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Reduced Intensity Chemotherapy and Radiation Therapy Before Donor Stem Cell Transplant in Treating Patients With Hematologic Malignancies

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ClinicalTrials.gov Identifier: NCT02566304
Recruitment Status : Recruiting
First Posted : October 2, 2015
Last Update Posted : April 11, 2019
Sponsor:
Information provided by (Responsible Party):
Thomas Jefferson University ( Sidney Kimmel Cancer Center at Thomas Jefferson University )

Brief Summary:
This clinical trial studies the use of reduced intensity chemotherapy and radiation therapy before donor stem cell transplant in treating patients with hematologic malignancies. Giving low doses of chemotherapy, such as cyclophosphamide and fludarabine phosphate, before a donor stem cell transplant may help 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). Reducing the intensity of the chemotherapy and radiation may also reduce the side effects of the donor stem cell transplant.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Acute Myeloid Leukemia in Remission Aplastic Anemia Chronic Myelomonocytic Leukemia Hodgkin Lymphoma Indolent Non-Hodgkin Lymphoma Malignant Neoplasm Myelodysplastic Syndrome Myeloproliferative Neoplasm Plasma Cell Myeloma Refractory Anemia Refractory Anemia With Excess Blasts Refractory Anemia With Ring Sideroblasts Refractory Cytopenia With Multilineage Dysplasia Refractory Cytopenia With Multilineage Dysplasia and Ring Sideroblasts Drug: Fludarabine Radiation: Total-Body Irradiation Biological: T Cell-Depleted Donor Lymphocyte Infusion Drug: Cyclophosphamide Procedure: Peripheral Blood Stem Cell Transplantation Procedure: Allogeneic Hematopoietic Stem Cell Transplantation Drug: Tacrolimus Drug: Mycophenolate mofetil Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To demonstrate efficacy of this approach over the historical 2 step reduced intensity conditioning (RIC) approaches in the "vulnerable" population defined as: patients with hematopoietic cell transplant (HCT)-co-morbidity index (CI)/age scores >= 2, but no more than a score of 5 as based on the Sorror et al. data.

SECONDARY OBJECTIVES:

I. To compare the non-relapse mortality (NRM) and relapse related mortality (RRM) rates at 1 year for patients treated on this study to the that of patients undergoing haploidentical RIC hematopoietic stem cell transplantation (HSCT) as reported in the literature and as observed in the 2 step RIC trials.

II. To determine the incidence and severity of graft-versus-host disease (GVHD) in patients undergoing treated on the Thomas Jefferson University (TJU) RIC 2 step approach.

III. To evaluate engraftment rates and lymphoid reconstitution in patients treated on the TJU RIC 2 step approach.

OUTLINE:

RIC: Patients receive fludarabine phosphate intravenously (IV) over 60 minutes on days -10 to -8 and cyclophosphamide IV over 2 hours on days -3 and -2. Patients also undergo total body irradiation (TBI) followed by a donor lymphocyte infusion (DLI) on day -6.

TRANSPLANT: Patients undergo cluster of differentiation (CD)34+ peripheral blood stem cell transplant on day 0.

GVHD PROPHYLAXIS: Patients receive tacrolimus orally (PO) beginning day -1 with a taper initiated on day 42 and mycophenolate mofetil IV twice daily (BID) on days -1 to 28 in the absence of GVHD.

After completion of study treatment, patients are followed up for 1 year.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Two Step Approach to Non-Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation for Patients With Hematologic Malignancies
Actual Study Start Date : November 13, 2015
Estimated Primary Completion Date : April 23, 2020
Estimated Study Completion Date : January 2021


Arm Intervention/treatment
Experimental: RIC HSCT, GVHD prophylaxis

RIC: Patients receive fludarabine phosphate IV on days -10 to -8 and cyclophosphamide IV on days -3 and -2. Patients also undergo TBI followed by a DLI on day -7.

TRANSPLANT: Patients undergo CD34+ peripheral blood stem cell transplant on day 0.

GVHD PROPHYLAXIS: Patients receive tacrolimus PO beginning day -1 with a taper initiated on day 42 and mycophenolate mofetil IV BID on days -1 to 28 in the absence of GVHD.

Drug: Fludarabine
Given IV
Other Names:
  • Fludarabine phosphate
  • Fludara

Radiation: Total-Body Irradiation
Undergo TBI

Biological: T Cell-Depleted Donor Lymphocyte Infusion
Undergo DLI

Drug: Cyclophosphamide
Given IV
Other Names:
  • Endoxan
  • Cytoxan
  • Neosar
  • Procytox
  • Revimmune
  • Cycloblastin
  • Cytophosphane
  • CP

Procedure: Peripheral Blood Stem Cell Transplantation
Undergo PBSC transplant

Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Undergo PBSC transplant

Drug: Tacrolimus
Given PO
Other Names:
  • FK-506
  • Fujimycin
  • Prograf
  • Advograf
  • Protopic

Drug: Mycophenolate mofetil
Given IV
Other Names:
  • Mycophenolic acid
  • MMF
  • CellCept
  • Myfortic




Primary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: At 1 year post HSCT ]
    OS will be estimated using Kaplan-Meier curves. The 1-year OS rate and corresponding 95% confidence interval will be estimated from the Kaplan-Meier curve for the OS.


Secondary Outcome Measures :
  1. Relapse Related Mortality (RRM) [ Time Frame: At 1 year post HSCT ]
    Will be reported descriptively. RRM may also be estimated using Kaplan Meier curves and/or cumulative incidence analyses.

  2. Non-Relapse Mortality (NRM) [ Time Frame: At 1 year post HSCT ]
    Will be reported descriptively. NRM may also be estimated using Kaplan Meier curves and/or cumulative incidence analyses.

  3. Incidence and severity of GVHD [ Time Frame: Up to 1 year post HSCT ]
    Will be reported descriptively

  4. Engraftment rates [ Time Frame: Up to 1 year post HSCT ]
    Will be reported descriptively

  5. Lymphoid reconstitution [ Time Frame: Up to 1 year post HSCT ]
    Lymphoid reconstitution will be evaluated monthly to every other month during the first year post HSCT and will be reported descriptively.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients treated on this study will have:

    1. Acute myeloid leukemia in morphologic CR not requiring treatment for their disease for 6 weeks
    2. A history of AML with < 20% residual blasts after induction therapy and persisting with <20% blasts for at least 8 weeks without reinduction.
    3. RA or RARS or isolated 5q- can proceed to transplant without any treatment
    4. RAEB-1, RCMD+/-RS, or MDS NOS with stable disease for 6 months (as documented by serial bone marrow examinations) in the absence of any therapy but growth factors or transfusion support. Patients who require treatment to "control their disease" must show chemo-responsiveness
    5. CMML or RAEB-2 must demonstrate chemo-responsiveness. Chemo-responsiveness is defined as a blast percentage decrease by at least 5 percentage points and there must be less than 20% blasts after treatment and at the time of transplant
    6. Hodgkin or Indolent Non-Hodgkin's lymphoma
    7. Myeloma with < 5% plasma cells in the marrow
    8. Myeloproliferative disorders
    9. Aplastic Anemia
    10. A hematological or oncological disease (not listed) in which allogeneic HSCT is thought to be beneficial, and the disease is chemoresponsive.
    11. Patients without clear manifestation of their disease status in terms of stage and/or responsiveness should be discussed with the PI and enrollment analysis should be documented in the study records.
  2. Patients must have a related donor who is HLA mismatched at 2, 3, or 4 antigens at the HLA-A; B; C; DR loci in the GVHD direction. (Patients with related donors who are HLA identical or are a 1-antigen mismatch may be treated on this therapeutic approach, but will have their outcomes will not be part of the statistical aims of the study (see Statistical Section). The HLA matched related category includes patients with a syngeneic donor.
  3. Patients must have had front line therapy for their disease.
  4. Patients must adequate organ function:

    1. LVEF (Left ventricular end diastolic function) of >/=45%.
    2. DLCO (Diffusing Capacity of the Lung for Carbon Monoxide ) ≥45% of predicted corrected for hemoglobin, FEV-1 (forced expiratory volume at 1 second ≥50% of predicted
    3. Adequate liver function as defined by a serum bilirubin <1.8, AST or ALT < 2.5X upper limit of normal
    4. Creatinine Clearance of ≥ 60 mL/min
  5. HCT-CI/Age Score ≤ 5 points (Patients with greater than 5 points will be allowed for trial with approval of the PI and the Co-PI or his designee. This is an adjustment to account for healthy patients who meet the spirit of this protocol but have histories that result in higher than HCT-CI 5 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.
  6. KPS≥ 90% patients older than 70 years, KPS≥ 80% patients younger than 70 years
  7. Patients must be willing to use contraception if they have childbearing potential

Exclusion Criteria:

  1. Performance status < 90% in patients 70 years old or greater, <80% in patients less than age 70 years
  2. HCT-CI/age Score >5 points (Patients with greater than 5 points will be allowed for trial with approval of the Principal Investigator and the Co-Principal Investigator or his designee. This is an adjustment to account for healthy patients who meet the spirit of this protocol but have histories that result in higher than HCT-CI 5 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.
  3. A diagnosis of CMML, unless in morphologic CR
  4. HIV positive
  5. Active involvement of the central nervous system with malignancy
  6. Inability to obtain informed consent from patient or surrogate
  7. Pregnancy
  8. Patients with life expectancy of < 6 months for reasons other than their underlying hematologic/oncologic disorder
  9. Patients who have received alemtuzumab or antithymocyte globulin within 8 weeks of the transplant admission. The absence of these therapies in the medical record will serve as documentation that they were not given.
  10. Patients with evidence of another malignancy, exclusive of a skin cancer that requires only local treatment, should not be enrolled on this protocol

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02566304


Contacts
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Contact: Dolores Grosso, DNP, CRNP 215-955-8874

Locations
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United States, Pennsylvania
Thomas Jefferson University Recruiting
Philadelphia, Pennsylvania, United States, 19107
Contact: Dolores Grosso, DNP, CRNP    215-955-8874      
Principal Investigator: Dolores Grosso, DNP, CRNP         
Principal Investigator: Neal Flomenberg, MD         
Sub-Investigator: S. Onder Alpdogan, MD         
Sub-Investigator: Matthew Carabasi, MD         
Sub-Investigator: Joanne Filicko-O'Hara, MD         
Sub-Investigator: Margaret Kasner, MD         
Sub-Investigator: Thomas Klumpp, MD         
Sub-Investigator: William O'Hara, PharmD         
Sub-Investigator: Ubaldo Martinez Outschoorn, MD         
Sub-Investigator: Manish Sharma, MD         
Sub-Investigator: John Wagner, MD         
Sub-Investigator: Mark Weiss, MD         
Sponsors and Collaborators
Sidney Kimmel Cancer Center at Thomas Jefferson University
Investigators
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Principal Investigator: Dolores Grosso, DNP, CRNP Thomas Jefferson University
Principal Investigator: Neal Flomenberg, MD Thomas Jefferson University

Additional Information:
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Responsible Party: Sidney Kimmel Cancer Center at Thomas Jefferson University
ClinicalTrials.gov Identifier: NCT02566304     History of Changes
Other Study ID Numbers: 15D.323
2015-054 ( Other Identifier: PRC )
NCI-2015-01506 ( Other Identifier: NCI Trial ID )
First Posted: October 2, 2015    Key Record Dates
Last Update Posted: April 11, 2019
Last Verified: April 2019

Additional relevant MeSH terms:
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Lymphoma
Leukemia
Neoplasms
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Anemia
Myelodysplastic Syndromes
Preleukemia
Lymphoma, Non-Hodgkin
Hodgkin Disease
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Anemia, Aplastic
Myeloproliferative Disorders
Anemia, Refractory
Anemia, Refractory, with Excess of Blasts
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Hematologic Diseases
Bone Marrow Diseases
Precancerous Conditions
Myelodysplastic-Myeloproliferative Diseases
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases