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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.

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

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.

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

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.

Antithymocyte globulin (ATG)

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.

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

Lia Perez, MD

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".

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".

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

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

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

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.

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).

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

National Institutes of Health (NIH)

National Cancer Institute (NCI)

H. Lee Moffitt Cancer Center and Research Institute

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.

Visilizumab, Tacrolimus and Methotrexate. All participants.

First Stage: Study Treatment

Age, Continuous

Age, Categorical

Sex: Female, Male

United States

Region of Enrollment

First Stage: Study Treatment. All participants.

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.

Lia Perez, M.D.

Grade II-IV Acute GVHD

Grade I-II Acute GVHD

Grade III-IV Acute GVHD

First Study Stage: Study Treatment

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

Incidence of Epstein-Barr Virus (EBV) Reactivation

Incidence of Rituximab Response to Reactivated EBV Without PTLD

First Study Stage: Study Treatment. Visilizumab, Tacrolimus and Methotrexate.

2 Year Analysis Group

5 Year Analysis Group

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

Overall Survival (OS)

Pharmacodynamics of Visilizumab - Test 1

Pharmacodynamics of Visilizumab - Test 2

Overall Study

Hodgkin Disease

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Hematologic Diseases

Hodgkin Lymphoma

Anti-Arrhythmia Agents

Vasodilator Agents

Analgesics

Pentostatin

Adenosine

Given intravenously on days +8, +15, +22 and +30 post transplant:

Group 2 - Pentostatin 0.5 mg/m\^2

Group 3 - Pentostatin 1 mg/m\^2

Group 4 - Pentostatin 1.5 mg/m\^2

Group 5 - Pentostatin 2 mg/m\^2

Given intravenously from day -2, and will be switched to oral dosing when tolerated.

Given intravenously on days +1, +3, and +6 at the dose of 5 mg/m2.

Marcos de Lima, MD

Primary Objective:

1. To determine efficacy of escalating doses of pentostatin in combination with tacrolimus and methotrexate for the prevention of acute graft-versus-host disease (GVHD) in the context of unrelated donor and one antigen mismatched related donor transplantation.

Secondary Objectives:

1. To determine safety of escalating doses of pentostatin in combination with tacrolimus and methotrexate.
2. To reduce the incidence of acute GVHD following transplants with unrelated donor to 40%.
3. To document blood levels of tacrolimus when combined with pentostatin.

During the study, patients will have blood, urine, bone marrow, and X-ray exams done. These exams are done to monitor the results of the transplantation. Blood tests will be done daily while patients are hospitalized.

Patients in this study will receive chemotherapy and/or radiation to treat their malignancy and prevent graft rejection. This is given before the infusion of donor cells.

Patients with myeloid leukemias may receive busulfan by vein (IV) for 4 days and cyclophosphamide by vein for 2 days.

Patients with lymphoid malignancies may receive thiotepa by vein in one dose, cyclophosphamide by vein for 2 days, and irradiation for 4 days.

Other chemotherapy treatments may be used before donor cell infusion.

IV injections will be given through a previously inserted catheter that extends into the vena cava (a large chest vein).

Patients will be randomly picked (as in the toss of a coin) to receive one of five different treatments. This is done to learn the benefit of pentostatin treatment and the appropriate dose. Four of the treatments will use different dose schedules of pentostatin. The fifth treatment group will receive no pentostatin at all. All patients receive tacrolimus and methotrexate.

Pentostatin will be given by vein in 4 doses during the first month after transplant. Tacrolimus (FK506) will be given by vein or mouth for 6 months. Methotrexate will be given by vein for 3 doses in the first week after transplant.

Patients will receive blood and platelet transfusions after the transplant. The number of transfusions will depend on how quickly the blood cell counts return to a normal range.

Patients will remain in the hospital for about 4-6 weeks and in the Houston area for 100 days after the transplant.

This is an investigational study. All of the study drugs are commercially available. Pentostatin will not be used for GVHD prevention outside of this study. A total of 150 patients will take part in this study.

Phase I/II Study of Pentostatin Combined With Tacrolimus and Mini-Methotrexate for GVHD Prevention After MUD BMT

Phase I/II Study of Pentostatin Combined With Tacrolimus and Mini-Methotrexate for GVHD Prevention After Matched-Unrelated Donor Blood and Marrow Transplantation

The primary efficacy endpoint of escalating doses Pentostatin with Tacrolimus + Methotrexate is success, defined to be that the patient is alive, engrafted, and without acute graft-versus-host disease (GVHD) at 100 days.

Astex Pharmaceuticals, Inc.

M.D. Anderson Cancer Center

No Pentostatin

Pentostatin 0.5

Pentostatin 1

Pentostatin 1.5

Pentostatin 2

Total

Marcos de Lima, MD / Professor

150 patients were enrolled, 2 patients not treated, 38 patients were Group 1 (no Pentostatin), the remaining Groups 2,3,4 and 5, 110 patients were analysed that received the Pentostatin.

All analysis was intention to treat (ITT).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Visilizumab for the Prevention of Graft-versus-Host Disease After Allogeneic Hematopoietic Cell Transplantation	NCT00720629	Graft Versus Ho...	Visilizumab Tacrolimus Methotrexate Antithymocyte g... Tacrolimus Methotrexate	18 Years - 60 Years	H. Lee Moffitt Cancer Center and Research Institute
Visilizumab for the Prevention of Graft-versus-Host Disease After Allogeneic Hematopoietic Cell Transplantation	NCT00720629	Graft Versus Ho...	Visilizumab Tacrolimus Methotrexate Antithymocyte g... Tacrolimus Methotrexate	18 Years - 60 Years	H. Lee Moffitt Cancer Center and Research Institute
Phase I/II Study of Pentostatin Combined With Tacrolimus and Mini-Methotrexate for GVHD Prevention After MUD BMT	NCT00506922	Leukemia Lymphoma	Pentostatin Tacrolimus Methotrexate	-	M.D. Anderson Cancer Center

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