Reduced Intensity Total Body Irradiation + Thymoglobulin Followed by Allogeneic PBSCT

• Sponsor: Virginia Commonwealth University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00709592
• Collaborator: Genzyme, a Sanofi Company (Industry)
• Enrollment: 42
• Location: 1
• Arms: 2
• Actual Duration (Months): 107.2
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

One of two different doses of thymoglobulin will allow bone marrow engraftment with minimal Graft-versus-Host Disease and allow adequate immune response to allow the transplanted stem cells to replace the tumor cells.

Condition or Disease	Intervention/Treatment	Phase
Non-Hodgkin's Lymphoma; Leukemia; Multiple Myeloma; Acute Myeloid Leukemia; Hodgkin Lymphoma; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Myelodysplastic Syndrome	Biological: Thymoglobulin; Radiation: Total-Body Irradiation; Procedure: Allogeneic PBSCT or BMT; Drug: Tacrolimus; Drug: Mycophenolate Mofetil	Phase 2

Detailed Description

This randomized phase II trial studies how well giving low dose total-body irradiation (TBI) with anti-thymocyte globulin followed by donor peripheral blood stem cell transplant (PBSCT) works in treating patients with hematologic malignancies. Giving reduced intensity total-body irradiation and anti-thymocyte globulin before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving total-body irradiation together with antithymocyte globulin before transplant may stop this from happening.

Study Design

• Study Type: Interventional
• Actual Enrollment: 42 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Reduced Intensity Myeloablative Total Body Irradiation and Thymoglobulin Followed by Allogeneic Peripheral Blood Stem Cell Transplantation
• Actual Study Start Date: Jul 21, 2008
• Actual Primary Completion Date: Feb 15, 2014
• Actual Study Completion Date: Jun 28, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ATG 1.7 mg/kg, TBI, transplant (Rabbit-ATG;Thymoglobulin,Genzyme) ATG 5.1 mg/kg in three divided doses (1.7 mg/kg/d) given over three days (day -9 to -7) followed by 450 cGy TBI and tacrolimus plus MMF GVHD prophylaxis. Patients receive lower dose anti-thymocyte globulin IV on days -9 to -7. Patients undergo total-body radiation (TBI) twice daily (BID) on day -1 and once daily (QD) on day 0. Patients then undergo peripheral blood stem cells or bone marrow transplant on day 0. GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: patients receive tacrolimus orally (PO) on days -2 to 90-120 with taper for 2 months, and mycophenolate mofetil (MMF) PO BID on days 0-30.	Biological: Thymoglobulin; Patients eligible for participation in this study will be randomized between receiving rabbit ATG for 3 days. Thymoglobulin will be administered according to VCU BMT standard of care starting day -9 and continued daily through day -7.; Other Names: anti-thymocyte globulin (rabbit) ATG Genzyme anti-thymocyte globulin Rabbit Rabbit-ATG ; Radiation: Total-Body Irradiation; Undergo TBI; Other Names: Whole-Body Irradiation Total Body Irradiation [TBI] ; Procedure: Allogeneic PBSCT or BMT; Undergo allogeneic PBSCT or BMT; Other Names: PBPC transplantation Peripheral Blood Progenitor Cell Transplantation Peripheral Blood Stem Cell Transplantation [Allogenic PBSCT] Allogeneic Bone Marrow Transplantation [BMT] Allogeneic BMT Allogeneic Hematopoietic Stem Cell Transplantation HSCT ; Drug: Tacrolimus; Given PO; Other Names: Fujimycin Hecoria Prograf Protopic ; Drug: Mycophenolate Mofetil; Given PO; Other Names: CellCept MMF
Experimental: ATG 2.5 mg/kg/d, TBI, transplant (Rabbit-ATG;Thymoglobulin,Genzyme) ATG 7.5 mg/kg in three divided doses (2.5 mg/kg/d) given over three days (day -9 to -7) followed by 450 cGy TBI and tacrolimus plus MMF GVHD prophylaxis. Patients receive higher dose anti-thymocyte globulin intravenously (IV) on days -9 to -7. Patients undergo total-body radiation (TBI) twice daily (BID) on day -1 and once daily (QD) on day 0. Patients then undergo peripheral blood stem cells or bone marrow transplant on day 0. GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: patients receive tacrolimus orally (PO) on days -2 to 90-120 with taper for 2 months, and mycophenolate mofetil (MMF) PO BID on days 0-30.	Biological: Thymoglobulin; Patients eligible for participation in this study will be randomized between receiving rabbit ATG for 3 days. Thymoglobulin will be administered according to VCU BMT standard of care starting day -9 and continued daily through day -7.; Other Names: anti-thymocyte globulin (rabbit) ATG Genzyme anti-thymocyte globulin Rabbit Rabbit-ATG ; Radiation: Total-Body Irradiation; Undergo TBI; Other Names: Whole-Body Irradiation Total Body Irradiation [TBI] ; Procedure: Allogeneic PBSCT or BMT; Undergo allogeneic PBSCT or BMT; Other Names: PBPC transplantation Peripheral Blood Progenitor Cell Transplantation Peripheral Blood Stem Cell Transplantation [Allogenic PBSCT] Allogeneic Bone Marrow Transplantation [BMT] Allogeneic BMT Allogeneic Hematopoietic Stem Cell Transplantation HSCT ; Drug: Tacrolimus; Given PO; Other Names: Fujimycin Hecoria Prograf Protopic ; Drug: Mycophenolate Mofetil; Given PO; Other Names: CellCept MMF

Outcome Measures

Primary Outcome Measures

1. The Comparison of Functional Immune Reconstitution at 6-9 Months Following Transplant as Measured by Antibody Response to Vaccination With Inactivated Hepatitis A or B Vaccine. [Up to 9 months following transplant]

   A positive test result will indicate immune reconstitution, while a negative test results will indicate lack of immune reconstitution. Participants not done (ND) will be counted with the negative (Neg).

Secondary Outcome Measures

1. Engraftment of Donor Hematopoietic Stem Cells, as Measured by Time in Days to Neutrophil and Platelet Count Recovery Following Allogeneic PBSCT. [Up to 52 weeks post transplant.]

2. Survival [2-year survival rate (%)]

3. Treatment Related Mortality [Day 100]

4. Event-free Survival [2 years]

5. Relapse [2 year relapse rate (%)]

   Patients with different disease relapses was determined according to current clinical standards based on the disease. For example, AML or MDS relapse is determined by a bone marrow biopsy. Multiple myeloma relapse requires a number of labs and/or biopsy to diagnose such as SPEP, UPEP, immunofixation, serum and urine light chains. In lymphoma disease is followed using CT and/or PET scans.

6. Donor Lymphocyte Infusion [2 year rate of DLI]

7. Acute Graft-Versus-Host Disease (GVHD) [2 year rate (%)]

8. Chronic Graft-Versus-Host Disease (GVHD) [2 year GVHD rate]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with hematological malignancies for which allogeneic stem cell transplantation indicated including non-Hodgkin lymphoma (NHL), multiple myeloma (MM), acute myeloid leukemia (AML), Hodgkin lymphoma (HD), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), and myelodysplastic syndrome (MDS)

• Patients with HLA compatible related or unrelated stem cell donor, willing and able to serve as an allogenic HSC donor. Unrelated donors have to be matched at HLA-A, B, C and DRB1 loci. A single locus mismatch will be tolerated in the event a more closely matched donor is not available.

• Patients age >/=40 to </=70 with an ECOG performance status < 2

• Patients between 18 and 40 years of age will be eligible only if they have co-morbidities precluding conventional allogeneic transplantation with full intensity myeloablative conditioning

• Adequate cardiac, pulmonary, renal and hepatic function for transplant

• Negative serology for HIV

• Negative serum pregnancy test

• Patients who have received therapeutic radiation to a localized field will be eligible, provided critical structure tolerance doses have not been exceeded

• Patients who have had prior myeloablative autologous transplant will be eligible

Exclusion Criteria:

• Evidence of uncontrolled viral, fungal, bacterial infection

• Evidence of active meningeal or CNS disease

• Prior therapy with rabbit ATG, prior treatment with equine ATG is allowed if more than 3 months ago

• Breast feeding mothers are excluded

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia	United States	23298-0037

Sponsors and Collaborators

• Virginia Commonwealth University
• Genzyme, a Sanofi Company

Investigators

• Principal Investigator: Amir Toor, MD, Massey Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• VCU Massey Cancer Center

Publications

None provided.

• Responsible Party: Virginia Commonwealth University
• ClinicalTrials.gov Identifier: NCT00709592
• Other Study ID Numbers: MCC-11561; NCI-2011-01698
• First Posted: Jul 3, 2008
• Last Update Posted: Nov 9, 2018
• Last Verified: Nov 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Keywords provided by Virginia Commonwealth University: total body irradiation; Allogeneic Peripheral Blood Stem Cell Transplantation; thymoglobulin
• Additional relevant MeSH terms: Lymphoma; Leukemia; Multiple Myeloma; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Myelodysplastic Syndromes; Mycophenolic Acid; Tacrolimus; Thymoglobulin; Antilymphocyte Serum

Study Results

Participant Flow

Recruitment Details	Consecutive patients enrolled have recurrent or high-risk hematologic malignancy, adequate end-organ function and performance status. Patient required to have 7/8 or 8/8 mismatched related donor (MRD) or unrelated donor (URD), with high-resolution typing performed for HLA-A, -B, -C, and -DRB1.
Pre-assignment Detail	Randomized to rabbit ATG (Thymoglobulin; Genzyme, Cambridge, MA), 2.5 or 1.7 mg/kg adjusted ideal body weight/day, followed by TBI to a total dose of 4.5 Gy. Methylprednisolone 2 mg/kg given pre-medication for ATG. GVHD prophylaxis was tacrolimus starting at approximately 12 weeks post transplantation.

Arm/Group Title	A:Thymoglobulin: 1.7 mg/kg/Day	B:Thymoglobulin: 2.5 mg/kg/Day
Arm/Group Description	1.7 mg/kg/d thymoglobulin IV d-9 to -7	2.5 mg/kg/d thymoglobulin IV d-9 to d-7
Period Title: Overall Study
STARTED	19	23
COMPLETED	19	22
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	A:Thymoglobulin: 1.7 mg/kg/Day	B:Thymoglobulin: 2.5 mg/kg/Day	Total
Arm/Group Description	1.7 mg/kg/d thymoglobulin IV d-9 to -7	2.5 mg/kg/d thymoglobulin IV d-9 to d-7	Total of all reporting groups
Overall Participants	19	23	42
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	57	57	57
Sex: Female, Male (Count of Participants)
Female	7 36.8%	8 34.8%	15 35.7%
Male	12 63.2%	15 65.2%	27 64.3%
Region of Enrollment (participants) [Number]
United States	19 100%	23 100%	42 100%

Outcome Measures

1. Primary Outcome

Title	The Comparison of Functional Immune Reconstitution at 6-9 Months Following Transplant as Measured by Antibody Response to Vaccination With Inactivated Hepatitis A or B Vaccine.
Description	A positive test result will indicate immune reconstitution, while a negative test results will indicate lack of immune reconstitution. Participants not done (ND) will be counted with the negative (Neg).
Time Frame	Up to 9 months following transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	A:Thymoglobulin: 1.7 mg/kg/Day	B:Thymoglobulin: 2.5 mg/kg/Day
Arm/Group Description	1.7 mg/kg/d thymoglobulin IV d-9 to -7	2.5 mg/kg/d thymoglobulin IV d-9 to d-7
Measure Participants	19	22
Positive	8 42.1%	3 13%
Negative/Not Done	11 57.9%	19 82.6%

2. Secondary Outcome

Title	Engraftment of Donor Hematopoietic Stem Cells, as Measured by Time in Days to Neutrophil and Platelet Count Recovery Following Allogeneic PBSCT.
Time Frame	Up to 52 weeks post transplant.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	A:Thymoglobulin: 1.7 mg/kg/Day	B:Thymoglobulin: 2.5 mg/kg/Day
Arm/Group Description	1.7 mg/kg/d thymoglobulin IV d-9 to -7	2.5 mg/kg/d thymoglobulin IV d-9 to d-7
Measure Participants	19	22
Median (95% Confidence Interval) [Days]	12	12

3. Secondary Outcome

Title	Survival
Time Frame	2-year survival rate (%)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	A:Thymoglobulin: 1.7 mg/kg/Day	B:Thymoglobulin: 2.5 mg/kg/Day
Arm/Group Description	1.7 mg/kg/d thymoglobulin IV d-9 to -7	2.5 mg/kg/d thymoglobulin IV d-9 to d-7
Measure Participants	19	22
Number [percentage of patient surviving]	71.3	62.4

4. Secondary Outcome

Title	Treatment Related Mortality
Time Frame	Day 100

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	A:Thymoglobulin: 1.7 mg/kg/Day	B:Thymoglobulin: 2.5 mg/kg/Day
Arm/Group Description	1.7 mg/kg/d thymoglobulin IV d-9 to -7	2.5 mg/kg/d thymoglobulin IV d-9 to d-7
Measure Participants	19	22
Number [percentage of patients]	0	0

5. Secondary Outcome

Title	Event-free Survival
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	A:Thymoglobulin: 1.7 mg/kg/Day	B:Thymoglobulin: 2.5 mg/kg/Day
Arm/Group Description	1.7 mg/kg/d thymoglobulin IV d-9 to -7	2.5 mg/kg/d thymoglobulin IV d-9 to d-7
Measure Participants	19	22
Number [percentage of participants]	62.2 327.4%	44.5 193.5%

6. Secondary Outcome

Title	Relapse
Description	Patients with different disease relapses was determined according to current clinical standards based on the disease. For example, AML or MDS relapse is determined by a bone marrow biopsy. Multiple myeloma relapse requires a number of labs and/or biopsy to diagnose such as SPEP, UPEP, immunofixation, serum and urine light chains. In lymphoma disease is followed using CT and/or PET scans.
Time Frame	2 year relapse rate (%)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	A:Thymoglobulin: 1.7 mg/kg/Day	B:Thymoglobulin: 2.5 mg/kg/Day
Arm/Group Description	1.7 mg/kg/d thymoglobulin IV d-9 to -7	2.5 mg/kg/d thymoglobulin IV d-9 to d-7
Measure Participants	19	22
Number [Percent patients relapsing]	28	50

7. Secondary Outcome

Title	Donor Lymphocyte Infusion
Time Frame	2 year rate of DLI

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	A:Thymoglobulin: 1.7 mg/kg/Day	B:Thymoglobulin: 2.5 mg/kg/Day
Arm/Group Description	1.7 mg/kg/d thymoglobulin IV d-9 to -7	2.5 mg/kg/d thymoglobulin IV d-9 to d-7
Measure Participants	19	22
Number [percentage of participants]	8.9 46.8%	45.5 197.8%

8. Secondary Outcome

Title	Acute Graft-Versus-Host Disease (GVHD)
Time Frame	2 year rate (%)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	A:Thymoglobulin: 1.7 mg/kg/Day	B:Thymoglobulin: 2.5 mg/kg/Day
Arm/Group Description	1.7 mg/kg/d thymoglobulin IV d-9 to -7	2.5 mg/kg/d thymoglobulin IV d-9 to d-7
Measure Participants	19	22
Number [percentage of participant]	27.2	4.5

9. Secondary Outcome

Title	Chronic Graft-Versus-Host Disease (GVHD)
Time Frame	2 year GVHD rate

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	A:Thymoglobulin: 1.7 mg/kg/Day	B:Thymoglobulin: 2.5 mg/kg/Day
Arm/Group Description	1.7 mg/kg/d thymoglobulin IV d-9 to -7	2.5 mg/kg/d thymoglobulin IV d-9 to d-7
Measure Participants	19	22
Number [percentage of participants]	23.8 125.3%	31.8 138.3%

Adverse Events

Time Frame	All events collected from first patient accrual up to day 180 or relapse for each subject on each arm.
Adverse Event Reporting Description	Still collecting SAEs, subjects on trial until death.
Arm/Group Title	A:Thymoglobulin: 1.7 mg/kg/Day		B:Thymoglobulin: 2.5 mg/kg/Day
Arm/Group Description	1.7 mg/kg/d thymoglobulin IV d-9 to -7		2.5 mg/kg/d thymoglobulin IV d-9 to d-7
All Cause Mortality
	A:Thymoglobulin: 1.7 mg/kg/Day		B:Thymoglobulin: 2.5 mg/kg/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	A:Thymoglobulin: 1.7 mg/kg/Day		B:Thymoglobulin: 2.5 mg/kg/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/19 (36.8%)		12/22 (54.5%)
Cardiac disorders
Cardiac dysrhythmia	1/19 (5.3%)	1	1/22 (4.5%)	1
Gastrointestinal disorders
Hepatic	2/19 (10.5%)	2	0/22 (0%)	0
Diarrhea	3/19 (15.8%)	3	1/22 (4.5%)	1
Intra-abdominal	1/19 (5.3%)	1	0/22 (0%)	0
Nausea	0/19 (0%)	0	2/22 (9.1%)	2
Infections and infestations
Fever with out bacteremia	2/19 (10.5%)	2	2/22 (9.1%)	2
Fever with Bacteremia +/- abscess	3/19 (15.8%)	3	6/22 (27.3%)	6
Nervous system disorders
Syncope	1/19 (5.3%)	1	1/22 (4.5%)	1
CNS toxicity	1/19 (5.3%)	1	1/22 (4.5%)	1
Brain abscess	1/19 (5.3%)	1	0/22 (0%)	0
Renal and urinary disorders
Hemorrhagic cystitis	1/19 (5.3%)	1	1/22 (4.5%)	1
Renal	2/19 (10.5%)	2	0/22 (0%)	0
Hyponatremia	1/19 (5.3%)	1	1/22 (4.5%)	1
Other (Not Including Serious) Adverse Events
	A:Thymoglobulin: 1.7 mg/kg/Day		B:Thymoglobulin: 2.5 mg/kg/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/19 (100%)		22/22 (100%)
Blood and lymphatic system disorders
Grade 3 neutropenia	19/19 (100%)	19	22/22 (100%)	22
Lymphopenia post conditioning	19/19 (100%)	19	22/22 (100%)	22
Thrombocytopenia	19/19 (100%)	19	22/22 (100%)	22
Post transplant neutropenia	1/19 (5.3%)	1	1/22 (4.5%)	1
Eye disorders
Ocular	0/19 (0%)	0	2/22 (9.1%)	2
Gastrointestinal disorders
Nausea	2/19 (10.5%)	2	0/22 (0%)	0
Diarrhea	1/19 (5.3%)	1	1/22 (4.5%)	1
Infections and infestations
Bacteremia/Fever	2/19 (10.5%)	2	1/22 (4.5%)	1
Renal and urinary disorders
Urinary tract infection	1/19 (5.3%)	1	0/22 (0%)	0
Skin and subcutaneous tissue disorders
Rash	0/19 (0%)	0	1/22 (4.5%)	1

Limitations/Caveats

[Not Specified]

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.