Early Administration of ATG Followed by Cyclophosphamide, Busulfan and Fludarabine Before a Donor Stem Cell Transplant in Patients With Hematological Cancer
|ClinicalTrials.gov Identifier: NCT00787761|
Recruitment Status : Completed
First Posted : November 10, 2008
Results First Posted : October 1, 2012
Last Update Posted : October 1, 2012
RATIONALE: Giving low doses of chemotherapy before a donor 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. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving antithymocyte globulin before the transplant and tacrolimus and methotrexate after the transplant may stop this from happening.
PURPOSE: This phase II trial is studying how well giving antithymocyte globulin together with cyclophosphamide, busulfan, and fludarabine works in treating patients with hematological cancer or kidney cancer undergoing donor stem cell transplant.
|Condition or disease||Intervention/treatment||Phase|
|Myeloproliferative Disorders Kidney Cancer Leukemia Lymphoma Multiple Myeloma and Plasma Cell Neoplasm Myelodysplastic Syndromes Myelodysplastic/Myeloproliferative Diseases||Biological: anti-thymocyte globulin Drug: busulfan Drug: cyclophosphamide Drug: fludarabine phosphate Drug: methotrexate Drug: tacrolimus Procedure: nonmyeloablative allogeneic HSCT||Phase 2|
- To assess the percentage of patients with hematological malignancies or renal cell carcinoma who achieve > 90% donor T-cell chimerism at 30 days after treatment with reduced-intensity conditioning comprising low-dose anti-thymocyte globulin, low-dose cyclophosphamide, busulfan, and fludarabine phosphate followed by allogeneic peripheral blood progenitor cell transplantation from a matched related donor.
- To assess the incidence of severe (grade 3 or 4) acute graft-versus-host disease (GVHD) and extensive chronic GVHD in these patients.
- To assess whether this regimen is associated with reduced transplant-related toxicity and increased tolerability in these patients.
- To assess the overall safety of this conditioning regimen as measured by 6-month transplant-related mortality in these patients.
- To determine the efficacy of this regimen in inducing durable remissions in these patients.
- Reduced-intensity conditioning (RIC): Patients receive anti-thymocyte globulin IV over 4-6 hours on day -16 and over 6-8 hours on day -15, fludarabine phosphate IV over 30 minutes on days -7 to -3, busulfan IV over 3 hours on days -4 and -3, and cyclophosphamide IV over 1-2 hours on day -2.
- Transplantation: Patients undergo allogeneic peripheral blood progenitor cell transplantation on day 0.
- Graft-vs-host disease (GVHD) prophylaxis: Patients receive oral tacrolimus every 12 hours on days -1 to 90, followed by a taper until day 150. Patients also receive methotrexate IV on days 1, 3, and 6.
Blood samples are collected periodically for pharmacokinetic studies of anti-thymocyte globulin and PCR analysis for chimerism.
After completion of study therapy, patients are followed periodically for up to 3 years.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||24 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Pre-administration of Rabbit Antithymocyte Globulin to Optimize Donor T-Cell Engraftment Following Reduced Intensity Allogeneic Peripheral Blood Progenitor Cell Transplantation From Matched-Related Donors|
|Study Start Date :||April 2007|
|Actual Primary Completion Date :||July 2010|
|Actual Study Completion Date :||May 2012|
Experimental: ATG, Cytoxan, Bu/Flu based Allogeneic Transplant
All patients will receive an ATG, Cyclosphosphamide, Busulfan and Fludarabine based Allogeneic Transplant
Biological: anti-thymocyte globulin
Anti-Thymocyte Globulin (ATG) is commercially available. The 1st vial contains 25 mg ATG, and the 2nd vial contains > 5 mL SWFI diluent. Ampuls must be refrigerated (2º C - 8º C). Do not freeze.
Reconstitute 25 mg vial with diluent provided by manufacturer. Roll vial gently to dissolve powder. Use contents of vial within 4 hours. Dilute dosage to a final concentration of 0.5 mg/mL in 0.9% sodium chloride injection or 5% dextrose injection. Gently invert admixture 1-2 times to mix. Use admixture solution immediately.
Infuse the 1st dose over at least 6 hours, and subsequent doses over at least 4 hours. Infuse through a 0.22 micron in-line filter. Premeds include acetaminophen 650 mg PO, diphenhydramine 25-50 mg PO/IV, and methyprednisolone 1mg/kg at the initiation and half-way through ATG administration.
Other Names:Drug: busulfan
Commercially available in 60 mg/10 mL ampuls.
Dilute busulfan injection in 0.9% sodium chloride injection or dextrose 5% in water. The dilution volume should be 10 times the volume of busulfan injection, ensuring that the final concentration of busulfan is ≥ 0.5 mg/mL.
Store unopened ampuls at 2º C to 8º C. The diluted solution is stable for up to 8 hours at room temperature (25º C) but the infusion must also be completed within that 8-hour time frame. Dilution of busulfan injection in 0.9% sodium chloride is stable for up to 12 hours under refrigeration (2º C to 8º C) but the infusion must also be completed within that 12-hour time frame.
IV Bu should be administered via a central venous catheter as a 2-hour infusion every 6 hours for 2 consecutive days for a total of 8 doses.
Drug: fludarabine phosphate
Cyclophosphamide is commercially available. Cyclophosphamide for injection is available in 2000 mg vials which are reconstituted with 100 ml sterile water for injection.
The concentration of the reconstituted product is 20 mg/ml. The calculated dose will be diluted further in 250-500 ml of Dextrose 5% in water.
Reconstituted solutions of lyophilized cyclophosphamide are chemically and physically stable for 24 hours at room temperature or for 6 days in the refrigerator. Specific temperatures are not provided by the manufacturer. Reconstitution of cyclophosphamide with bacteriostatic water containing benzyl alcohol preservative may result in decomposition.
Each dose will be infused over 1-2 hr (depending on the total volume).
Fludarabine is commercially available as a white, lyophilized powder. Each vial contains 50 mg of fludarabine, 50 mg of mannitol and sodium hydroxide to adjust pH.
Intact vials should be stored under refrigeration. Reconstituted vials are stable for 16 days and solutions diluted in D5W or NS are stable for 48 hours at room temperature or under refrigeration.
Fludarabine should be reconstituted with 2 mL of Sterile Water for Injection, USP. Each mL of the resulting solution will contain 25 mg of fludarabine, 25 mg of mannitol, and sodium hydroxide to adjust the pH to 7-8.5. The product should be further diluted for intravenous administration in 5% Dextrose for Injection, USP or in 0.9% Sodium Chloride, USP.
Fludarabine will be administered as an IV infusion over 30 minutes.
Other Name: FludaraDrug: methotrexate
Commercially available for injection in 2 mL (2.5 mg/mL), 2 mL, 4 mL, 8 mL, 10 mL (25 mg/mL) vials, or 20 mg, 25 mg, 50 mg, or 100 mg vials for reconstitution.
Vials requiring reconstitution should be reconstituted to a concentration of 25 mg/mL.
Intact vials should be stored at room temperature and protected from light. Once opened, solutions containing preservatives are stable for 4 weeks at room temperature and up to 3 months refrigerated.
Administer via slow IV push.
Other Name: Amethopterin, MTXDrug: tacrolimus
Tacrolimus is commercially available as an injection (5 mg/mL; 1 mL ampuls) and as oral capsules (1 mg and 5 mg).
Tacrolimus injection must be diluted prior to IV infusion with 0.9% sodium chloride or 5% dextrose injection to a concentration of 4-20 μg/mL. Solutions should be prepared in non-PVC plastic or glass. Tacrolimus injection and diluted solutions of the drug should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
Oral therapy should be started as possible as per protocol and 8 to 12 hours after stopping intravenous therapy. Oral doses will be administered twice a day.
Store tacrolimus capsules and injection at controlled room temperature, 15-30º C (59-86º F).
Other Name: Prograf, FK506Procedure: nonmyeloablative allogeneic HSCT
As demonstrated by groups in Houston, Jerusalem & Seattle, RICT has been used to treat hematologic & solid malignancies with related & unrelated donors. Although adequate comparisons of RICT versus ablative alloHCT remain to be reported, the studies of RICT so far suggest that TRM is generally less than would be expected for similar patients undergoing ablative alloHCT; incidence of acute & chronic GVHD is similar or less than ablative alloHCT; autologous hematopoietic recovery is more common than seen following ablative alloHCT if graft failure occurs; powerful GVT effects can be seen but are dependent on high levels of donor T-cell chimerism and RICT are less effective than ablative alloHCT in controlling aggressive malignancies
- Achievement of > 90% (Full) Donor Chimerism in the T-cell Lineage as Measured by PCR at Day 30 Post-transplantation [ Time Frame: Day 30 ]Chimerism analysis of peripheral blood mononuclear cells using PCR for STR/VNTR will be performed post transplant. On each occasion, the peripheral blood will be separated into the T-cell component (using e.g. CD3 selection) and the myeloid component (using e.g.CD14/15 selection) before assessment of chimerism.
- T-cell and Myeloid Chimerism at Days 90 Post-transplantation (>90% Chimerism) [ Time Frame: Day 90 ]Chimerism analysis of peripheral blood mononuclear cells using PCR for STR/VNTR will be performed post transplant. On each occasion, the peripheral blood will be separated into the T-cell component (using e.g. CD3 selection) and the myeloid component (using e.g.CD14/15 selection) before assessment of chimerism.
- T-cell and Myeloid Chimerism at Days 180 Post-transplantation (>90%) [ Time Frame: 180 days ]Chimerism analysis of peripheral blood mononuclear cells using PCR for STR/VNTR will be performed post transplant. On each occasion, the peripheral blood will be separated into the T-cell component (using e.g. CD3 selection) and the myeloid component (using e.g.CD14/15 selection) before assessment of chimerism.
- Number of Patients Who Experience Severe (Grade 3 or 4) Acute Graft-versus-host Disease [ Time Frame: Day 100 ]number of patients who experienced post-transplant complication (GVHD) as seen by clinical evidence including but not limited to skin rash, elevated liver function tests, nausea/vomiting/diarrhea.
- Number of Patients Experiencing Extensive Chronic Graft Versus Host Disease (GVHD) [ Time Frame: 2 years ]Patients who had post-transplant complication (GVHD) as seen by clinical evidence including but not limited to skin rash, elevated liver function tests, nausea/vomiting/diarrhea.
- Non-relapse Mortality (NRM) at Day 180 Post-transplantation [ Time Frame: Day 180 ]non-relapse mortality refers to the death of a patient for causes other than relapsed disease.
- Disease-free Survival (DFS) at 24 Months [ Time Frame: 24 months ]Disease Free survival is measured by the amount of time a patient spends in a disease free state after being transplanted.
- Overall Survival (OS) at 24 Months [ Time Frame: 24 months ]Overall survival refers to the length of time a patient is alive after transplant regardless of whether they have progressive or relapsed disease.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00787761
|United States, Georgia|
|Blood and Marrow Transplant Group of Georgia|
|Atlanta, Georgia, United States, 30342|
|Principal Investigator:||Asad Bashey, MD, PhD||Blood and Marrow Transplant Group of Georgia|