Early Administration of ATG Followed by Cyclophosphamide, Busulfan and Fludarabine Before a Donor Stem Cell Transplant in Patients With Hematological Cancer

This study has been completed.
Sponsor:
Collaborator:
Blood and Marrow Transplant Group of Georgia
Information provided by (Responsible Party):
Northside Hospital, Inc.
ClinicalTrials.gov Identifier:
NCT00787761
First received: November 7, 2008
Last updated: August 29, 2012
Last verified: August 2012
  Purpose

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 Intervention 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

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Northside Hospital, Inc.:

Primary Outcome Measures:
  • Achievement of > 90% (Full) Donor Chimerism in the T-cell Lineage as Measured by PCR at Day 30 Post-transplantation [ Time Frame: Day 30 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • T-cell and Myeloid Chimerism at Days 90 Post-transplantation (>90% Chimerism) [ Time Frame: Day 90 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    Overall survival refers to the length of time a patient is alive after transplant regardless of whether they have progressive or relapsed disease.


Enrollment: 24
Study Start Date: April 2007
Study Completion Date: May 2012
Primary Completion Date: July 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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:
  • Thymoglobulin
  • ATG
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: cyclophosphamide

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).

Drug: fludarabine phosphate

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: Fludara
Drug: 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, MTX
Drug: 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, FK506
Procedure: 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

Detailed Description:

OBJECTIVES:

  • 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.

OUTLINE:

  • 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.

  Eligibility

Ages Eligible for Study:   up to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Histologically confirmed diagnosis of one of the following:

    • Chronic myeloid leukemia (CML)

      • Philadelphia chromosome (Ph)- and/or BCR-ABL-positive disease
      • In chronic or accelerated phase
      • Suboptimal response to imatinib mesylate (i.e., no hematologic complete response by 3 months, no major cytogenetic response by 6 months, or no complete cytogenetic response by 1 year)
      • CML in blastic transformation allowed provided patient achieved complete remission (CR) or second chronic phase after treatment with imatinib mesylate or chemotherapy
    • Chronic lymphocytic leukemia meeting one of the following criteria:

      • Rai stage III or IV disease
      • Rai stage I or II disease that failed standard therapy (i.e., disease is progressing after ≥ 1 course of standard therapy)
    • Non-Hodgkin lymphoma (NHL) meeting one of the following criteria:

      • Indolent NHL

        • Clinical stage III or IV disease or bulky stage II disease (i.e., ≥ one lymphoid mass > 5 cm in ≥ one dimension)
        • Relapsed after primary therapy OR is refractory to therapy
      • Aggressive NHL

        • Is not considered curable with standard chemotherapy or autologous stem cell transplantation (i.e., relapsed after autologous stem cell transplantation)
        • Chemotherapy-responsive disease
    • Multiple myeloma

      • Durie-Salmon stage II or III disease

        • Durie Salmon stage I disease allowed provided β2 microglobulin level > 3 mg/dL
    • Acute myeloid leukemia or acute lymphocytic leukemia

      • In CR (defined as < 5% blasts in bone marrow and no circulating blasts) AND has any of the following poor prognostic features:

        • WBC > 100,000/mm^3 at presentation
        • In second or greater remission
        • Adverse-risk cytogenetics (i.e., Ph1-positive, 11q23 translocation, -5, -7, complex translocations, or other recognized adverse-risk cytogenetics)
    • Renal cell carcinoma

      • Stage IV disease
      • Clear cell morphology
    • Myelodysplastic syndromes

      • Bone marrow blasts ≤ 10% on last bone marrow biopsy prior to transplantation
    • Myeloproliferative disease

      • Anticipated life expectancy on conventional therapy < 10 years
      • No uncomplicated essential thrombocythemia or primary polycythemia
    • Hodgkin lymphoma

      • Relapsed after ≥ 1 standard-dose chemotherapy regimen
      • Not considered curable by autologous stem cell transplantation
  • No clinical evidence of active CNS involvement

    • Previously treated leptomeningeal disease allowed provided CSF cytology is negative at the time of assessment for transplantation
  • Available 6/6 allele match (i.e., HLA-A, B, DRβ1)matched related donor

PATIENT CHARACTERISTICS:

  • ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
  • Bilirubin < 3 times normal (unless abnormality due to malignancy)
  • AST and ALT < 3 times normal (unless abnormality due to malignancy)
  • Creatinine ≤ 2.0 mg/dL
  • LVEF ≥ 40% by MUGA or ECHO
  • DLCO ≥ 40% of predicted
  • FEV-1 ≥ 50% of predicted
  • Not pregnant or nursing
  • Fertile patients must use effective contraception
  • Deemed to be an appropriate candidate for allogeneic SCT
  • No evidence of myocardial infarction within the past 6 months
  • No psychological or social condition that may interfere with study participation
  • No serious uncontrolled localized or active systemic infection
  • No second malignancy within the past 3 years except for completely excised nonmelanotic skin cancer or in situ carcinoma of the cervix
  • No chronic inflammatory disorder requiring the continued use of glucocorticoids or other immunosuppressive medications
  • No known HIV positivity
  • No hypersensitivity to E. coli-derived proteins
  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: NCT00787761

Locations
United States, Georgia
Blood and Marrow Transplant Group of Georgia
Atlanta, Georgia, United States, 30342
Sponsors and Collaborators
Northside Hospital, Inc.
Blood and Marrow Transplant Group of Georgia
Investigators
Principal Investigator: Asad Bashey, MD, PhD Blood and Marrow Transplant Group of Georgia
  More Information

Additional Information:
Publications:

Responsible Party: Northside Hospital, Inc.
ClinicalTrials.gov Identifier: NCT00787761     History of Changes
Other Study ID Numbers: CDR0000618483, BMTGG-NSH-807
Study First Received: November 7, 2008
Results First Received: July 9, 2012
Last Updated: August 29, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Northside Hospital, Inc.:
accelerated phase CML
blastic phase CML
Philadelphia chromosome positive CML
stage I CLL
stage II CLL
stage III CLL
stage IV CLL
stage I multiple myeloma
stage II multiple myeloma
stage III multiple myeloma
adult AML with 11q23 (MLL) abnormalities
adult CML in remission
adult ALL in remission
stage IV renal cell cancer
de novo MDS
previously treated MDS
secondary MDS
atypical CML, BCR-ABL negative
chronic myelomonocytic leukemia
MDS/myeloproliferative neoplasm, unclassifiable
primary myelofibrosis
chronic neutrophilic leukemia
recurrent adult Hodgkin lymphoma
clear cell renal cell carcinoma
adult AML with inv(16)(p13;q22)
adult AML with t(15;17)(q22;q12)
adult AML with t(16;16)(p13;q22)
adult AML with t(8;21)(q22;q22)
adult nasal type extranodal NK/T-cell lymphoma
AML/transient myeloproliferative disorder

Additional relevant MeSH terms:
Carcinoma, Renal Cell
Kidney Neoplasms
Leukemia
Lymphoma
Multiple Myeloma
Myelodysplastic Syndromes
Myelodysplastic-Myeloproliferative Diseases
Myeloproliferative Disorders
Neoplasms
Neoplasms, Plasma Cell
Plasmacytoma
Preleukemia
Adenocarcinoma
Blood Protein Disorders
Bone Marrow Diseases
Carcinoma
Cardiovascular Diseases
Hematologic Diseases
Hemorrhagic Disorders
Hemostatic Disorders
Immune System Diseases
Immunoproliferative Disorders
Kidney Diseases
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Glandular and Epithelial
Paraproteinemias
Precancerous Conditions

ClinicalTrials.gov processed this record on October 23, 2014