Sirolimus, Tacrolimus and Short Course Methotrexate for Prevention of Acute GVHD in Recipients of Mismatched Unrelated Donor Allogeneic Stem Cell Transplantation - Full Text View

Purpose

The primary objective of this trial is to study the safety and efficacy of a novel regimen of sirolimus, tacrolimus and methotrexate as prophylaxis against acute graft versus host disease (GVHD) in recipients of mismatched unrelated donor stem cell grafts. Methotrexate is administered in a low dose format of 5mg/m2 on days +1,3 and 6 only.

Condition	Intervention	Phase
Stem Cell Transplantation	Drug: tacrolimus Drug: Sirolimus Drug: Methotrexate	Phase 0


Study Type:	Interventional
Study Design:	Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Pilot Study of Sirolimus, Tacrolimus and Short Course Methotrexate for Prevention of Acute Graft Versus Host Disease in Recipients of Mismatched Unrelated Donor Allogeneic Stem Cell Transplantation

Resource links provided by NLM:

Drug Information available for: Methotrexate Methotrexate sodium Sirolimus Tacrolimus Everolimus Temsirolimus

Genetic and Rare Diseases Information Center resources: Acute Graft Versus Host Disease Homologous Wasting Disease

U.S. FDA Resources

Further study details as provided by Yale University:

Primary Outcome Measures:

Safety/Efficacy of a novel regimen of sirolimus, tacrolimus and methotrexate [ Time Frame: Upon completion of study ] [ Designated as safety issue: Yes ]


Estimated Enrollment:	20
Study Start Date:	October 2007
Estimated Study Completion Date:	October 2014
Estimated Primary Completion Date:	October 2014 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: 1 sirolimus, tacrolimus and short course methotrexate	Drug: tacrolimus Tacrolimus will be administered at a dose of .02mg/kg/d IVCI beginning day -3 until able to take oral medicines reliably. Blood levels will be maintained at 5-10 ng/ml. The oral dose will be 4 times the IV dose. Tacrolimus will be converted to oral dosing prior to hospital discharge. Tacrolimus will be continued until 4 months post transplant (day +120) unless toxicity, refractory GVHD or the development of disease recurrence mandate discontinuation of the drug. Other Names: FK506 Prograf(TM) Drug: Sirolimus Sirolimus will be administered as a 12 mg oral loading dose on day -3 followed by 4mg daily. Sirolimus levels will be obtained on day +0 and then at least twice weekly to maintain a trough serum level of 3-12 ng/ml. Sirolimus will be continued until 5 months post transplant (day +150) unless toxicity, refractory GVHD or the development of disease recurrence mandate discontinuation of the drug. Other Name: Rapamune Drug: Methotrexate Methotrexate, dose #1 will be administered on day +1 post transplantation, as an IV bolus, provided at least 24 hours have elapsed following infusion of donor stem cells at a dose of 10mg/m2. Dose #2 of Methotrexate will be administered 48 hours later, as IV bolus on day +3 at a dose of 5mg/m2.

Arms

Assigned Interventions

Experimental: 1

sirolimus, tacrolimus and short course methotrexate

Drug: tacrolimus

Tacrolimus will be administered at a dose of .02mg/kg/d IVCI beginning day -3 until able to take oral medicines reliably. Blood levels will be maintained at 5-10 ng/ml. The oral dose will be 4 times the IV dose. Tacrolimus will be converted to oral dosing prior to hospital discharge. Tacrolimus will be continued until 4 months post transplant (day +120) unless toxicity, refractory GVHD or the development of disease recurrence mandate discontinuation of the drug.

Other Names:

FK506
Prograf(TM)

Drug: Sirolimus

Sirolimus will be administered as a 12 mg oral loading dose on day -3 followed by 4mg daily. Sirolimus levels will be obtained on day +0 and then at least twice weekly to maintain a trough serum level of 3-12 ng/ml. Sirolimus will be continued until 5 months post transplant (day +150) unless toxicity, refractory GVHD or the development of disease recurrence mandate discontinuation of the drug.

Other Name: Rapamune

Drug: Methotrexate

Methotrexate, dose #1 will be administered on day +1 post transplantation, as an IV bolus, provided at least 24 hours have elapsed following infusion of donor stem cells at a dose of 10mg/m2. Dose #2 of Methotrexate will be administered 48 hours later, as IV bolus on day +3 at a dose of 5mg/m2.

Eligibility


Ages Eligible for Study:	16 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Patients must have an identified 8/10 or 9/10 matched unrelated donor identified following a formal search with confirmatory typing through the national marrow donor program as the best available donor. No matched sibling or fully matched unrelated donor has been identified. HLA typing of donor and recipient will be performed by high resolution molecular typing at HLA A, B, C and DRB1/DQ loci. Patients whose best available donor is matched at 8/10 loci must have at least one of the mismatches at the DQ locus. (no more than one mismatch at HLA A,B,C,DR allowed).
Candidates for this trial will meet the following criteria:
1. Adequate organ function for conditioning type:
  
  For patients receiving ablative conditioning
  - Left Ventricular ejection fraction >45%
  - DLCO >50%
  - Creatinine <1.5
  - Hepatic enzymes <3x upper limit of normal.
  - KPS >70%
  For patients receiving non-ablative conditioning:
  - KPS >70%
2. Patients with the following diseases will be considered eligible:
  - AML in first remission with high risk features (poor risk cytogenetic abnormalities9, persistent elevated blast count on day +15 or recovery marrow after induction therapy).
  - AML beyond first remission
  - ALL in first remission with high risk features (ph+, t4:11)
  - ALL beyond first remission
  - High risk Myelodysplasia (RAEB-II, RAEB-I with poor-risk cytogenetics)
  - Recurrent Aggressive Non-Hodgkins or Hodgkins lymphoma (indolent histologies excluded) who have failed autologous transplant or have had inadequate response to salvage therapy.
  - CML with transformation
  - CLL with transformation or Fludarabine failure.
  - Severe aplastic anemia with recurrence or failure after immunosuppressive therapy.

Exclusion Criteria:

Prior allogeneic transplantation
Active CNS leukemia.
Female patients who are pregnant or breast feeding
Karnofsky performance status <70%.
Active viral, bacterial or fungal infection.
Patients seropositive for HIV -1,2; HTLV -1,2 (due to the additional immunodeficiency induced by transplantation and immunosuppressive therapy) Requirement for antifungal prophylaxis with Voriconazole for the first 30 days is prohibited.
Patients not providing informed consent.

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00612274

Locations


United States, Connecticut
Yale University School of Medicine
New Haven, Connecticut, United States, 06520

Sponsors and Collaborators

Stuart Seropian

Investigators


Principal Investigator:	Stuart Seropian, M.D.	Yale University

More Information

No publications provided


Responsible Party:	Stuart Seropian, Principal Investigator, Yale University
ClinicalTrials.gov Identifier:	NCT00612274 History of Changes
Other Study ID Numbers:	0703002455
Study First Received:	January 29, 2008
Last Updated:	July 15, 2013
Health Authority:	United States: Institutional Review Board

Keywords provided by Yale University:


allogeneic

Additional relevant MeSH terms:


Everolimus Methotrexate Sirolimus Tacrolimus Abortifacient Agents Abortifacient Agents, Nonsteroidal Anti-Bacterial Agents Anti-Infective Agents Antibiotics, Antineoplastic Antifungal Agents Antimetabolites Antimetabolites, Antineoplastic Antineoplastic Agents	Antirheumatic Agents Dermatologic Agents Enzyme Inhibitors Folic Acid Antagonists Immunologic Factors Immunosuppressive Agents Molecular Mechanisms of Pharmacological Action Nucleic Acid Synthesis Inhibitors Pharmacologic Actions Physiological Effects of Drugs Reproductive Control Agents Therapeutic Uses

ClinicalTrials.gov processed this record on February 27, 2015