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

Primary Purpose

Hematologic Malignancy, Bone Marrow Transplant

Status

Active

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Tocilizumab

Fludarabine

Melphalan

Anti-thymocyte globulin (rabbit)

Total Body Irradiation

About this trial

This is an interventional treatment trial for Hematologic Malignancy focused on measuring Tocilizumab, Haplo-Cord Transplant, Allogeneic Transplant, Hematologic Malignancies

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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)
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:
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
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.

Sites / Locations

Weill Cornell Medical College

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

ATG Group I

ATG Group II

ATG Group III

ATG Group IV

Arm Description

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

Overall Survival

Time elapsed between Day 0 and death from any cause, assessed up to 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.

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.

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)

Proportion of Acute Graft-versus-Host Disease

Proportion of patients who develop acute graft-versus-host disease

Proportion of Chronic Graft-versus-Host Disease

Proportion of patients who develop chronic graft-versus-host disease

Full Information

NCT ID

NCT04395222

First Posted

May 15, 2020

Last Updated

September 26, 2023

Sponsor

Weill Medical College of Cornell University

1. Study Identification

Unique Protocol Identification Number

NCT04395222

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

October 7, 2020 (Actual)

Primary Completion Date

September 28, 2022 (Actual)

Study Completion Date

May 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Weill Medical College of Cornell University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hematologic Malignancy, Bone Marrow Transplant

Keywords

Tocilizumab, Haplo-Cord Transplant, Allogeneic Transplant, Hematologic Malignancies

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

21 (Actual)

8. Arms, Groups, and Interventions

Arm Title

ATG Group I

Arm Type

Experimental

Arm Description

Arm Title

ATG Group II

Arm Type

Experimental

Arm Description

Arm Title

ATG Group III

Arm Type

Experimental

Arm Description

Arm Title

ATG Group IV

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Tocilizumab

Other Intervention Name(s)

Actemra

Intervention Description

Tocilizumab 8 mg/kg intravenously administered as a single dose on Day -1 of transplant conditioning regimen

Intervention Type

Drug

Intervention Name(s)

Fludarabine

Other Intervention Name(s)

Fludara

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Melphalan

Other Intervention Name(s)

Alkeran

Intervention Description

Melphalan 140 mg/m2 intravenously administered on Day -2 of transplant conditioning regimen.

Intervention Type

Drug

Intervention Name(s)

Anti-thymocyte globulin (rabbit)

Other Intervention Name(s)

Thymoglobulin

Intervention Description

Anti-thymocyte globulin (ATG) 1.5 mg/kg

Intervention Type

Radiation

Intervention Name(s)

Total Body Irradiation

Intervention Description

Total Body Irradiation (TBI) 2 Gray, administered on Day -4 and Day -3 of transplant conditioning regimen

Primary Outcome Measure Information:

Title

Percentage of Subjects With Successful Haplo-derived Neutrophil Engraftment

Description

Time Frame

21 days post-transplant

Secondary Outcome Measure Information:

Title

Progression-Free Survival

Description

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

Title

Overall Survival

Description

Time elapsed between Day 0 and death from any cause, assessed up to 5 years post-transplant.

Time Frame

5 years post-transplant

Title

Transplant-Related Mortality

Description

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

Title

Proportion of Platelet Engraftment Success

Description

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

Title

Proportion of Failure of the Haplo-Graft

Description

Time Frame

21 days post-transplant

Title

Proportion of Acute Graft-versus-Host Disease

Description

Proportion of patients who develop acute graft-versus-host disease

Time Frame

1 year post-transplant

Title

Proportion of Chronic Graft-versus-Host Disease

Description

Proportion of patients who develop chronic graft-versus-host disease

Time Frame

5 years post-transplant

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Alexandra Gomez Arteaga, MD

Organizational Affiliation

Weill Medical College of Cornell University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Weill Cornell Medical College

City

New York

State/Province

New York

ZIP/Postal Code

10065

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

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

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