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

Primary Purpose

Hematologic Malignancies, Acute Leukemia, Myelodysplastic Syndromes (MDS) Other Than RA or RARS Subtypes

Status

Terminated

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Fludarabine

Thiotepa

Total Body Irradiation (TBI)

Donor Lymphocyte Infusion (DLI)

Melphalan

Hematopoietic stem cell transplantation (HSCT)

About this trial

This is an interventional treatment trial for Hematologic Malignancies focused on measuring allogeneic HSCT, Hematopoietic stem cell transplantation

Eligibility Criteria

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

Inclusion Criteria:

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
Patients must have a related donor who is at least a 4 antigen match at the HLA-A; B; C; DR loci.
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
Performance status > or = 80% (TJU Karnofsky) for patients > or = 60 years old or > or = 70% for patients < 60.
HCT-CI Score < or = 4 points for patients > or = 60 years old or < or = 5 points for patients < 60.
Patients must be willing to use contraception if they have childbearing potential
Able to give informed consent

Exclusion Criteria:

Performance status < 80% (TJU Karnofsky) for patients > or = 60 years old or < 70% for patients < 60.
HCT-CI Score > 4 points for patients > or = 60 years old or > 5 points for patients < 60.
HIV positive
Active involvement of the central nervous system with malignancy
Inability to obtain informed consent
Pregnancy
Patients with life expectancy of < 6 months for reasons other than their underlying hematologic/oncologic disorder
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
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.

Sites / Locations

Thomas Jefferson University

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Transplant Treatment Group

Arm Description

All patients treated on this research study.

Outcomes

Primary Outcome Measures

Phase 1: Defined Dose of Melphalan (MEL)

To define the dose of MEL required for the establishment of peripheral T cell tolerance with concomitant immune reconstitution.

Phase 2: Non-Relapse Mortality (NRM)

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

Relapse Rate

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.

GVHD Incidence and Severity

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.

Engraftment Rate and Lymphoid Reconstitution

To evaluate engraftment rates and lymphoid reconstitution in patients treated on this trial.

Overall Survival

To assess overall survival in patients undergoing HSCT treated on this trial.

Full Information

NCT ID

NCT01350258

First Posted

May 4, 2011

Last Updated

November 28, 2016

Sponsor

Sidney Kimmel Cancer Center at Thomas Jefferson University

1. Study Identification

Unique Protocol Identification Number

NCT01350258

Brief Title

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

Official Title

A Two Step Approach to Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation for Hematologic Malignancies Using Melphalan for T-Cell Tolerization

Study Type

Interventional

2. Study Status

Record Verification Date

October 2016

Overall Recruitment Status

Terminated

Why Stopped

Poor accrual

Study Start Date

April 2011 (undefined)

Primary Completion Date

May 2012 (Actual)

Study Completion Date

August 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Sidney Kimmel Cancer Center at Thomas Jefferson University

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

Keywords

allogeneic HSCT, Hematopoietic stem cell transplantation

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

8 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Transplant Treatment Group

Arm Type

Experimental

Arm Description

All patients treated on this research study.

Intervention Type

Drug

Intervention Name(s)

Fludarabine

Other Intervention Name(s)

fludarabine phosphate, Fludara

Intervention Description

Part of the conditioning regimen

Intervention Type

Drug

Intervention Name(s)

Thiotepa

Other Intervention Name(s)

N,N'N'-triethylenethiophosphoramide

Intervention Description

Part of the conditioning regimen

Intervention Type

Radiation

Intervention Name(s)

Total Body Irradiation (TBI)

Other Intervention Name(s)

radiotherapy

Intervention Description

There is one fraction of total body irradiation (2Gy) as part of the conditioning regimen.

Intervention Type

Biological

Intervention Name(s)

Donor Lymphocyte Infusion (DLI)

Other Intervention Name(s)

buffy coat fusion

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Melphalan

Other Intervention Name(s)

MEL, Melphalan hydrochloride, Alkeran

Intervention Description

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.

Intervention Type

Device

Intervention Name(s)

Hematopoietic stem cell transplantation (HSCT)

Other Intervention Name(s)

CliniMACS

Intervention Description

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.

Primary Outcome Measure Information:

Title

Phase 1: Defined Dose of Melphalan (MEL)

Description

To define the dose of MEL required for the establishment of peripheral T cell tolerance with concomitant immune reconstitution.

Time Frame

100 days post-transplant

Title

Phase 2: Non-Relapse Mortality (NRM)

Description

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.

Time Frame

100 days post-treatment

Secondary Outcome Measure Information:

Title

Relapse Rate

Description

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.

Time Frame

At 1 and 3 years

Title

GVHD Incidence and Severity

Description

Time Frame

At 1 and 3 years

Title

Engraftment Rate and Lymphoid Reconstitution

Description

To evaluate engraftment rates and lymphoid reconstitution in patients treated on this trial.

Time Frame

100 days post-transplant

Title

Overall Survival

Description

To assess overall survival in patients undergoing HSCT treated on this trial.

Time Frame

At 1 and 3 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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 Patients must have a related donor who is at least a 4 antigen match at the HLA-A; B; C; DR loci. 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 Performance status > or = 80% (TJU Karnofsky) for patients > or = 60 years old or > or = 70% for patients < 60. HCT-CI Score < or = 4 points for patients > or = 60 years old or < or = 5 points for patients < 60. Patients must be willing to use contraception if they have childbearing potential Able to give informed consent Exclusion Criteria: Performance status < 80% (TJU Karnofsky) for patients > or = 60 years old or < 70% for patients < 60. HCT-CI Score > 4 points for patients > or = 60 years old or > 5 points for patients < 60. HIV positive Active involvement of the central nervous system with malignancy Inability to obtain informed consent Pregnancy Patients with life expectancy of < 6 months for reasons other than their underlying hematologic/oncologic disorder 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 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Dolores Grosso, DNP, CRNP

Organizational Affiliation

Thomas Jefferson University

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Neal Flomenberg, MD

Organizational Affiliation

Thomas Jefferson University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Thomas Jefferson University

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19107

Country

United States

12. IPD Sharing Statement

Links:

URL

http://www.JeffersonHospital.org/

Description

Thomas Jefferson University Hospitals

Learn more about this trial

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

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