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Bone Marrow Transplant Using a Reduced Intensity Regimen That is Given in Two Steps

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01350258
Recruitment Status : Terminated (Poor accrual)
First Posted : May 9, 2011
Results First Posted : October 24, 2014
Last Update Posted : November 29, 2016
Information provided by (Responsible Party):
Thomas Jefferson University ( Sidney Kimmel Cancer Center at Thomas Jefferson University )

Brief Summary:

This is a research study involving the treatment of patients with hematological cancers with allogeneic (cells from a donor) hematopoietic stem cell transplant (HSCT). HSCT is often referred to as bone marrow transplant. Patients who are not expected to have long term survival after conventional therapy will undergo HSCT as a curative therapy after receiving front line therapy for their disease. This project is based on an HSCT approach that has been used at TJU since 2006 with the goal of optimizing this type of treatment further. In this new study, the investigators will substitute the chemotherapy agent, Melphalan (Mel), for cyclophosphamide (CY). Cyclophosphamide was used in the original trial. The research question is whether side effects are less using Mel and if donor T cells can be made tolerant to the recipient with the use of Mel. The proposed study is also more specific in terms of performance status and organ function entry criterion. The investigators observed in the original trial that patients with poor performance upon admission for transplant did not have as good outcomes.

Because many older patients are treated according to this type of transplant, the chemotherapy and radiation used are less intensive than other types of transplant. The name for this in the transplant field is a reduced intensity hematopoietic stem cell transplant. The abbreviations most used in this document are RIC for reduced intensity conditioning, HSCT which refers to the transplant itself, and MEL which refers to the drug, Melphalan.

Condition or disease Intervention/treatment Phase
Hematologic Malignancies Acute Leukemia Myelodysplastic Syndromes (MDS) Other Than RA or RARS Subtypes Hodgkin's Lymphoma Non-Hodgkin's Lymphoma Myeloma Chronic Myelogenous (or Myeloid) Leukemia (CML) Resistant to STI Therapy Drug: Fludarabine Drug: Thiotepa Radiation: Total Body Irradiation (TBI) Biological: Donor Lymphocyte Infusion (DLI) Drug: Melphalan Device: Hematopoietic stem cell transplantation (HSCT) Phase 1 Phase 2

Detailed Description:

Twenty-nine patients in the Thomas Jefferson University (TJU) Blood and Marrow Transplantation Program have been treated on the research protocol, A Two Step Approach To Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation for Hematologic Malignancies from HLA Partially-Matched Related Donors (TJU 2 Step RIC, TJU IRB# 06U.328) as of July, 2010. While treatment on this protocol has resulted in durable responses for many older patients and younger, heavily pretreated patients with hematological malignancies, poor performance status at the time of transplant and morbidities related to cyclophosphamide (CY) administration in the regimen have contributed to decreased survival. In addition, disease relapse after hematopoietic stem cell transplantation (HSCT) has been a major cause of mortality for those patients with disease at the time of transplant.

The objective of this research is to improve patient outcomes after treatment on the TJU 2 Step RIC protocol by refining the approach based on outcomes observed in the initial trial. More thorough assessment of performance status prior to HSCT and the substitution of the alkylating agent Melphalan (MEL) for CY to decrease CY-related toxicity while strengthening the anti-leukemic intensity of the regimen for patients with poor-risk disease will be the major strategies used to increase the efficacy of the regimen. MEL has shown efficacy against myeloid malignancies when used in conditioning in RIC HSCT. Patients with AML and MDS were the most common group treated on the initial TJU 2 Step RIC trial and also comprise the largest patient group treated in the TJU Medical Oncology Program.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 8 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Two Step Approach to Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation for Hematologic Malignancies Using Melphalan for T-Cell Tolerization
Study Start Date : April 2011
Actual Primary Completion Date : May 2012
Actual Study Completion Date : August 2012

Arm Intervention/treatment
Experimental: Transplant Treatment Group
All patients treated on this research study.
Drug: Fludarabine
Part of the conditioning regimen
Other Names:
  • fludarabine phosphate
  • Fludara

Drug: Thiotepa
Part of the conditioning regimen
Other Name: N,N'N'-triethylenethiophosphoramide

Radiation: Total Body Irradiation (TBI)
There is one fraction of total body irradiation (2Gy) as part of the conditioning regimen.
Other Name: radiotherapy

Biological: Donor Lymphocyte Infusion (DLI)
Immediately following the conditioning regimen of fludarabine, thiotepa, and TBI, the patient receives a set dose of their donor's T cells (DLI), After the DLI, the donor's T cells will react with the remaining parts of the recipients immune system.
Other Name: buffy coat fusion

Drug: Melphalan
Two days after the DLI, Melphalan will be given to eliminate the reacting T cells to avoid graft versus host disease. Non-activated T cells should not be affected by the Melphalan and remain to help fight infection.
Other Names:
  • MEL
  • Melphalan hydrochloride
  • Alkeran

Device: Hematopoietic stem cell transplantation (HSCT)

One day after the Melphalan ends, the patient will receive their donor's stem cells. This is the actual day of transplant.

The CliniMACS® Plus Instrument will be used for the selection of human CD34+ hematopoietic stem and progenitor cells in human allogeneic hematopoietic stem cell transplantation.

Other Name: CliniMACS

Primary Outcome Measures :
  1. Phase 1: Defined Dose of Melphalan (MEL) [ Time Frame: 100 days post-transplant ]
    To define the dose of MEL required for the establishment of peripheral T cell tolerance with concomitant immune reconstitution.

  2. Phase 2: Non-Relapse Mortality (NRM) [ Time Frame: 100 days post-treatment ]
    To evaluate the 100 day non-relapse mortality (NRM) rate in patients undergoing HSCT treated on this successor TJU 2 Step RIC haploidentical regimen and compare it with that of the initial regimen.

Secondary Outcome Measures :
  1. Relapse Rate [ Time Frame: At 1 and 3 years ]
    To compare relapse rates in patients undergoing HSCT treated on this successor TJU 2 Step RIC haploidentical regimen and compare it with that of the initial regimen.

  2. GVHD Incidence and Severity [ Time Frame: At 1 and 3 years ]
    To determine the incidence and severity of graft-versus-host disease (GVHD) in patients undergoing treatment on this regimen using MEL for T cell tolerization as well as tacrolimus and mycophenolate mofetil (MMF) as GVHD prophylaxis.

  3. Engraftment Rate and Lymphoid Reconstitution [ Time Frame: 100 days post-transplant ]
    To evaluate engraftment rates and lymphoid reconstitution in patients treated on this trial.

  4. Overall Survival [ Time Frame: At 1 and 3 years ]
    To assess overall survival in patients undergoing HSCT treated on this trial.

Information from the National Library of Medicine

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

Inclusion Criteria:

  1. Any patient with a high-risk hematologic or oncologic diagnosis in which allogeneic HSCT is thought to be beneficial, and in whom front-line therapy has already been applied. High risk is defined as:

    • Acute leukemia in 3rd or greater CR or with persistent disease
    • Myelodysplastic syndrome (MDS) other than RA or RARS subtypes.
    • Hodgkin's or Non-Hodgkin's lymphoma in 3rd or greater remission or with persistent disease.
    • Myeloma in 3rd or greater remission or with less than PR to most recent therapy.
    • Chronic myelogenous (or myeloid) leukemia (CML) resistant to STI therapy
  2. Patients must have a related donor who is at least a 4 antigen match at the HLA-A; B; C; DR loci.
  3. Patients must adequate organ function:

    • LVEF of > or = 50%
    • DLCO > or = 50% of predicted corrected for hemoglobin
    • Adequate liver function as defined by a serum bilirubin < or = 1.8, AST or ALT < or = 2.5X upper limit of normal
    • GFR of > or = 60 mL/min/1.73m2
  4. Performance status > or = 80% (TJU Karnofsky) for patients > or = 60 years old or > or = 70% for patients < 60.
  5. HCT-CI Score < or = 4 points for patients > or = 60 years old or < or = 5 points for patients < 60.
  6. Patients must be willing to use contraception if they have childbearing potential
  7. Able to give informed consent

Exclusion Criteria:

  1. Performance status < 80% (TJU Karnofsky) for patients > or = 60 years old or < 70% for patients < 60.
  2. HCT-CI Score > 4 points for patients > or = 60 years old or > 5 points for patients < 60.
  3. HIV positive
  4. Active involvement of the central nervous system with malignancy
  5. Inability to obtain informed consent
  6. Pregnancy
  7. Patients with life expectancy of < 6 months for reasons other than their underlying hematologic/oncologic disorder
  8. Patients who have received alemtuzumab within 8 weeks of the transplant admission, or who have recently received horse or rabbit ant-thymocyte globulin and have an ATG level of > or = 2 ugm/ml
  9. Patients with evidence of another malignancy, exclusive of a skin cancer that requires only local treatment, should not be enrolled on this protocol

Donor Selection All donors are selected and screened for their ability to provide adequate infection-free apheresis products for the patient in a manner that does not put the donor at risk for negative consequences. Donor selection will be in compliance with 21 CFR 1271 and TJU BMT Program SOP CP: P009.03.

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 identifier (NCT number): NCT01350258

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United States, Pennsylvania
Thomas Jefferson University
Philadelphia, Pennsylvania, United States, 19107
Sponsors and Collaborators
Sidney Kimmel Cancer Center at Thomas Jefferson University
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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 Identifier: NCT01350258     History of Changes
Other Study ID Numbers: 10D.535
2010-40 ( Other Identifier: CCRRC )
First Posted: May 9, 2011    Key Record Dates
Results First Posted: October 24, 2014
Last Update Posted: November 29, 2016
Last Verified: October 2016
Keywords provided by Thomas Jefferson University ( Sidney Kimmel Cancer Center at Thomas Jefferson University ):
allogeneic HSCT
Hematopoietic stem cell transplantation
Additional relevant MeSH terms:
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Myelodysplastic Syndromes
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Bone Marrow Diseases
Hematologic Diseases
Fludarabine phosphate
Antineoplastic Agents
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antiviral Agents
Anti-Infective Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Myeloablative Agonists