Sirolimus, Tacrolimus, Thymoglobulin and Rituximab as Graft-versus-Host-Disease Prophylaxis in Patients Undergoing Haploidentical and HLA Partially Matched Donor Hematopoietic Cell Transplantation
Official Title
A Pilot Phase II Study of Sirolimus, Tacrolimus, Thymoglobulin and Rituximab as Graft-versus-Host-Disease Prophylaxis in Patients Undergoing Haploidentical and HLA Partially Matched Donor Hematopoietic Cell Transplantation
Acronym
Not provided
Organization
Barbara Ann Karmanos Cancer InstituteOTHER
Status Module
Record Verification Date
Mar 2019
Overall Recruitment Status or Expanded Access Status
Terminated
Last Known Status
Not provided
Delayed Posting
Not provided
Why Stopped
Lack of funding.
Expanded Access Info
No
Start Date
Aug 2010
Primary Completion Date
May 2013Actual
Completion Date
Jun 2013Actual
First Submitted Date
May 3, 2010
First Submission Date that Met QC Criteria
May 3, 2010
First Posted Date
May 4, 2010Estimated
Results Waived
Not provided
Results First Submitted Date
Oct 22, 2013
Results First Submitted that Met QC Criteria
Oct 22, 2013
Results First Posted Date
Dec 13, 2013Estimated
Certification/Extension (aka Delayed Results) First Submitted Date
Not provided
Certification/Extension First Submitted that Passed QC Review
Not provided
Certification/Extension First Posted Date
Not provided
Last Update Submitted Date
Mar 13, 2019
Last Update Posted Date
Mar 26, 2019Actual
Sponsor/Collaborators Module
Responsible Party, by Official Title
Zaid Al-Kadhimi, Principal Investigator, Barbara Ann Karmanos Cancer InstitutePrincipal Investigator
Lead Sponsor
Barbara Ann Karmanos Cancer InstituteOTHER
Collaborators
Name
Class
National Cancer Institute (NCI)
NIH
Oversight Module
Has Data Monitoring Committee (DMC)
Yes
Is FDA Regulated Drug
Not provided
Is FDA Regulated Device
Not provided
Is Unapproved Device
Not provided
Pediatric Postmarket Surveillance of a Device Product
Not provided
Product Exported from US
Not provided
FDAAA801 Violation
Not provided
Description Module
Brief Summary
This Phase II clinical trial was designed for patients with hematologic malignancies in need of donor peripheral blood stem cell transplant, and have no HLA matched donor. Therefore It will test the efficacy of combining sirolimus, tacrolimus, antithymocyte globulin, and rituximab in preventing graft versus host disease in transplants from HLA Haploidentical and partially mismatched donors.
Detailed Description
OBJECTIVES:
Primary
Determine the incidence and severity of acute graft-vs-host disease (GVHD) in patients with hematologic malignancies undergoing donor peripheral blood stem cell transplantation who are receiving sirolimus, tacrolimus, anti-thymocyte globulin, and rituximab as GVHD prophylaxis.
Assess time to engraftment absolute neutrophil count (> 0.5 x 10^9/L for 3 consecutive days) and platelet count (> 20 x 10^9/L for 3 consecutive days) in these patients.
Determine the safety, as defined by serious adverse events and adverse events related to this immunosuppressive regimen, in the first 6 months after treatment.
Secondary
Assess the incidence of chronic GVHD measured within 2 years after transplantation.
Assess overall and disease-free survival at 2 years after transplantation.
Examine the incidence of opportunistic infections including fungal infections, pneumocystis carinii pneumonia, and viral infections (cytomegalovirus, varicella zoster virus, herpes simplex virus, BK virus, Epstein-Barr virus, and post-transplant lymphoproliferative disorder).
Assess the incidence of thrombotic microangiopathy within 100 days of transplantation.
Perform immunocorrelative studies, including T-cell, B-cell, NK-cell, regulatory cell, and allo-reactive T-cell measurement studies via flow cytometry, at 30, 60, 90, and 180 days after transplantation.
OUTLINE: Patients receive rituximab IV on days -7 and 3, tacrolimus IV continuously (may switch to orally when the patient is able to eat) and oral sirolimus beginning on day -3, and anti-thymocyte globulin IV over 6 hours on days -3 to -1. Tacrolimus and sirolimus are tapered at the discretion of the treating physician.
All patients also receive a standard transplant-preparative regimen and undergo transplantation on day 0.
Blood samples are collected before the preparative regimen and at 30, 60, 90, and 180 days after transplantation for correlative immunologic studies.
After completion of study treatment, patients are followed up for 2 years.
Conditions Module
Conditions
Chronic Myeloproliferative Disorders
Graft Versus Host Disease
Leukemia
Lymphoma
Lymphoproliferative Disorder
Multiple Myeloma and Plasma Cell Neoplasm
Myelodysplastic Syndromes
Myelodysplastic/Myeloproliferative Neoplasms
Keywords
graft versus host disease
accelerated phase chronic myelogenous leukemia
adult acute lymphoblastic leukemia in remission
adult acute myeloid leukemia in remission
adult acute myeloid leukemia with 11q23 (MLL) abnormalities
adult acute myeloid leukemia with inv(16)(p13;q22)
adult acute myeloid leukemia with t(15;17)(q22;q12)
adult acute myeloid leukemia with t(16;16)(p13;q22)
adult acute myeloid leukemia with t(8;21)(q22;q22)
anti-thymocyte globulin: Infuse the first dose over a minimum of 6 hours, and subsequent doses over a minimum of 4 hours via a 0.22 micron in-line filter
Rituximab: The total dose chosen for this protocol is 28 mg/kg divided in two doses (14 mg/kg on days -7 and +3). Initial infusion: Start rate of 50 mg/hour;
For adults, Sirolimus will be administered at 12 mg orally loading dose on day -3, followed by 4 mg orally single morning daily dose (target serum level 3-12 ng/ml by HPLC).
Tacrolimus will be administered intravenously at a dose of 0.03 mg/kg (ideal body weight) q 24h by continuous infusion starting on Day -3. Intravenous Tacrolimus will be discontinued once the patient starts eating and the drug will then be given orally at a dose of approximately 4 times the intravenous dose.
Incidence and Severity of Acute Graft-vs-host Disease (GVHD)
During the first six months post transplant
Time to Engraftment
During the first six months post transplant
Safety Assessment
During the first six months post transplant
Secondary Outcomes
Measure
Description
Time Frame
Incidence of Chronic GVHD
Within two years after transplant
Incidence of Infections Including Cytomegalovirus, Epstein-Barr Virus Reactivation, and Post-transplant Lymphoproliferative Disorder
At one year
Other Outcomes
Not provided
Eligibility Module
Eligibility Criteria
DISEASE CHARACTERISTICS:
Diagnosis of a hematological malignancy, including:
Non-Hodgkin lymphoma
Hodgkin lymphoma
Acute myeloid leukemia or acute lymphoblastic leukemia
Myelodysplastic syndrome (treated or untreated)
Chronic myelogenous leukemia
Multiple myeloma
Chronic lymphocytic leukemia
Myelofibrosis and other myeloproliferative disorders
No suitable related HLA-matched or unrelated HLA-matched (8/8 or 7/8 matched) donor
Available suitable haploidentical or partial-matched unrelated donor (high-resolution molecular HLA typing is mandatory for HLA Class I and II)
No more than 4/8 HLA allele or antigen mismatch for a haploidentical-related first-degree family member donor
Only 6/8 or 5/8 allele or antigen match for an unrelated donor
Scheduled to undergo peripheral blood stem cell transplantation
Not receiving bone marrow or ex vivo engineered or processed graft (e.g., CD34+ enrichment, T-cell depletion)
No documented uncontrolled CNS disease
PATIENT CHARACTERISTICS:
Karnofsky performance status (PS) 70-100%
ECOG PS 0-2
Serum bilirubin < 3 times upper limit of normal (ULN)
ALT and AST < 3 times ULN
Creatinine clearance > 60 mL/min
Ejection fraction > 50%
Forced vital capacity, FEV_1, or DLCO > 50% predicted
Negative pregnancy test
Able to cooperate with oral medication intake
Patients with coronary heart disease (recent myocardial infarctions, angina, cardiac stent, or bypass surgery in the past 6 months) are eligible provided they are cleared with a stress echo or nuclear myocardial perfusions stress test and a cardiology consult
No ascites
No HIV positivity
No active hepatitis B or C virus infection
No known contraindication to the administration of sirolimus, tacrolimus, anti-thymocyte globulin, or rituximab
PRIOR CONCURRENT THERAPY:
See Disease Characteristics
Not on home oxygen
Accepts Healthy Volunteers
No
Sex
All
Sex/Gender Based
Not provided
Sex/Gender Description
Not provided
Minimum Age
18 Years
Maximum Age
120 Years
Standard Ages
AdultOlder Adult
Study Population
Not provided
Sampling Method
Not provided
Contacts/Locations Module
Central Contacts
Not provided
Overall Officials
Name
Affiliation
Role
Zaid Al-Kadhimi, M.D.
Barbara Ann Karmanos Cancer Institute
Principal Investigator
Locations
Facility
Status
City
State
ZIP
Country
Contacts
Karmanos Cancer Institute
Detroit
Michigan
48201
United States
References Module
Citations
Not provided
See Also Links
Label
URL
Clinical trial summary from the National Cancer Institute's PDQ® database
anti-thymocyte globulin: Infuse the first dose over a minimum of 6 hours, and subsequent doses over a minimum of 4 hours via a 0.22 micron in-line filter
Rituximab: The total dose chosen for this protocol is 28 mg/kg divided in two doses (14 mg/kg on days -7 and +3). Initial infusion: Start rate of 50 mg/hour;
For adults, Sirolimus will be administered at 12 mg orally loading dose on day -3, followed by 4 mg orally single morning daily dose (target serum level 3-12 ng/ml by HPLC).
Tacrolimus will be administered intravenously at a dose of 0.03 mg/kg (ideal body weight) q 24h by continuous infusion starting on Day -3. Intravenous Tacrolimus will be discontinued once the patient starts eating and the drug will then be given orally at a dose of approximately 4 times the intravenous dose.
peripheral blood stem cell transplantation
sirolimus: For adults, will be administered at 12 mg orally loading dose on day -3, follow
The total dose chosen for this protocol is 28 mg/kg divided in two doses (14 mg/kg on days -7 and +3). Initial infusion: Start rate of 50 mg/hour; if there is no reaction, increase the rate by 50 mg/hour increments every 30 minutes, to a maximum rate of 400 mg/hour. Subsequent infusions: If patient did not tolerate initial infusion follow initial infusion guidelines. If patient tolerated initial infusion, start at 100 mg/hour; if there is no reaction, increase the rate by 100 mg/hour increments every 30 minutes, to a maximum rate of 400 mg/hour. Note: If a reaction occurs, slow or stop the infusion. If the reaction abates, restart infusion at 50% of the previous rate.
In patients who tolerated the Rituximab well in the past, a rapid infusion rate can be used over 90 minutes with 20% of the dose administered in the first 30 minutes and the remaining 80% is given over 60 minutes.
For adults, Sirolimus will be administered at 12 mg orally loading dose on day -3, followed by 4 mg orally single morning daily dose (target serum level 3-12 ng/ml by HPLC).
Tacrolimus will be administered intravenously at a dose of 0.03 mg/kg (ideal body weight) q 24h by continuous infusion starting on Day -3. Intravenous Tacrolimus will be discontinued once the patient starts eating and the drug will then be given orally at a dose of approximately 4 times the intravenous dose.
anti-thymocyte globulin: Infuse the first dose over a minimum of 6 hours, and subsequent doses over a minimum of 4 hours via a 0.22 micron in-line filter
Rituximab: The total dose chosen for this protocol is 28 mg/kg divided in two doses (14 mg/kg on days -7 and +3). Initial infusion: Start rate of 50 mg/hour;
For adults, Sirolimus will be administered at 12 mg orally loading dose on day -3, followed by 4 mg orally single morning daily dose (target serum level 3-12 ng/ml by HPLC).
Tacrolimus will be administered intravenously at a dose of 0.03 mg/kg (ideal body weight) q 24h by continuous infusion starting on Day -3. Intravenous Tacrolimus will be discontinued once the patient starts eating and the drug will then be given orally at a dose of approximately 4 times the intravenous dose.
peripheral blood stem cell transplantation
sirolimus: For adults, will be administered at 12 mg orally loading dose on day -3, follow
Denominators
Units
Counts
Participants
BG0004
Baseline Measures
Title
Description
Population Description
Parameter Type
Dispersion Type
Unit of Measure
Calculate Percentage
Denominator Units Selected
Denominators
Classes
Age, Categorical
Count of Participants
Participants
Title
Denominators
Categories
Title
Measurements
<=18 years
BG0000
Between 18 and 65 years
BG0004
>=65 years
BG000
Age, Continuous
Mean
Standard Deviation
years
Title
Denominators
Categories
Title
Measurements
BG00050± 2.82
Sex: Female, Male
Count of Participants
Participants
Title
Denominators
Categories
Title
Measurements
Female
BG0002
Male
BG0002
Region of Enrollment
Number
participants
Title
Denominators
Categories
United States
Title
Measurements
BG0004
Type
Title
Description
Population Description
Reporting Status
Anticipated Posting Date
Parameter Type
Dispersion Type
Unit of Measure
Calculate Percentage
Time Frame
Units Analyzed
Denominator Units Selected
Arm/Group Information
Denominators
Classes
Analyses
Primary
Incidence and Severity of Acute Graft-vs-host Disease (GVHD)
Study terminated due to lack of funding, no analysis was done for this protocol due to the fact that only four patients were accrued, no data was collected.
anti-thymocyte globulin: Infuse the first dose over a minimum of 6 hours, and subsequent doses over a minimum of 4 hours via a 0.22 micron in-line filter
Rituximab: The total dose chosen for this protocol is 28 mg/kg divided in two doses (14 mg/kg on days -7 and +3). Initial infusion: Start rate of 50 mg/hour;
For adults, Sirolimus will be administered at 12 mg orally loading dose on day -3, followed by 4 mg orally single morning daily dose (target serum level 3-12 ng/ml by HPLC).
Tacrolimus will be administered intravenously at a dose of 0.03 mg/kg (ideal body weight) q 24h by continuous infusion starting on Day -3. Intravenous Tacrolimus will be discontinued once the patient starts eating and the drug will then be given orally at a dose of approximately 4 times the intravenous dose.
peripheral blood stem cell transplantation
sirolimus: For adults, will be administered at 12 mg orally loading dose on day -3, follow
Units
Counts
Participants
OG0000
Primary
Time to Engraftment
Study terminated due to lack of funding, no analysis was done for this protocol due to the fact that only four patients were accrued, no data was collected.
Anti-thymocyte globulin infuse the 1st dose, minimum of 6 hrs subsequent doses minimum of 4 hrs via a 0.22 micron in-line filter
Rituximab, total dose is 28 mg/kg divided in 2 doses (14 mg/kg, days -7 & +3) Initial infusion, start rate 50 mg/hour
Sirolimus 12 mg orally loading dose on day -3, followed by 4 mg orally single morning daily dose (target serum level 3-12 ng/ml by HPLC).
Tacrolimus (IV) dose of 0.03 mg/kg (ideal body weight) every 24hr by continuous infusion starting on Day -3, discontinued once the pt. starts eating & the drug will then be given orally at a dose of approximately 4 times the IV dose.
.
Units
Counts
Participants
OG000
Primary
Safety Assessment
Study terminated due to lack of funding, no analysis was done for this protocol due to the fact that only four patients were accrued, no data was collected.
anti-thymocyte globulin: Infuse the first dose over a minimum of 6 hours, and subsequent doses over a minimum of 4 hours via a 0.22 micron in-line filter
Rituximab: The total dose chosen for this protocol is 28 mg/kg divided in two doses (14 mg/kg on days -7 and +3). Initial infusion: Start rate of 50 mg/hour;
For adults, Sirolimus will be administered at 12 mg orally loading dose on day -3, followed by 4 mg orally single morning daily dose (target serum level 3-12 ng/ml by HPLC).
Tacrolimus will be administered intravenously at a dose of 0.03 mg/kg (ideal body weight) q 24h by continuous infusion starting on Day -3. Intravenous Tacrolimus will be discontinued once the patient starts eating and the drug will then be given orally at a dose of approximately 4 times the intravenous dose.
peripheral blood stem cell transplantation
sirolimus: For adults, will be administered at 12 mg orally loading dose on day -3, follow
Units
Counts
Participants
Secondary
Incidence of Chronic GVHD
Study terminated due to lack of funding, no analysis was done for this protocol due to the fact that only four patients were accrued, no data was collected.
anti-thymocyte globulin: Infuse the first dose over a minimum of 6 hours, and subsequent doses over a minimum of 4 hours via a 0.22 micron in-line filter
Rituximab: The total dose chosen for this protocol is 28 mg/kg divided in two doses (14 mg/kg on days -7 and +3). Initial infusion: Start rate of 50 mg/hour;
For adults, Sirolimus will be administered at 12 mg orally loading dose on day -3, followed by 4 mg orally single morning daily dose (target serum level 3-12 ng/ml by HPLC).
Tacrolimus will be administered intravenously at a dose of 0.03 mg/kg (ideal body weight) q 24h by continuous infusion starting on Day -3. Intravenous Tacrolimus will be discontinued once the patient starts eating and the drug will then be given orally at a dose of approximately 4 times the intravenous dose.
anti-thymocyte globulin: Infuse the first dose over a minimum of 6 hours, and subsequent doses over a minimum of 4 hours via a 0.22 micron in-line filter.
rituximab: The total dose chosen
Units
Counts
Participants
Secondary
Incidence of Infections Including Cytomegalovirus, Epstein-Barr Virus Reactivation, and Post-transplant Lymphoproliferative Disorder
Study terminated due to lack of funding, no analysis was done for this protocol due to the fact that only four patients were accrued, no data was collected.
anti-thymocyte globulin: Infuse the first dose over a minimum of 6 hours, and subsequent doses over a minimum of 4 hours via a 0.22 micron in-line filter
Rituximab: The total dose chosen for this protocol is 28 mg/kg divided in two doses (14 mg/kg on days -7 and +3). Initial infusion: Start rate of 50 mg/hour;
For adults, Sirolimus will be administered at 12 mg orally loading dose on day -3, followed by 4 mg orally single morning daily dose (target serum level 3-12 ng/ml by HPLC).
Tacrolimus will be administered intravenously at a dose of 0.03 mg/kg (ideal body weight) q 24h by continuous infusion starting on Day -3. Intravenous Tacrolimus will be discontinued once the patient starts eating and the drug will then be given orally at a dose of approximately 4 times the intravenous dose.
anti-thymocyte globulin: Infuse the first dose over a minimum of 6 hours, and subsequent doses over a minimum of 4 hours via a 0.22 micron in-line filter.
rituximab: The total dose chosen
Units
Counts
Participants
Secondary
Incidence of Thrombotic Microangiopathy
Study terminated due to lack of funding, no analysis was done for this protocol due to the fact that only four patients were accrued, no data was collected.
Anti-thymocyte globulin infuse the 1st dose, minimum of 6 hrs subsequent doses minimum of 4 hrs via a 0.22 micron in-line filter
Rituximab, total dose is 28 mg/kg divided in 2 doses (14 mg/kg, days -7 & +3) Initial infusion, start rate 50 mg/hour
Sirolimus 12 mg orally loading dose on day -3, followed by 4 mg orally single morning daily dose (target serum level 3-12 ng/ml by HPLC).
Tacrolimus (IV) dose of 0.03 mg/kg (ideal body weight) every 24hr by continuous infusion starting on Day -3, discontinued once the pt. starts eating & the drug will then be given orally at a dose of approximately 4 times the IV dose.
.
Units
Counts
Participants
OG000
Secondary
Overall and Disease-free Survival
Study terminated due to lack of funding, no analysis was done for this protocol due to the fact that only four patients were accrued, no data was collected.
Anti-thymocyte globulin infuse the 1st dose, minimum of 6 hrs subsequent doses minimum of 4 hrs via a 0.22 micron in-line filter
Rituximab, total dose is 28 mg/kg divided in 2 doses (14 mg/kg, days -7 & +3) Initial infusion, start rate 50 mg/hour
Sirolimus 12 mg orally loading dose on day -3, followed by 4 mg orally single morning daily dose (target serum level 3-12 ng/ml by HPLC).
Tacrolimus (IV) dose of 0.03 mg/kg (ideal body weight) every 24hr by continuous infusion starting on Day -3, discontinued once the pt. starts eating & the drug will then be given orally at a dose of approximately 4 times the IV dose.
Units
Counts
Participants
OG000
Secondary
Immunocorrelative Studies Pre- and Periodically Post-transplantation
Study terminated due to lack of funding, no analysis was done for this protocol due to the fact that only four patients were accrued, no data was collected.
Posted
Using flow cytometry at 30, 60, 90, and 180 days post transplant.
Anti-thymocyte globulin infuse the 1st dose, minimum of 6 hrs subsequent doses minimum of 4 hrs via a 0.22 micron in-line filter
Rituximab, total dose is 28 mg/kg divided in 2 doses (14 mg/kg, days -7 & +3) Initial infusion, start rate 50 mg/hour
Sirolimus 12 mg orally loading dose on day -3, followed by 4 mg orally single morning daily dose (target serum level 3-12 ng/ml by HPLC).
Tacrolimus (IV) dose of 0.03 mg/kg (ideal body weight) every 24hr by continuous infusion starting on Day -3, discontinued once the pt. starts eating & the drug will then be given orally at a dose of approximately 4 times the IV dose.
anti-thymocyte globulin: Infuse the first dose over a minimum of 6 hours, and subsequent doses over a minimum of 4 hours via a 0.22 micron in-line filter
Rituximab: The total dose chosen for this protocol is 28 mg/kg divided in two doses (14 mg/kg on days -7 and +3). Initial infusion: Start rate of 50 mg/hour;
For adults, Sirolimus will be administered at 12 mg orally loading dose on day -3, followed by 4 mg orally single morning daily dose (target serum level 3-12 ng/ml by HPLC).
Tacrolimus will be administered intravenously at a dose of 0.03 mg/kg (ideal body weight) q 24h by continuous infusion starting on Day -3. Intravenous Tacrolimus will be discontinued once the patient starts eating and the drug will then be given orally at a dose of approximately 4 times the intravenous dose.
peripheral blood stem cell transplantation
sirolimus: For adults, will be administered at 12 mg orally loading dose on day -3, follow
0
4
0
4
Serious Adverse Events
Not provided
Other Adverse Events
Not provided
Study terminated due to lack of funding. No analysis, patient data on this protocol due to the fact that only four patients was able to be accrued.