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Reduced-Intensity Conditioning for the Prevention of Treatment-Related Mortality in Patients Who Undergo a Hematopoietic Stem Cell Transplant

Primary Purpose

Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Aplastic Anemia

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Hematopoietic Cell Transplantation
Mycophenolate Mofetil
Tacrolimus
Cyclophosphamide
Total-Body Irradiation
Donor Lymphocyte Infusion
Fludarabine
Melphalan
Sponsored by
Thomas Jefferson University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Lymphoblastic Leukemia

Eligibility Criteria

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

Inclusion Criteria:

  • Radiation-based cohort diagnoses:

    • Acute myeloid leukemia
    • Acute lymphoid leukemia in remission
    • Myelodysplasia (MDS)
    • Chronic lymphocytic leukemia (CLL) with no or minimal lymph node involvement
    • Multiple myeloma
    • Chronic myeloid leukemia
    • Myelofibrosis
    • Myeloid malignancy not otherwise specified
    • Chronic myelomonocytic leukemia
    • Essential thrombocytopenia or polycythemia vera
    • T cell leukemia
    • T cell lymphoma without significant lymph node disease burden
    • Any hematological malignancy or dyscrasia not cited above in which HSCT is potentially curable * Any patient who has a hematological disease that would normally be treated on a myeloablative study, but is prevented from doing so by factors in their past medical history. Examples are patients with previous treatment with radiation therapy precluding total-body irradiation (TBI), or a past history of myeloablative therapy, precluding a 2nd myeloablative regimen.
    • Patients must have a donor who is one-haplotype mismatched (number of mismatches in either direction not considered)

  • Chemotherapy-based cohort diagnoses:

    • Hodgkin or non-Hodgkin lymphoma
    • Small lymphocytic lymphoma/CLL
    • Any other diagnosis in which chemotherapy is thought to be superior to radiotherapy for treatment of the disease
    • Hematological malignancy in patients who cannot receive > 2 Gy radiation * Aplastic anemia and other non-malignant hematologic dyscrasias
    • Patients must have a donor who is one-haplotype mismatched (number of mismatches in either direction not considered)

  • HLA identical cohort diagnoses:

    * Patients in this group will be treated in parallel to the radiation-based cohort or the chemotherapy-based group based on what category their diagnosis falls into. However, these patients will have HLA identical related donors (one-antigen cross-over event included).

  • Left ventricular ejection fraction of >= 50%
  • Diffusion lung capacity of oxygen >= 50% and forced expiratory volume at 1 second >= 50% of predicted corrected for hemoglobin
  • Adequate liver function as defined by a serum bilirubin =< 1.8, aspartate aminotransferase or alanine aminotransferase =< 2.5 x upper limit of normal
  • Creatinine clearance of >= 60 mL/min

  • Patients must have adequate Karnofsky performance status (KPS) and hematopoietic cell transplantation-comorbidity index (HCT-CI) scores:

    • Patients < age 60 years must have a KPS of >= 80% and an HCT-CI score of 5 or less
    • Patients aged 60 to 65 years must have a KPS of >= 80% and an HCT-CI score of 4 or less
    • Patients aged 66 to 69 years must have a KPS of 90% and an HCT-CI score of 3 or less * Patients aged 70 years or more must have a KPS of 90% and an HCT-CI score of 2 or less
    • (Patients with greater than the allowable HCT-CI points for age can be enrolled for trial with approval of the principal investigator and at least 1 co-investigator not on the primary care team of the patient). This is an adjustment to account for healthy patients who meet the spirit of this protocol but have histories that result in higher than guideline HCT-CI points. An example is a patient with a solid tumor malignancy in their remote history (adds 3 points to HCT-CI total) where the treatment for the malignancy occurred years to decades before and there has been complete recovery of toxicities
  • Patients must be willing to use contraception if they have childbearing potential
  • Patient or patient's guardian is able to give informed consent
  • Patients should have a life expectancy of >= 6 months for reasons other than their underlying hematologic/oncologic disorder

Exclusion Criteria:

  • Patients with evidence of another malignancy, exclusive of a skin cancer that requires only local treatment, should not be enrolled on this protocol

  • Patients should not be:

    • Human immunodeficiency virus positive
    • Have active involvement of the central nervous system with malignancy. This can be documented by a normal neurological exam, magnetic resonance imaging (MRI) of the head, and/or a negative cerebral spinal fluid analysis
  • Pregnant or breastfeeding

Sites / Locations

  • Sidney Kimmel Cancer Center at Thomas Jefferson UniversityRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Radiation-Based Cohort (fludarabine, TBI, infusion)

Chemotherapy-Based Cohort (fludarabine, melphalan, TBI)

Arm Description

Patients receive fludarabine IV on days -11, -10, -9, and -8, undergo TBI BID on days -10 and -9, undergo DLI on day -6, and receive cyclophosphamide IV on days -3 and -2. Patients begin tacrolimus and mycophenolate mofetil IV on day -1. Patients then undergo HSCT on day 0. Treatment continues in the absence of disease progression or unacceptable toxicity.

Patients receive fludarabine IV on days -11, -10, -9, and -8 and melphalan IV on days -10 and -9. Patients undergo TBI and DLI once on day -6. Patients receive cyclophosphamide IV on days -3 and -2 and begin tacrolimus and mycophenolate mofetil on day -1. Patients undergo hematopoietic stem cell transplant on day 0.

Outcomes

Primary Outcome Measures

Incidence of treatment-related mortality (TRM)
TRM is defined as death without evidence of recurrent disease in the 2 year period post HSCT. Summarized using Kaplan-Meier curves and the respective Kaplan-Meier estimates of the 2-year event rate are reported as well as their 95% confidence intervals.

Secondary Outcome Measures

Development of relapsed disease
Relapse is measured by evidence of recurrent disease in the blood, marrow, or lymph nodes. Summarized using Kaplan-Meier curves and the respective Kaplan-Meier estimates of the 2-year event rate are reported as well as their 95% confidence intervals.
Engraftment
Measure by chimerism studies of the blood and marrow at multiple time points after the HSCT. Chimerism refers to the percentage of donor cells in the hematopoietic system of the patient post HSCT. Reported using mean and standard deviations.
Immune reconstitution
Evaluated by T-cell recovery and B-cell recovery. Assessed by the quantitative measurement of CD3/4 and CD3/8 cells and immunoglobulin levels in the blood at multiple time points post HSCT. CD3/4 and CD3/8 counts are measured by an immune reconstitution panel and immunoglobulin levels are measured by a quantitative immunoglobulin assay. Reported using mean and standard deviations
Incidence and degree of graft versus host disease (GVHD) after HSCT
Assessment includes presence and degree of skin rash, presence and amount of diarrhea, and/or abnormal liver function test. Summarized using Kaplan-Meier curves and the respective Kaplan-Meier estimates of the 2-year event rate are reported as well as their 95% confidence intervals.

Full Information

First Posted
August 31, 2021
Last Updated
December 13, 2022
Sponsor
Thomas Jefferson University
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1. Study Identification

Unique Protocol Identification Number
NCT05031897
Brief Title
Reduced-Intensity Conditioning for the Prevention of Treatment-Related Mortality in Patients Who Undergo a Hematopoietic Stem Cell Transplant
Official Title
A 2 Step Approach to Haploidentical Transplant Using Radiation-Based Reduced Intensity Conditioning
Study Type
Interventional

2. Study Status

Record Verification Date
December 2022
Overall Recruitment Status
Recruiting
Study Start Date
October 25, 2021 (Actual)
Primary Completion Date
October 1, 2024 (Anticipated)
Study Completion Date
October 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Thomas Jefferson University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This phase II clinical trial evaluates whether a modified modality of conditioning reduces treatment-related mortality (TRM) in patients who undergo a hematopoietic stem cell transplant (HSCT) for a hematological malignancy. HSCT is a curative therapy for many hematopoietic malignancies, however this regimen results in higher rates of TRM than other forms of treatment. In recent years, less intense conditioning regimens with radiation and chemotherapy prior to HSCT have been developed. Radiation therapy uses high energy sources to kill cancer cells and shrink tumors while chemotherapy drugs like fludarabine and cyclophosphamide work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. This study evaluates whether a two-step approach with lower-intensity regimens of these treatments prior to HSCT reduces the rate of TRM.
Detailed Description
PRIMARY OBJECTIVE: I. To assess the 2 year cumulative incidence of TRM in patients undergoing reduced intensity conditioning (RIC) haploidentical (HI) HSCT in this protocol. SECONDARY OBJECTIVES: I. To assess the 2 year cumulative incidence of relapse in patients undergoing RIC HI HSCT in this protocol. II. To assess the consistency and pace of engraftment. III. To assess the pace of T cell and B cell immune recovery. IV. To assess the incidence and severity of graft versus host disease (GVHD). OUTLINE: Patients are assigned to 1 of 2 cohorts. RADIATION-BASED COHORT: Patients receive fludarabine intravenously (IV) on days -11, -10, -9, and -8, undergo total-body irradiation (TBI) twice a day (BID) on days -10 and -9, undergo donor lymphocyte infusion (DLI) on day -6, and receive cyclophosphamide IV on days -3 and -2. Patients begin tacrolimus and mycophenolate mofetil IV on day -1. Patients then undergo HSCT on day 0. Treatment continues in the absence of disease progression or unacceptable toxicity. CHEMOTHERAPY-BASED COHORT: Patients receive fludarabine IV on days -11, -10, -9, and -8 and melphalan IV on days -10 and -9. Patients undergo TBI and DLI once on day -6. Patients receive cyclophosphamide IV on days -3 and -2 and begin tacrolimus and mycophenolate mofetil on day -1. Patients undergo HSCT on day 0. Treatment continues in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed for 2 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Aplastic Anemia, Chronic Lymphocytic Leukemia, Chronic Myelomonocytic Leukemia, Essential Thrombocythemia, Hematopoietic and Lymphoid Cell Neoplasm, Hodgkin Lymphoma, Myelodysplastic Syndromes, Myelofibrosis, Myeloid Leukemia, Myeloid Neoplasm, Non-Hodgkin Lymphoma, Plasma Cell Myeloma, Polycythemia Vera, Small Lymphocytic Lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
67 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Radiation-Based Cohort (fludarabine, TBI, infusion)
Arm Type
Experimental
Arm Description
Patients receive fludarabine IV on days -11, -10, -9, and -8, undergo TBI BID on days -10 and -9, undergo DLI on day -6, and receive cyclophosphamide IV on days -3 and -2. Patients begin tacrolimus and mycophenolate mofetil IV on day -1. Patients then undergo HSCT on day 0. Treatment continues in the absence of disease progression or unacceptable toxicity.
Arm Title
Chemotherapy-Based Cohort (fludarabine, melphalan, TBI)
Arm Type
Experimental
Arm Description
Patients receive fludarabine IV on days -11, -10, -9, and -8 and melphalan IV on days -10 and -9. Patients undergo TBI and DLI once on day -6. Patients receive cyclophosphamide IV on days -3 and -2 and begin tacrolimus and mycophenolate mofetil on day -1. Patients undergo hematopoietic stem cell transplant on day 0.
Intervention Type
Procedure
Intervention Name(s)
Hematopoietic Cell Transplantation
Other Intervention Name(s)
HCT, Hematopoietic Stem Cell Infusion, Hematopoietic Stem Cell Transplantation, HSCT, Stem Cell Transplant
Intervention Description
Undergo HSCT
Intervention Type
Drug
Intervention Name(s)
Mycophenolate Mofetil
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Tacrolimus
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Intervention Description
Given IV
Intervention Type
Radiation
Intervention Name(s)
Total-Body Irradiation
Intervention Description
Undergo TBI
Intervention Type
Procedure
Intervention Name(s)
Donor Lymphocyte Infusion
Intervention Description
Undergo DLI
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Melphalan
Intervention Description
Given IV
Primary Outcome Measure Information:
Title
Incidence of treatment-related mortality (TRM)
Description
TRM is defined as death without evidence of recurrent disease in the 2 year period post HSCT. Summarized using Kaplan-Meier curves and the respective Kaplan-Meier estimates of the 2-year event rate are reported as well as their 95% confidence intervals.
Time Frame
At 2 years post hematopoietic stem cell transplant (HSCT)
Secondary Outcome Measure Information:
Title
Development of relapsed disease
Description
Relapse is measured by evidence of recurrent disease in the blood, marrow, or lymph nodes. Summarized using Kaplan-Meier curves and the respective Kaplan-Meier estimates of the 2-year event rate are reported as well as their 95% confidence intervals.
Time Frame
Up to 2 years
Title
Engraftment
Description
Measure by chimerism studies of the blood and marrow at multiple time points after the HSCT. Chimerism refers to the percentage of donor cells in the hematopoietic system of the patient post HSCT. Reported using mean and standard deviations.
Time Frame
Up to 2 years
Title
Immune reconstitution
Description
Evaluated by T-cell recovery and B-cell recovery. Assessed by the quantitative measurement of CD3/4 and CD3/8 cells and immunoglobulin levels in the blood at multiple time points post HSCT. CD3/4 and CD3/8 counts are measured by an immune reconstitution panel and immunoglobulin levels are measured by a quantitative immunoglobulin assay. Reported using mean and standard deviations
Time Frame
Up to 2 years
Title
Incidence and degree of graft versus host disease (GVHD) after HSCT
Description
Assessment includes presence and degree of skin rash, presence and amount of diarrhea, and/or abnormal liver function test. Summarized using Kaplan-Meier curves and the respective Kaplan-Meier estimates of the 2-year event rate are reported as well as their 95% confidence intervals.
Time Frame
Up to 2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Radiation-based cohort diagnoses: Acute myeloid leukemia Acute lymphoid leukemia in remission Myelodysplasia (MDS) Chronic lymphocytic leukemia (CLL) with no or minimal lymph node involvement Multiple myeloma Chronic myeloid leukemia Myelofibrosis Myeloid malignancy not otherwise specified Chronic myelomonocytic leukemia Essential thrombocytopenia or polycythemia vera T cell leukemia T cell lymphoma without significant lymph node disease burden Any hematological malignancy or dyscrasia not cited above in which HSCT is potentially curable * Any patient who has a hematological disease that would normally be treated on a myeloablative study, but is prevented from doing so by factors in their past medical history. Examples are patients with previous treatment with radiation therapy precluding total-body irradiation (TBI), or a past history of myeloablative therapy, precluding a 2nd myeloablative regimen. Patients must have a donor who is one-haplotype mismatched (number of mismatches in either direction not considered) Chemotherapy-based cohort diagnoses: Hodgkin or non-Hodgkin lymphoma Small lymphocytic lymphoma/CLL Any other diagnosis in which chemotherapy is thought to be superior to radiotherapy for treatment of the disease Hematological malignancy in patients who cannot receive > 2 Gy radiation * Aplastic anemia and other non-malignant hematologic dyscrasias Patients must have a donor who is one-haplotype mismatched (number of mismatches in either direction not considered) HLA identical cohort diagnoses: * Patients in this group will be treated in parallel to the radiation-based cohort or the chemotherapy-based group based on what category their diagnosis falls into. However, these patients will have HLA identical related donors (one-antigen cross-over event included). Left ventricular ejection fraction of >= 50% Diffusion lung capacity of oxygen >= 50% and forced expiratory volume at 1 second >= 50% of predicted corrected for hemoglobin Adequate liver function as defined by a serum bilirubin =< 1.8, aspartate aminotransferase or alanine aminotransferase =< 2.5 x upper limit of normal Creatinine clearance of >= 60 mL/min Patients must have adequate Karnofsky performance status (KPS) and hematopoietic cell transplantation-comorbidity index (HCT-CI) scores: Patients < age 60 years must have a KPS of >= 80% and an HCT-CI score of 5 or less Patients aged 60 to 65 years must have a KPS of >= 80% and an HCT-CI score of 4 or less Patients aged 66 to 69 years must have a KPS of 90% and an HCT-CI score of 3 or less * Patients aged 70 years or more must have a KPS of 90% and an HCT-CI score of 2 or less (Patients with greater than the allowable HCT-CI points for age can be enrolled for trial with approval of the principal investigator and at least 1 co-investigator not on the primary care team of the patient). This is an adjustment to account for healthy patients who meet the spirit of this protocol but have histories that result in higher than guideline HCT-CI points. An example is a patient with a solid tumor malignancy in their remote history (adds 3 points to HCT-CI total) where the treatment for the malignancy occurred years to decades before and there has been complete recovery of toxicities Patients must be willing to use contraception if they have childbearing potential Patient or patient's guardian is able to give informed consent Patients should have a life expectancy of >= 6 months for reasons other than their underlying hematologic/oncologic disorder Exclusion Criteria: Patients with evidence of another malignancy, exclusive of a skin cancer that requires only local treatment, should not be enrolled on this protocol Patients should not be: Human immunodeficiency virus positive Have active involvement of the central nervous system with malignancy. This can be documented by a normal neurological exam, magnetic resonance imaging (MRI) of the head, and/or a negative cerebral spinal fluid analysis Pregnant or breastfeeding
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Usama Gergis, MD
Phone
215-503-2455
Email
usama.gergis@jefferson.edu
Facility Information:
Facility Name
Sidney Kimmel Cancer Center at Thomas Jefferson University
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19107
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Usama Gergis, MD
Phone
215-503-2455
Email
usama.gergis@jefferson.edu

12. IPD Sharing Statement

Learn more about this trial

Reduced-Intensity Conditioning for the Prevention of Treatment-Related Mortality in Patients Who Undergo a Hematopoietic Stem Cell Transplant

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