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

• Sponsor: H. Lee Moffitt Cancer Center and Research Institute (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00720629
• Collaborator: National Institutes of Health (NIH) (NIH), National Cancer Institute (NCI) (NIH)
• Enrollment: 8
• Location: 1
• Arms: 2
• Duration (Months): 72
• Patients Per Site Per Month: 0.1

Study Details

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".

Condition or Disease	Intervention/Treatment	Phase
Graft Versus Host Disease	Drug: Visilizumab; Drug: Tacrolimus; Drug: Methotrexate; Drug: Antithymocyte globulin (ATG); Drug: Tacrolimus; Drug: Methotrexate	Phase 2

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".

Study Design

• Study Type: Interventional
• Actual Enrollment: 8 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: A Phase II Study of Visilizumab for the Prevention of Graft-versus-Host Disease After Allogeneic Hematopoietic Cell Transplantation
• Study Start Date: Dec 1, 2007
• Actual Primary Completion Date: Dec 1, 2013
• Actual Study Completion Date: Dec 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: First Study Stage: Study Treatment Visilizumab, Tacrolimus and Methotrexate.	Drug: Visilizumab; 3 mg/m^3, IV (in the vein) on day 0, prior to hematopoietic cell infusion (transplant).; Drug: Tacrolimus; 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.; Drug: Methotrexate; 15 mg/m^2 intravenously (IV) on Day 1 after transplant; 10 mg/m^2 IV on Days 3, 6 and 11 after transplant.
Active Comparator: Second Study Stage: Standard Treatment 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.	Drug: Antithymocyte globulin (ATG); 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.; Other Names: Thymoglobulin-ATG ; Drug: Tacrolimus; 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.; Drug: Methotrexate; 15 mg/m^2 IV on Day 1 after transplant; 10 mg/m^2 IV on Days 3, 6 and 11 after transplant.

Outcome Measures

Primary Outcome Measures

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

1. Incidence of Epstein-Barr Virus (EBV) Reactivation [3 months]

   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.

2. Incidence of Rituximab Response to Reactivated EBV Without PTLD [100 days]

   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).

3. Overall Survival (OS) [At 2 years and 5 years]

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

4. Pharmacodynamics of Visilizumab - Test 1 [At 1 - 2 hours]

   Mean Cmax (±SD)

5. Pharmacodynamics of Visilizumab - Test 2 [Up to 205 hours]

   Mean terminal half-life (±SD)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	H. Lee Moffitt Cancer Center & Research Institute	Tampa	Florida	United States	33612

Sponsors and Collaborators

• H. Lee Moffitt Cancer Center and Research Institute
• National Institutes of Health (NIH)
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Lia Perez, MD, H. Lee Moffitt Cancer Center and Research Institute

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• H. Lee Moffitt Cancer Center & Research Institute

Publications

None provided.

• Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
• ClinicalTrials.gov Identifier: NCT00720629
• Other Study ID Numbers: MCC-15033; R01CA132197-06A2
• First Posted: Jul 23, 2008
• Last Update Posted: Jul 18, 2014
• Last Verified: Apr 1, 2014

• Keywords provided by H. Lee Moffitt Cancer Center and Research Institute: 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
• Additional relevant MeSH terms: Graft vs Host Disease; Methotrexate; Tacrolimus; Thymoglobulin; Antilymphocyte Serum; Visilizumab

Study Results

Participant Flow

Recruitment Details	Participants were enrolled at Moffitt Cancer Center between February 2008 and April 2010.
Pre-assignment Detail	The study was closed during the single-arm, first stage and did not proceed to the second stage comparison to antithymocyte globulin (ATG) in combination with tacrolimus/methotrexate as originally planned.

Arm/Group Title	First Study Stage: Study Treatment
Arm/Group Description	Visilizumab, Tacrolimus and Methotrexate. All participants.
Period Title: Overall Study
STARTED	8
COMPLETED	8
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	First Stage: Study Treatment
Arm/Group Description	Visilizumab, Tacrolimus and Methotrexate. All participants.
Overall Participants	8
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	36.5
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	8 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	6 75%
Male	2 25%
Region of Enrollment (participants) [Number]
United States	8 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All participants

Arm/Group Title	First Study Stage: Study Treatment
Arm/Group Description	Visilizumab, Tacrolimus and Methotrexate. All participants.
Measure Participants	8
Grade II-IV Acute GVHD	8 100%
Grade I-II Acute GVHD	6 75%
Grade III-IV Acute GVHD	2 25%

2. Secondary Outcome

Title	Incidence of Epstein-Barr Virus (EBV) Reactivation
Description	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.
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

All participants

Arm/Group Title	First Study Stage: Study Treatment
Arm/Group Description	Visilizumab, Tacrolimus and Methotrexate. All participants.
Measure Participants	8
Number [participants]	6 75%

3. Secondary Outcome

Title	Incidence of Rituximab Response to Reactivated EBV Without PTLD
Description	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).
Time Frame	100 days

Outcome Measure Data

Analysis Population Description

Reactivated EBV participants

Arm/Group Title	First Study Stage: Study Treatment
Arm/Group Description	Visilizumab, Tacrolimus and Methotrexate. All participants.
Measure Participants	6
Number [participants]	6 75%

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Participants who had died by Year 2 and additional participants who had died by Year 5.

Arm/Group Title	2 Year Analysis Group	5 Year Analysis Group
Arm/Group Description	First Study Stage: Study Treatment. Visilizumab, Tacrolimus and Methotrexate.	First Study Stage: Study Treatment. Visilizumab, Tacrolimus and Methotrexate.
Measure Participants	6	2
Median (Full Range) [days]	197	1803

5. Secondary Outcome

Title	Pharmacodynamics of Visilizumab - Test 1
Description	Mean Cmax (±SD)
Time Frame	At 1 - 2 hours

Outcome Measure Data

Analysis Population Description

All participants

Arm/Group Title	First Study Stage: Study Treatment
Arm/Group Description	Visilizumab, Tacrolimus and Methotrexate. All participants.
Measure Participants	8
Mean (Standard Deviation) [ng/mL]	1564 (428)

6. Secondary Outcome

Title	Pharmacodynamics of Visilizumab - Test 2
Description	Mean terminal half-life (±SD)
Time Frame	Up to 205 hours

Outcome Measure Data

Analysis Population Description

All participants

Arm/Group Title	First Study Stage: Study Treatment
Arm/Group Description	Visilizumab, Tacrolimus and Methotrexate. All participants.
Measure Participants	8
Mean (Standard Deviation) [hours]	157 (48)

Adverse Events

Time Frame	5 years
Adverse Event Reporting Description	The time of administration of visilizumab on Day 1 through Day 360. Per protocol, expected transplant/GVHD-related (other than serious) adverse event details were not tabulated in the same manner as serious adverse events.
Arm/Group Title	First Stage: Study Treatment
Arm/Group Description	Visilizumab, Tacrolimus and Methotrexate. All participants.
All Cause Mortality
	First Stage: Study Treatment
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	First Stage: Study Treatment
	Affected / at Risk (%)	# Events
Total	8/8 (100%)
Gastrointestinal disorders
Hemorrhage, GI - Colon	2/8 (25%)
Diarrhea	1/8 (12.5%)
Infections and infestations
Febrile neutropenia	2/8 (25%)
Infection - Blood	1/8 (12.5%)
Infection - Bronchus	1/8 (12.5%)
Respiratory, thoracic and mediastinal disorders
Adult Respiratory Distress Syndrome (ARDS)	1/8 (12.5%)
Dyspnea (shortness of breath)	1/8 (12.5%)
Pneumonitis/pulmonary infiltrates	1/8 (12.5%)
Pulmonary/Upper Respiratory - Other - pseudomonas pneumonia	1/8 (12.5%)
Skin and subcutaneous tissue disorders
Rash/desquamation	1/8 (12.5%)
Other (Not Including Serious) Adverse Events
	First Stage: Study Treatment
	Affected / at Risk (%)	# Events
Total	0/8 (0%)

Limitations/Caveats

Study closed early during the first stage, did not proceed to the second stage comparison as planned. Investigators exercised right to close the study prematurely for lack of efficacy, although no protocol-defined end points had been met.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.