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Reduced Intensity Conditioning With Clofarabine, Antithymocyte Globulin (ATG), Total Lymphoid Irradiation (TLI) Followed by Allogeneic Stem Cell Transplant

Primary Purpose

Acute Myeloid Leukemia, Myelodysplastic Syndrome, Acute Lymphocytic Leukemia

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Antithymocyte Globulin
Clofarabine
Clofarabine
Clofarabine
Sponsored by
Beth Israel Deaconess Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia focused on measuring Reduced Intensity Allogeneic Stem Cell Transplant, Clofarabine, Rabbit Antithymocyte Globulin, Total Lymphoid Radiation

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Patients with a)acute myeloid leukemia exclusive of patients in first complete remission with good risk cytogenetics (translocation 8,21,translocation 15, 17 or inversion 16); B)myelodysplastic syndrome; c)acute lymphocytic leukemia exclusive of patients in first remission without negative prognostic markers; d) relapsed or refractory nonHodgkin's lymphoma or Hodgkin's disease; e)relapsed or refractory multiple myeloma or f)relapsed or refractory chronic lymphocytic leukemia.
  2. Patients who are considered appropriate for reduced intensity transplantation must present with at least one of the following: A. Age over 50 B. History of a prior hematopoietic stem cell transplant C. Patient with compromised organ function or comorbid conditioning such that a standard ablative transplant would be considered high risk. D. Patient with low grade Lymphoma or CLL for which reduced intensity transplant would be the optimal therapy compared to an ablative regimen
  3. Patients will have a related or unrelated donor matched at 5/6 or 6/6 HLA loci.
  4. Patients must be greater than or equal to 18 years old, and younger than or equal to 75 years old to participate in the study.
  5. Patients must have ECOG performance status of 0-2
  6. Pulmonary function tests demonstrate DLCO (adjusted for Hgb)>50% predicted
  7. Cardiac ejection fraction >40%
  8. Laboratories:

    • Bilirubin less than or equal to 1.5mg/dL x ULN
    • AST/ALT/Alkaline Phosphatase less than or equal to 2.5x ULN
    • Serum creatinine less than or equal to 1.0mg/dL; if serum creatinine > 1.0MG/dL, then the estimated glomerular filtration rate (GFR) must be >60mL/min/1.73m^2 as calculated by the Modification of Diet in Renal Disease equation where Predicted GRF (ml/min/1.73m^2)=186x (serum creatinine)^1.154x(age in years)^-0.203x(0.742 if patient is female) x (1.212 if patient is black)
  9. Patients with serologic evidence of hepatitis B or C exposure will undergo liver biopsy to assess for presence of active hepatitis or fibrosis and quantification of risk of proceeding with transplant.

10. All patients must be capable of understanding the investigational nature, potential risks and benefits of the study, and able to provide valid informed consent. All patients must be informed of the investigational nature of this study and must give written informed consent in accordance with institutional and federal guidelines.

11. Female patients of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to enrollment.

12. Male and female patients must use an effective contraceptive method during the study and for a minimum of 6 months after study treatment

Exclusion Criteria:

  1. Patients who are HIV+ will be excluded.
  2. Patients must not have serious intercurrent illness such as uncontrolled systemic infection or significant organ compromise which significantly increases the risk of undergoing allogeneic transplantation.
  3. Pregnant and lactating women will be excluded.

Sites / Locations

  • Massachusetts General Hospital
  • Beth Israel Deaconess Medical Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

No Intervention

Experimental

Experimental

Experimental

Arm Label

Cohort 1

Cohort 2

Cohort 3

Cohort 4

Arm Description

Transplant conditioning will begin day -11 with 5 days of TLI at a dose of 80 cGy per day administered in conjunction with rabbit ATG at a dose of 1.5 mg/kg per day (day -11 to -7). TLI will be completed at 80 cGy per day (day -4 to 0) for a total of 10 fractions (800 cGy).

Transplant conditioning will begin day -11 with 5 days of TLI at a dose of 80 cGy per day administered in conjunction with rabbit ATG at a dose of 1.5 mg/kg per day (day -11 to -7). Clofarabine will be given at 20mg/m2/d IV infused over 1 hour x 5 days (day -6 to -2), for a total dose of 100 mg/m(2). TLI will be completed at 80 cGy per day (day -4 to 0) for a total of 10 fractions (800 cGy).

Transplant conditioning will begin day -11 with 5 days of TLI at a dose of 80 cGy per day administered in conjunction with rabbit ATG at a dose of 1.5 mg/kg per day (day -11 to -7). Clofarabine will be given at 30mg/m2/d IV infused over 1 hour x 5 days (day -6 to -2), for a total dose of 150 mg/m(2). TLI will be completed at 80 cGy per day (day -4 to 0) for a total of 10 fractions (800 cGy).

Transplant conditioning will begin day -11 with 5 days of TLI at a dose of 80 cGy per day administered in conjunction with rabbit ATG at a dose of 1.5 mg/kg per day (day -11 to -7). Clofarabine will be given at 40mg/m2/d IV infused over 1 hour x 5 days (day -6 to -2), for a total dose of 200 mg/m(2). TLI will be completed at 80 cGy per day (day -4 to 0) for a total of 10 fractions (800 cGy).

Outcomes

Primary Outcome Measures

To assess the toxicity and donor engraftment following treatment with a reduced intensity preparative regimen consisting of clofarabine, rabbit antithymocyte globulin (ATG), and total lymphoid irradiation followed by the infusion of allogeneic stem cells

Secondary Outcome Measures

To determine the incidence of acute and chronic graft versus host disease following clofarabine, rabbit ATG, total lymphoid irradiation, and allogeneic transplantation.
2. To evaluate the nature of immunologic reconstitution in patients treated clofarabine, rabbit ATG, total lymphoid irradiation, and allogeneic transplantation. The impact of the regimen on the phenotypic and functional characteristics of dendritic cell
To determine the disease free survival and overall survival of patients undergoing allogeneic transplantation following following clofarabine, rabbit ATG, and total lymphoid irradiation.

Full Information

First Posted
June 12, 2008
Last Updated
June 16, 2023
Sponsor
Beth Israel Deaconess Medical Center
Collaborators
Genzyme, a Sanofi Company
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1. Study Identification

Unique Protocol Identification Number
NCT00697684
Brief Title
Reduced Intensity Conditioning With Clofarabine, Antithymocyte Globulin (ATG), Total Lymphoid Irradiation (TLI) Followed by Allogeneic Stem Cell Transplant
Official Title
A Reduced Intensity Conditioning With Clofarabine Antithymocyte Globulin and Total Lymphoid Irradiation Followed by Allogeneic Hematopoietic Stem Cell Transplantation
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
June 2008 (undefined)
Primary Completion Date
December 2020 (Actual)
Study Completion Date
December 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Beth Israel Deaconess Medical Center
Collaborators
Genzyme, a Sanofi Company

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study will examine the safety of clofarabine, TLI and ATG as a reduced conditioning regimen prior to allogeneic transplantation. The impact of the conditioning regimen on the presence of the circulating regulatory as compared to activated T cell populations will be assessed.The recovery of DC populations post-transplant will be examined, along with the effect of the regimen on disease free and overall survival.
Detailed Description
One approach to limit the toxicity of allogeneic transplantation has been the use of nonmyeloablative regimens preceding the infusion of allogeneic cells.In this strategy, patients receive immunosuppressive therapy that allows for the engraftment of donor cells without the immediate eradication of patient hematopoiesis.The primary mechanism by which the underlying disease is eradicated is not through chemotherapy mediated cytoreduction, but rather through the donor lymphocyte mediated graft versus tumor effect.As a result, patients experience far less regimen related toxicity.Therefore, the adoption of this strategy may allow for the use of allogeneic transplantation in disease settings and patient populations for which it had not been readily applicable in the past. Over the past several years, the use nonmyeloablative transplant has rapidly expanded.Several reduced intensity conditioning regimens have been developed including fludarabine and cyclophosphamide; fludarabine and melphalan; fludarabine, ATG and low dose busulfan; and fludarabine and low dose TBI. Investigators have demonstrated the feasibility of this treatment approach with the majority of patients demonstrating donor engraftment,decreased regimen related toxicity, and graft mediated regression of disease.In some studies, patients demonstrate a period of mixed donor/host chimerism in which the infusion of donor lymphocytes is associated with achievement of complete donor chimerism. Although regimen related toxicity is decreased following reduced intensive conditioning regimens, graft versus host disease and opportunistic infections remain a significant source of morbidity and mortality following nonmyeloablative allogeneic transplantation. The impact of nonmyeloablative transplantation on immunological reconstitution has not been fully defined. Persistence of host antigen presenting cells in the post-transplant period may increase the incidence of GVHD due to the presentation of alloantigens to donor T cells. In contrast, residual host cellular immunity may provide enhanced protection against infectious pathogens and allow for more rapid education of donor lymphocytes. The use of clofarabine in place of fludarabine in combination with cyclophosphamide may augment the anti-leukemia effect of the regimen, enhance cytoreduction, and increase the efficacy of reduced intensity allogeneic transplantation in this setting.A potential issue associated with the use of clofarabine and cyclophosphamide as pre-transplant conditioning is whether the regimen would be sufficiently immunosuppressive to reliably facilitate engraftment of donor hematopoiesis.Another concern relates to the significant incidence of graft versus host disease which remains a major source of morbidity and mortality following reduced intensity transplantation.The use of TLI and ATG has been studied in the context of allogeneic transplantation and has been shown to effectively support engraftment in animal models and clinical trials.TLI has been shown to promote immune tolerance resulting in a decrease in the incidence of graft versus host disease (GVHD).It has been shown to decrease the incidence of rejection following transplantation of a T cell depleted allograft.The conditioning regimen of TLI and cyclophosphamide results in successful engraftment in patients with aplastic anemia. Regulatory T cells represent a population of T lymphocytes that demonstrate an immunosuppressive phenotype and play an important role in the prevention of autoimmunity and transplant rejection.Regulatory cells express the inhibitory cytokines IL-10 and TGFβ and are thought to suppress immune activation through direct cell contact.Similar to activated effector cells they coexpress CD4 and CD25.Regulatory T cells may be identified by the high levels of CD25 expression and the presence of CTLA-4 and FOXP3.Regulatory T cells demonstrate minimal proliferation to allogeneic stimuli and inhibit third party mixed lymphocyte responses. Increased presence of regulatory T cells have been found in the tumor bed, draining lymph nodes, and circulation in patients with malignancy and inhibit host anti-tumor immune responses. There has been increasing interest in evaluating the role of regulatory T cells as a means of inhibiting graft versus host disease. In animal models, selective introduction of regulatory T cells prevents the development of graft versus host disease without compromising immune reconstitution or anti-tumor immunity. A variety of strategies for the ex vivo expansion and isolation of regulatory T cells have been explored. A limiting factor has been the similar patterns of expression of cell surface markers between regulatory and activated T cell populations. iNKT cells represent another population of immunomodulatory cells thought to be essential for the generation of tolerance.In pre-clinical models, TLI has been shown to modulate immune effector cells resulting in increased levels of circulating regulatory T cells, preventing GVHD in a mismatched transplant setting.It is thought that iNKT cells are selectively preserved after TLI which polarize T cells towards an inhibitory phenotype. In a clinical study, 37 patients with lymphoid malignancies or acute leukemia underwent conditioning with TLI administered as 10 fractions of 80cGy and ATG.Only 2 patients developed acute GVHD despite the observation of a graft versus disease effect.Of note, a significant increase in the number of donor CD4+ T cells expressing IL-4 was observed suggesting that the immune modulation resulting from TLI/ATG polarized cells towards a TH-2 phenotype.As such, TLI/ATG would like facilitate engraftment and decrease the incidence of GVHD in patients undergoing conditioning with clofarabine.Most importantly, by modulating the host immune effectors but not depleting donor T cells, this strategy should not significantly inhibit the graft versus tumor effect.The prevalence of dendritic cell (DC) subsets (DC1 vs. DC2) in the hematopoietic graft have also been shown to effect the risk of GVHD.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia, Myelodysplastic Syndrome, Acute Lymphocytic Leukemia, Relapsed/Refractory Chronic Lymphocytic Leukemia, Relapsed/Refractory Non Hodgkin's Lymphoma, Hodgkins Disease, Relapsed Refractory Multiple Myeloma
Keywords
Reduced Intensity Allogeneic Stem Cell Transplant, Clofarabine, Rabbit Antithymocyte Globulin, Total Lymphoid Radiation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Cohort 1
Arm Type
No Intervention
Arm Description
Transplant conditioning will begin day -11 with 5 days of TLI at a dose of 80 cGy per day administered in conjunction with rabbit ATG at a dose of 1.5 mg/kg per day (day -11 to -7). TLI will be completed at 80 cGy per day (day -4 to 0) for a total of 10 fractions (800 cGy).
Arm Title
Cohort 2
Arm Type
Experimental
Arm Description
Transplant conditioning will begin day -11 with 5 days of TLI at a dose of 80 cGy per day administered in conjunction with rabbit ATG at a dose of 1.5 mg/kg per day (day -11 to -7). Clofarabine will be given at 20mg/m2/d IV infused over 1 hour x 5 days (day -6 to -2), for a total dose of 100 mg/m(2). TLI will be completed at 80 cGy per day (day -4 to 0) for a total of 10 fractions (800 cGy).
Arm Title
Cohort 3
Arm Type
Experimental
Arm Description
Transplant conditioning will begin day -11 with 5 days of TLI at a dose of 80 cGy per day administered in conjunction with rabbit ATG at a dose of 1.5 mg/kg per day (day -11 to -7). Clofarabine will be given at 30mg/m2/d IV infused over 1 hour x 5 days (day -6 to -2), for a total dose of 150 mg/m(2). TLI will be completed at 80 cGy per day (day -4 to 0) for a total of 10 fractions (800 cGy).
Arm Title
Cohort 4
Arm Type
Experimental
Arm Description
Transplant conditioning will begin day -11 with 5 days of TLI at a dose of 80 cGy per day administered in conjunction with rabbit ATG at a dose of 1.5 mg/kg per day (day -11 to -7). Clofarabine will be given at 40mg/m2/d IV infused over 1 hour x 5 days (day -6 to -2), for a total dose of 200 mg/m(2). TLI will be completed at 80 cGy per day (day -4 to 0) for a total of 10 fractions (800 cGy).
Intervention Type
Drug
Intervention Name(s)
Antithymocyte Globulin
Intervention Type
Drug
Intervention Name(s)
Clofarabine
Intervention Description
Transplant conditioning will begin day -11 with 5 days of TLI at a dose of 80 cGy per day administered in conjunction with rabbit ATG at a dose of 1.5 mg/kg per day (day -11 to -7). Clofarabine will be given at 20mg/m2/d IV infused over 1 hour x 5 days (day -6 to -2), for a total dose of 100 mg/m(2). TLI will be completed at 80 cGy per day (day -4 to 0) for a total of 10 fractions (800 cGy).
Intervention Type
Drug
Intervention Name(s)
Clofarabine
Intervention Description
Transplant conditioning will begin day -11 with 5 days of TLI at a dose of 80 cGy per day administered in conjunction with rabbit ATG at a dose of 1.5 mg/kg per day (day -11 to -7). Clofarabine will be given at 30mg/m2/d IV infused over 1 hour x 5 days (day -6 to -2), for a total dose of 150 mg/m(2). TLI will be completed at 80 cGy per day (day -4 to 0) for a total of 10 fractions (800 cGy).
Intervention Type
Drug
Intervention Name(s)
Clofarabine
Intervention Description
Transplant conditioning will begin day -11 with 5 days of TLI at a dose of 80 cGy per day administered in conjunction with rabbit ATG at a dose of 1.5 mg/kg per day (day -11 to -7). Clofarabine will be given at 40mg/m2/d IV infused over 1 hour x 5 days (day -6 to -2), for a total dose of 200 mg/m(2). TLI will be completed at 80 cGy per day (day -4 to 0) for a total of 10 fractions (800 cGy).
Primary Outcome Measure Information:
Title
To assess the toxicity and donor engraftment following treatment with a reduced intensity preparative regimen consisting of clofarabine, rabbit antithymocyte globulin (ATG), and total lymphoid irradiation followed by the infusion of allogeneic stem cells
Time Frame
30 days
Secondary Outcome Measure Information:
Title
To determine the incidence of acute and chronic graft versus host disease following clofarabine, rabbit ATG, total lymphoid irradiation, and allogeneic transplantation.
Time Frame
1 year
Title
2. To evaluate the nature of immunologic reconstitution in patients treated clofarabine, rabbit ATG, total lymphoid irradiation, and allogeneic transplantation. The impact of the regimen on the phenotypic and functional characteristics of dendritic cell
Time Frame
1 year
Title
To determine the disease free survival and overall survival of patients undergoing allogeneic transplantation following following clofarabine, rabbit ATG, and total lymphoid irradiation.
Time Frame
Patient lifetime

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with a)acute myeloid leukemia exclusive of patients in first complete remission with good risk cytogenetics (translocation 8,21,translocation 15, 17 or inversion 16); B)myelodysplastic syndrome; c)acute lymphocytic leukemia exclusive of patients in first remission without negative prognostic markers; d) relapsed or refractory nonHodgkin's lymphoma or Hodgkin's disease; e)relapsed or refractory multiple myeloma or f)relapsed or refractory chronic lymphocytic leukemia. Patients who are considered appropriate for reduced intensity transplantation must present with at least one of the following: A. Age over 50 B. History of a prior hematopoietic stem cell transplant C. Patient with compromised organ function or comorbid conditioning such that a standard ablative transplant would be considered high risk. D. Patient with low grade Lymphoma or CLL for which reduced intensity transplant would be the optimal therapy compared to an ablative regimen Patients will have a related or unrelated donor matched at 5/6 or 6/6 HLA loci. Patients must be greater than or equal to 18 years old, and younger than or equal to 75 years old to participate in the study. Patients must have ECOG performance status of 0-2 Pulmonary function tests demonstrate DLCO (adjusted for Hgb)>50% predicted Cardiac ejection fraction >40% Laboratories: Bilirubin less than or equal to 1.5mg/dL x ULN AST/ALT/Alkaline Phosphatase less than or equal to 2.5x ULN Serum creatinine less than or equal to 1.0mg/dL; if serum creatinine > 1.0MG/dL, then the estimated glomerular filtration rate (GFR) must be >60mL/min/1.73m^2 as calculated by the Modification of Diet in Renal Disease equation where Predicted GRF (ml/min/1.73m^2)=186x (serum creatinine)^1.154x(age in years)^-0.203x(0.742 if patient is female) x (1.212 if patient is black) Patients with serologic evidence of hepatitis B or C exposure will undergo liver biopsy to assess for presence of active hepatitis or fibrosis and quantification of risk of proceeding with transplant. 10. All patients must be capable of understanding the investigational nature, potential risks and benefits of the study, and able to provide valid informed consent. All patients must be informed of the investigational nature of this study and must give written informed consent in accordance with institutional and federal guidelines. 11. Female patients of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to enrollment. 12. Male and female patients must use an effective contraceptive method during the study and for a minimum of 6 months after study treatment Exclusion Criteria: Patients who are HIV+ will be excluded. Patients must not have serious intercurrent illness such as uncontrolled systemic infection or significant organ compromise which significantly increases the risk of undergoing allogeneic transplantation. Pregnant and lactating women will be excluded.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David E Avigan, MD
Organizational Affiliation
Beth Israel Deaconess Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Beth Israel Deaconess Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Reduced Intensity Conditioning With Clofarabine, Antithymocyte Globulin (ATG), Total Lymphoid Irradiation (TLI) Followed by Allogeneic Stem Cell Transplant

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