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Visilizumab for the Prevention of Graft-versus-Host Disease After Allogeneic Hematopoietic Cell Transplantation

Primary Purpose

Graft Versus Host Disease

Status

Terminated

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Visilizumab

Tacrolimus

Methotrexate

Antithymocyte globulin (ATG)

Tacrolimus

Methotrexate

About this trial

This is an interventional prevention trial for Graft Versus Host Disease focused on measuring graft versus host disease, GVHD, allogeneic transplant, GVHD prevention, unrelated donors, mismatched unrelated donors, hematological malignancies, Leukemia, Lymphoma, Myelodysplastic Syndrome, Myelofibrosis, Aplastic Anemia, Multiple Myeloma

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

One of the following diagnoses with histological confirmation by the Pathology Department at H. Lee Moffitt Cancer Center:
Acute Lymphocytic Leukemia (ALL) in complete remission 1 (CR1) with t(9:22) or t(4:11), or any ALL beyond CR1
Acute Myelogenous Leukemia (AML) with high risk cytogenetics in CR1 as defined by Bloomfield any AML beyond CR1
Myelodysplastic Syndrome (MDS) with International Prognostic Scoring System (IPSS) score > 1
Chronic myelomonocytic leukemia (CMML)
Chronic Myelogenous Leukemia (CML) with Imatinib-refractory chronic phase, or beyond chronic phase by morphology or cytogenetics
Myelofibrosis
Severe aplastic anemia
Chemosensitive Non-Hodgkin's lymphoma and Hodgkin's disease that are not candidate to autologous transplant due to prior autologous transplantation
Multiple Myeloma patient not candidate for autologous stem cell transplantation
Karnofsky performance status ≥ 70% (adult)
Normal organ and marrow function as defined below:
Hepatic: Total bilirubin must be less than or equal to 2mg/dL (Gilbert and other syndromes with increased indirect bilirubin are allowed); serum transaminases must be less than two times the upper limit of normal
Pulmonary: diffusing capacity of lung for carbon monoxide (DLCO) (corrected for Hgb), forced expiratory volume-one second (FEV1), forced vital capacity (FVC) must be greater than 50% predicted
Cardiac: Left ventricular ejection fraction at rest must be greater than 50%
Renal: Creatinine clearance (measured or calculated) must be equal or greater than 50 ml/min/1.73m^2

Exclusion Criteria:

Anti thymocyte globulin (ATG) or anti T cell therapy in prior 45 days
Splenectomized patients;
A positive pregnancy test administered to all females of childbearing potential prior to allogeneic stem cell transplant
Inability to comply with follow up as determined by the patient's physician
HIV-I/II infection prior to hematopoietic stem cell (HSC) transplantation, confirmed by nucleic acid test (NAT)
Uncontrolled bacterial or fungal infection
History of documented invasive aspergillosis or cytomegalovirus (CMV) pneumonia
Presence of any of the following comorbid conditions:
History of myocardial infarction
Congestive heart failure (even if symptomatically controlled)
Peripheral vascular disease (including intermittent claudication or history of bypass for arterial insufficiency)
Untreated thoracic or abdominal aneurysm (6cm or more)
History of any cerebrovascular accident including transient ischemic attacks
Dementia
History of peptic ulcer disease requiring treatment
Connective tissue/rheumatologic disorders
Diabetes unless being managed with dietary changes only
Hemiplegia/paraplegia
History of solid tumor excluding skin or cervical carcinoma after curative resection

Sites / Locations

H. Lee Moffitt Cancer Center & Research Institute

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

First Study Stage: Study Treatment

Second Study Stage: Standard Treatment

Arm Description

Visilizumab, Tacrolimus and Methotrexate.

Second Stage: Antithymocyte-globulin (ATG), Tacrolimus and Methotrexate. The study was closed during first stage and did not proceed to the second stage comparison to ATG in combination with tacrolimus/methotrexate as originally planned.

Outcomes

Primary Outcome Measures

Number of Participants With Grade II-IV Acute Graft-versus-Host Disease (GVHD) Score at 100 Days

Cumulative Incidence of Grade II-IV Acute GVHD Score at 100 Days. Investigators had planned to assess whether the grade of acute GVHD was decreased by visilizumab in combination with tacrolimus/methotrexate compared to standard treatment with thymoglobulin/tacrolimus/methotrexate after transplantation from unrelated mismatched donors, from day of transplant up to one year. Study was closed during the first treatment stage and did not proceed to the second stage treatment comparison to ATG in combination with tacrolimus/methotrexate as originally planned. Overall GVHD Grade: From Filipovich AH, Weisdorf D, Pavletic S, etal: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. Diagnosis and Staging Working Group Report. Biology of Blood and Marrow Transplantation 11:945-955 (2005). Grade I: Skin Stage 1-2, Liver Stage 0, Gut State 0; Grade II: Skin Stage 3 or, Liver Stage 1 or, Gut Stage 1; Grade II

Secondary Outcome Measures

Incidence of Epstein-Barr Virus (EBV) Reactivation

Number of participants who reactivated EBV. Patients had their plasma tested once weekly using the TaqMan polymerase chain reaction (PCR) for quantitative determination of EBV-DNA for 6 weeks. Plasma levels > 1000 copies per ml plasma were scored as positive.

Incidence of Rituximab Response to Reactivated EBV Without PTLD

Participants who developed plasma EBV-DNA of >1000 copies/mL on any tests received rituximab. Incidence of Rituximab Response: Reactivated EBV participants whose plasma titers cleared after rituximab, without post-transplant lymphoproliferative disorder (PTLD).

Overall Survival (OS)

Median OS in days. Survival was measured from the time of transplant to the time of death.

Pharmacodynamics of Visilizumab - Test 1

Mean Cmax (±SD)

Pharmacodynamics of Visilizumab - Test 2

Mean terminal half-life (±SD)

Full Information

NCT ID

NCT00720629

First Posted

July 21, 2008

Last Updated

July 10, 2014

Sponsor

H. Lee Moffitt Cancer Center and Research Institute

Collaborators

National Institutes of Health (NIH), National Cancer Institute (NCI)

1. Study Identification

Unique Protocol Identification Number

NCT00720629

Brief Title

Visilizumab for the Prevention of Graft-versus-Host Disease After Allogeneic Hematopoietic Cell Transplantation

Official Title

A Phase II Study of Visilizumab for the Prevention of Graft-versus-Host Disease After Allogeneic Hematopoietic Cell Transplantation

Study Type

Interventional

2. Study Status

Record Verification Date

April 2014

Overall Recruitment Status

Terminated

Study Start Date

December 2007 (undefined)

Primary Completion Date

December 2013 (Actual)

Study Completion Date

December 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

H. Lee Moffitt Cancer Center and Research Institute

Collaborators

National Institutes of Health (NIH), National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this study was to test whether a new drug named visilizumab would decrease the severity of graft-versus-host disease in patients treated with a mismatched donor. Investigators planned to use visilizumab in combination with tacrolimus and methotrexate as the "study treatment".

Detailed Description

The protocol plan was a two stage, controlled, phase II study to assess safety and compare the grade of acute graft-versus-host disease (GVHD) with visilizumab, or Anti-thymocyte Globulin (ATG) in combination with tacrolimus + methotrexate in patients at high risk of GVHD after transplant from unrelated donors mismatched for 1-2 alleles of any type at human leukocyte antigen (HLA) A, B, C and DRB1. The study design included two stages. The first stage of the trial was to enroll 15 patients on a single arm to be treated with "study treatment" (visilizumab, tacrolimus and methotrexate) to assess for treatment safety and exclude intolerable GVHD. The second stage of the trial was to include a random control group of patients treated with the current "standard treatment" (ATG, tacrolimus, and methotrexate) or "study treatment". The purpose of this comparison was to determine if the "study treatment" visilizumab causes less severe side effects and if it is more potent in reducing graft-versus-host disease symptoms than the "standard treatment".

6. Conditions and Keywords

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

Graft Versus Host Disease

Keywords

graft versus host disease, GVHD, allogeneic transplant, GVHD prevention, unrelated donors, mismatched unrelated donors, hematological malignancies, Leukemia, Lymphoma, Myelodysplastic Syndrome, Myelofibrosis, Aplastic Anemia, Multiple Myeloma

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

8 (Actual)

8. Arms, Groups, and Interventions

Arm Title

First Study Stage: Study Treatment

Arm Type

Experimental

Arm Description

Visilizumab, Tacrolimus and Methotrexate.

Arm Title

Second Study Stage: Standard Treatment

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Visilizumab

Intervention Description

3 mg/m^3, IV (in the vein) on day 0, prior to hematopoietic cell infusion (transplant).

Intervention Type

Drug

Intervention Name(s)

Tacrolimus

Intervention Description

0.02 mg/kg/24h (based on ideal body weight) continuous infusion (over 24 hours) beginning on day 4 after transplant up to approximately day 180 after transplant. Switch to oral tacrolimus as able. Dose adjusted based on levels. In the absence of GVHD, the dose to be tapered beginning 100 days after transplant.

Intervention Type

Drug

Intervention Name(s)

Methotrexate

Intervention Description

15 mg/m^2 intravenously (IV) on Day 1 after transplant; 10 mg/m^2 IV on Days 3, 6 and 11 after transplant.

Intervention Type

Drug

Intervention Name(s)

Antithymocyte globulin (ATG)

Other Intervention Name(s)

Thymoglobulin-ATG

Intervention Description

1 mg/kg IV over 6 hours on Day 3 before transplant; 3.25 mg/kg IV over 4 hours on days 2 and 1 before transplant.

Intervention Type

Drug

Intervention Name(s)

Tacrolimus

Intervention Description

0.03 mg/kg/24h (based on ideal body weight) continuous infusion (over 24 hours) beginning on day 3 before transplant up to approximately day 180 after transplant. Switch to oral tacrolimus as able. Dose adjusted based on levels. In the absence of GVHD, the dose to be tapered beginning 100 days after transplant.

Intervention Type

Drug

Intervention Name(s)

Methotrexate

Intervention Description

15 mg/m^2 IV on Day 1 after transplant; 10 mg/m^2 IV on Days 3, 6 and 11 after transplant.

Primary Outcome Measure Information:

Title

Number of Participants With Grade II-IV Acute Graft-versus-Host Disease (GVHD) Score at 100 Days

Description

Time Frame

100 days

Secondary Outcome Measure Information:

Title

Incidence of Epstein-Barr Virus (EBV) Reactivation

Description

Time Frame

3 months

Title

Incidence of Rituximab Response to Reactivated EBV Without PTLD

Description

Time Frame

100 days

Title

Overall Survival (OS)

Description

Median OS in days. Survival was measured from the time of transplant to the time of death.

Time Frame

At 2 years and 5 years

Title

Pharmacodynamics of Visilizumab - Test 1

Description

Mean Cmax (±SD)

Time Frame

At 1 - 2 hours

Title

Pharmacodynamics of Visilizumab - Test 2

Description

Mean terminal half-life (±SD)

Time Frame

Up to 205 hours

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

60 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: One of the following diagnoses with histological confirmation by the Pathology Department at H. Lee Moffitt Cancer Center: Acute Lymphocytic Leukemia (ALL) in complete remission 1 (CR1) with t(9:22) or t(4:11), or any ALL beyond CR1 Acute Myelogenous Leukemia (AML) with high risk cytogenetics in CR1 as defined by Bloomfield any AML beyond CR1 Myelodysplastic Syndrome (MDS) with International Prognostic Scoring System (IPSS) score > 1 Chronic myelomonocytic leukemia (CMML) Chronic Myelogenous Leukemia (CML) with Imatinib-refractory chronic phase, or beyond chronic phase by morphology or cytogenetics Myelofibrosis Severe aplastic anemia Chemosensitive Non-Hodgkin's lymphoma and Hodgkin's disease that are not candidate to autologous transplant due to prior autologous transplantation Multiple Myeloma patient not candidate for autologous stem cell transplantation Karnofsky performance status ≥ 70% (adult) Normal organ and marrow function as defined below: Hepatic: Total bilirubin must be less than or equal to 2mg/dL (Gilbert and other syndromes with increased indirect bilirubin are allowed); serum transaminases must be less than two times the upper limit of normal Pulmonary: diffusing capacity of lung for carbon monoxide (DLCO) (corrected for Hgb), forced expiratory volume-one second (FEV1), forced vital capacity (FVC) must be greater than 50% predicted Cardiac: Left ventricular ejection fraction at rest must be greater than 50% Renal: Creatinine clearance (measured or calculated) must be equal or greater than 50 ml/min/1.73m^2 Exclusion Criteria: Anti thymocyte globulin (ATG) or anti T cell therapy in prior 45 days Splenectomized patients; A positive pregnancy test administered to all females of childbearing potential prior to allogeneic stem cell transplant Inability to comply with follow up as determined by the patient's physician HIV-I/II infection prior to hematopoietic stem cell (HSC) transplantation, confirmed by nucleic acid test (NAT) Uncontrolled bacterial or fungal infection History of documented invasive aspergillosis or cytomegalovirus (CMV) pneumonia Presence of any of the following comorbid conditions: History of myocardial infarction Congestive heart failure (even if symptomatically controlled) Peripheral vascular disease (including intermittent claudication or history of bypass for arterial insufficiency) Untreated thoracic or abdominal aneurysm (6cm or more) History of any cerebrovascular accident including transient ischemic attacks Dementia History of peptic ulcer disease requiring treatment Connective tissue/rheumatologic disorders Diabetes unless being managed with dietary changes only Hemiplegia/paraplegia History of solid tumor excluding skin or cervical carcinoma after curative resection

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Lia Perez, MD

Organizational Affiliation

H. Lee Moffitt Cancer Center and Research Institute

Official's Role

Principal Investigator

Facility Information:

Facility Name

H. Lee Moffitt Cancer Center & Research Institute

City

Tampa

State/Province

Florida

ZIP/Postal Code

33612

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

21874061

Citation

Pidala J, Perez L, Beato F, Anasetti C. Ustekinumab demonstrates activity in glucocorticoid-refractory acute GVHD. Bone Marrow Transplant. 2012 May;47(5):747-8. doi: 10.1038/bmt.2011.172. Epub 2011 Aug 29. No abstract available.

Results Reference

derived

Links:

URL

http://www.moffitt.org/

Description

H. Lee Moffitt Cancer Center & Research Institute

Learn more about this trial

Visilizumab for the Prevention of Graft-versus-Host Disease After Allogeneic Hematopoietic Cell Transplantation

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