Sirolimus, Tacrolimus, Thymoglobulin and Rituximab as Graft-versus-Host-Disease Prophylaxis in Patients Undergoing Haploidentical and HLA Partially Matched Donor Hematopoietic Cell Transplantation
Study Details
Study Description
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.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Phase 2 |
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 109/L for 3 consecutive days) and platelet count (> 20 x 109/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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: anti-thymocyte globulin, rituximab, sirolimus, tacrolimus, 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. |
Biological: 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.
Biological: 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; 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.
Other Names:
Drug: sirolimus
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).
Other Names:
Drug: tacrolimus
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.
Other Names:
Other: laboratory biomarker analysis
laboratory biomarker analysis
Procedure: allogeneic hematopoietic stem cell transplantation
allogeneic hematopoietic stem cell transplantation
Procedure: management of therapy complications
management of therapy complications
Procedure: peripheral blood stem cell transplantation
peripheral blood stem cell transplantation
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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]
- Incidence of Thrombotic Microangiopathy [Within 100 days of HCT]
- Overall and Disease-free Survival [At 1 year]
- Immunocorrelative Studies Pre- and Periodically Post-transplantation [Using flow cytometry at 30, 60, 90, and 180 days post transplant.]
Eligibility Criteria
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
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Karmanos Cancer Institute | Detroit | Michigan | United States | 48201 |
Sponsors and Collaborators
- Barbara Ann Karmanos Cancer Institute
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Zaid Al-Kadhimi, M.D., Barbara Ann Karmanos Cancer Institute
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- CDR0000671822
- P30CA022453
- U4781s
- 2009-150
- NCT01534767
Study Results
Participant Flow
Recruitment Details | Cancer center clinic. |
---|---|
Pre-assignment Detail |
Arm/Group Title | Anti-thymocyte Globulin, Rituximab, Sirolimus, Tacrolimus, |
---|---|
Arm/Group Description | 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 |
Period Title: Overall Study | |
STARTED | 4 |
COMPLETED | 0 |
NOT COMPLETED | 4 |
Baseline Characteristics
Arm/Group Title | Anti-thymocyte Globulin, Rituximab, Sirolimus, Tacrolimus, |
---|---|
Arm/Group Description | 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 |
Overall Participants | 4 |
Age (Count of Participants) | |
<=18 years |
0
0%
|
Between 18 and 65 years |
4
100%
|
>=65 years |
0
0%
|
Age (years) [Mean (Standard Deviation) ] | |
Mean (Standard Deviation) [years] |
50
(2.82)
|
Sex: Female, Male (Count of Participants) | |
Female |
2
50%
|
Male |
2
50%
|
Region of Enrollment (participants) [Number] | |
United States |
4
100%
|
Outcome Measures
Title | Incidence and Severity of Acute Graft-vs-host Disease (GVHD) |
---|---|
Description | |
Time Frame | During the first six months post transplant |
Outcome Measure Data
Analysis Population Description |
---|
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. |
Arm/Group Title | Anti-thymocyte Globulin, Rituximab, Sirolimus, Tacrolimus, |
---|---|
Arm/Group Description | 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 |
Measure Participants | 0 |
Title | Time to Engraftment |
---|---|
Description | |
Time Frame | During the first six months post transplant |
Outcome Measure Data
Analysis Population Description |
---|
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. |
Arm/Group Title | Anti-thymocyte Globulin, Rituximab, Sirolimus, Tacrolimus, |
---|---|
Arm/Group Description | 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. . |
Measure Participants | 0 |
Title | Safety Assessment |
---|---|
Description | |
Time Frame | During the first six months post transplant |
Outcome Measure Data
Analysis Population Description |
---|
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. |
Arm/Group Title | Anti-thymocyte Globulin, Rituximab, Sirolimus, Tacrolimus, |
---|---|
Arm/Group Description | 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 |
Measure Participants | 0 |
Title | Incidence of Chronic GVHD |
---|---|
Description | |
Time Frame | Within two years after transplant |
Outcome Measure Data
Analysis Population Description |
---|
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. |
Arm/Group Title | Anti-thymocyte Globulin, Rituximab, Sirolimus, Tacrolimus, |
---|---|
Arm/Group Description | 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 |
Measure Participants | 0 |
Title | Incidence of Infections Including Cytomegalovirus, Epstein-Barr Virus Reactivation, and Post-transplant Lymphoproliferative Disorder |
---|---|
Description | |
Time Frame | At one year |
Outcome Measure Data
Analysis Population Description |
---|
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. |
Arm/Group Title | Anti-thymocyte Globulin, Rituximab, Sirolimus, Tacrolimus, |
---|---|
Arm/Group Description | 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 |
Measure Participants | 0 |
Title | Incidence of Thrombotic Microangiopathy |
---|---|
Description | |
Time Frame | Within 100 days of HCT |
Outcome Measure Data
Analysis Population Description |
---|
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. |
Arm/Group Title | Anti-thymocyte Globulin, Rituximab, Sirolimus, Tacrolimus, |
---|---|
Arm/Group Description | 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. . |
Measure Participants | 0 |
Title | Overall and Disease-free Survival |
---|---|
Description | |
Time Frame | At 1 year |
Outcome Measure Data
Analysis Population Description |
---|
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. |
Arm/Group Title | Anti-thymocyte Globulin, Rituximab, Sirolimus, Tacrolimus, |
---|---|
Arm/Group Description | 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. |
Measure Participants | 0 |
Title | Immunocorrelative Studies Pre- and Periodically Post-transplantation |
---|---|
Description | |
Time Frame | Using flow cytometry at 30, 60, 90, and 180 days post transplant. |
Outcome Measure Data
Analysis Population Description |
---|
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. |
Arm/Group Title | Anti-thymocyte Globulin, Rituximab, Sirolimus, Tacrolimus, |
---|---|
Arm/Group Description | 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. . |
Measure Participants | 0 |
Adverse Events
Time Frame | ||
---|---|---|
Adverse Event Reporting Description | ||
Arm/Group Title | Anti-thymocyte Globulin, Rituximab, Sirolimus, Tacrolimus, | |
Arm/Group Description | 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 | |
All Cause Mortality |
||
Anti-thymocyte Globulin, Rituximab, Sirolimus, Tacrolimus, | ||
Affected / at Risk (%) | # Events | |
Total | / (NaN) | |
Serious Adverse Events |
||
Anti-thymocyte Globulin, Rituximab, Sirolimus, Tacrolimus, | ||
Affected / at Risk (%) | # Events | |
Total | 0/4 (0%) | |
Other (Not Including Serious) Adverse Events |
||
Anti-thymocyte Globulin, Rituximab, Sirolimus, Tacrolimus, | ||
Affected / at Risk (%) | # Events | |
Total | 0/4 (0%) |
Limitations/Caveats
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.
Results Point of Contact
Name/Title | Zaid Al-Kadhimi, M.D. |
---|---|
Organization | Barbara Ann Karmanos Cancer Institute |
Phone | 404-778-5984 |
zalkadh@emory.edu |
- CDR0000671822
- P30CA022453
- U4781s
- 2009-150
- NCT01534767