop acute graft-versus-host disease | 1 year post-transplant | 
| Proportion of Chronic Graft-versus-Host Disease | Proportion of patients who develop chronic graft-versus-host disease | 5 years post-transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tocilizumab, Haplo-Cord Transplant, Allogeneic Transplant, Hematologic Malignancies