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Study of Fludarabine Based Conditioning for Allogeneic Stem Cell Transplantation for Myelofibrosis

Primary Purpose

Myelofibrosis

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Fludarabine, Melphalan +/- ATG
Sponsored by
John Mascarenhas
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Myelofibrosis focused on measuring Myelofibrosis, Myeloproliferative disease, Stem Cell Transplant, Allogeneic Transplant, Conditioning Regimen, Reduced Intensity Regimen, Fludarabine, Melphalan, ATG

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients with the following disease: Idiopathic myelofibrosis, or spent PV-, or ET-related myelofibrosis in chronic phase (<20% blast cells in the bone marrow) with Lille score >1 at any time, or platelet <100K.
  • Age 18-65 years.
  • ECOG performance status < 3.
  • Life expectancy >3 months.
  • Adequate cardiac function, normal LVEF ≥ 45% by MUGA or echocardiogram and adequate pulmonary function DLCO ≥ 50% of predicted.
  • Serum creatinine < 1.1 x the upper limit of normal (ULN) or Creatinine Clearance >50 ml/min.
  • Serum bilirubin < 2.0 mg/dl, SGPT <2.5 x upper limit of normal
  • No evidence of chronic active hepatitis or cirrhosis
  • HIV-negative
  • Patient is not pregnant
  • Patient or guardian able to sign informed consent.
  • Patients with >20% myeloblasts in the blood or marrow, extramedullary blast cell proliferation or large foci of blasts in bone marrow biopsy specimens are not eligible.
  • Pretransplant splenectomy: MMM patients with variable degrees of splenomegaly, or splenectomized, are eligible to be enrolled. Any decision of having a patient splenectomized prior to transplant will be made in each center prior to enrolling the patient in the study.
  • Patients should be off treatment with investigational for at least 4 weeks and have recovered from all toxicities.

Exclusion Criteria:

  • Pregnancy
  • HIV positive
  • > 20% myeloblasts in the peripheral blood or bone marrow
  • LVEF < 45%
  • DLCO < 50% of predicted
  • ECOG performance status ≥ 3
  • Chronic active hepatitis or cirrhosis
  • Chronic renal insufficiency

Sites / Locations

  • University of Illinois at Chicago
  • Johns Hopkins
  • Roswell Park Cancer Institute
  • Icahn School of Medicine at Mount Sinai
  • Weill Cornell Medical College
  • Ohio State Univesity
  • University of Utah
  • Princess Margaret Hospital
  • University of Florence
  • Ospedali Riuniti di Bergamo
  • University of San Martino
  • Regionala etikprovningsnamnden Goteborg

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Fludarabine, Melphalan +/- ATG

Arm Description

Fludarabine, Melphalan +/- ATG

Outcomes

Primary Outcome Measures

The Primary Endpoint is Progression-free Survival.
Number of participants alive at 2 years who are progression-free

Secondary Outcome Measures

Response Outcomes
assessed according to the IWG Criteria
Overall Survival
The number of patients alive at last follow-up.
Absolute Neutrophil Count (ANC)
Patients with ANC ≥0.5 × 10^9/L
PLT
Patients with PLT ≥20 × 109/L
Transplant-related Mortality
Transplant-related Mortality including Graft-versus-host disease (GVHD)

Full Information

First Posted
December 11, 2007
Last Updated
April 7, 2017
Sponsor
John Mascarenhas
Collaborators
National Institutes of Health (NIH), Myeloproliferative Disorders-Research Consortium, National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00572897
Brief Title
Study of Fludarabine Based Conditioning for Allogeneic Stem Cell Transplantation for Myelofibrosis
Official Title
Study of Fludarabine Based Conditioning for Allogeneic Stem Cell Transplantation for Myelofibrosis
Study Type
Interventional

2. Study Status

Record Verification Date
April 2017
Overall Recruitment Status
Completed
Study Start Date
August 2007 (undefined)
Primary Completion Date
August 2011 (Actual)
Study Completion Date
June 15, 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
John Mascarenhas
Collaborators
National Institutes of Health (NIH), Myeloproliferative Disorders-Research Consortium, National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Stem cell transplantation is used to treat may types of diseases. There a 2 types of transplants, conventional (very intense) and reduced intensity-non-myeloablative, also called mini-transplants. This study proposes to use a conditioning regimen for allogeneic transplantation along with a reduced intensity transplant. Conditioning regiment is the name for the combination of chemotherapy drugs that is given to patients before receiving a transplantation of donor stem cells. It is hoped that the regimen designed for this study proves to be less toxic and has an equal or better anticancer effect than the regimens that are normally used. The regimen being used is a combination of two chemotherapy drugs, fludarabine and melphalan. This regimen has been studied in recipients of matched sibling transplants and in recipients of alternative donor stem cells in other hematologic malignancies. Those subjects, who receive stem cells from an unrelated donor, will also receive and additional drug called ATG or anti thymocyte globulin. ATG suppresses the immune system, thus reducing the chances for the recipient rejecting the transplant (graft). The purpose of this study is to observe if reduced intensity transplants can be used to allow engraftment or "take" of the donor's bone marrow. Studies conducted in the past show this type of transplant is much less toxic than traditional bone marrow transplants. Reduced intensity transplants may be better tolerated by patients who may experience serious side effects from standard (very intense) stem cell transplant. The study has been recently amended to follow all subjects for survival.
Detailed Description
This study is designed as a single arm Phase II clinical trial in patients with myelofibrosis who are eligible for transplantation from a related donor or from an unrelated donor source. Patients will be accrued into two separate strata defined by donor type. Each of the two strata will be analyzed separately. Patients will be followed yearly from time of enrollment into the study to assess clinical response and overall, progression and event free survival, as well as incidence and degree of acute and chronic GVHD. We will estimate cumulative survival and transplant related mortality in patients enrolled in each of the two strata.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myelofibrosis
Keywords
Myelofibrosis, Myeloproliferative disease, Stem Cell Transplant, Allogeneic Transplant, Conditioning Regimen, Reduced Intensity Regimen, Fludarabine, Melphalan, ATG

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
66 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Fludarabine, Melphalan +/- ATG
Arm Type
Experimental
Arm Description
Fludarabine, Melphalan +/- ATG
Intervention Type
Drug
Intervention Name(s)
Fludarabine, Melphalan +/- ATG
Intervention Description
Conditioning regimen for Allogenic Stem Cell Transplant: Related Donor Fludarabine days -6 to -2 (30mg/m2 IVPB over 30 minutes daily) Melphalan days -3 to -2 (70mg/m2 IVPB over 30 minutes daily) Unrelated Donor Fludarabine days -6 to -2 (30mg/m2 IVPB over 30 minutes daily) Melphalan days -3 to -2 (70mg/m2 IVPB over 30 minutes daily) ATG (Thymoglobulin®) days -3 to -1 (0.5 mg/kg IV on day -3 [given over 6 hours], and 2 mg/kg on days -2 and -1 [given over 4 hours])
Primary Outcome Measure Information:
Title
The Primary Endpoint is Progression-free Survival.
Description
Number of participants alive at 2 years who are progression-free
Time Frame
2 years
Secondary Outcome Measure Information:
Title
Response Outcomes
Description
assessed according to the IWG Criteria
Time Frame
180 days
Title
Overall Survival
Description
The number of patients alive at last follow-up.
Time Frame
73 months
Title
Absolute Neutrophil Count (ANC)
Description
Patients with ANC ≥0.5 × 10^9/L
Time Frame
2 years
Title
PLT
Description
Patients with PLT ≥20 × 109/L
Time Frame
2 years
Title
Transplant-related Mortality
Description
Transplant-related Mortality including Graft-versus-host disease (GVHD)
Time Frame
2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with the following disease: Idiopathic myelofibrosis, or spent PV-, or ET-related myelofibrosis in chronic phase (<20% blast cells in the bone marrow) with Lille score >1 at any time, or platelet <100K. Age 18-65 years. ECOG performance status < 3. Life expectancy >3 months. Adequate cardiac function, normal LVEF ≥ 45% by MUGA or echocardiogram and adequate pulmonary function DLCO ≥ 50% of predicted. Serum creatinine < 1.1 x the upper limit of normal (ULN) or Creatinine Clearance >50 ml/min. Serum bilirubin < 2.0 mg/dl, SGPT <2.5 x upper limit of normal No evidence of chronic active hepatitis or cirrhosis HIV-negative Patient is not pregnant Patient or guardian able to sign informed consent. Patients with >20% myeloblasts in the blood or marrow, extramedullary blast cell proliferation or large foci of blasts in bone marrow biopsy specimens are not eligible. Pretransplant splenectomy: MMM patients with variable degrees of splenomegaly, or splenectomized, are eligible to be enrolled. Any decision of having a patient splenectomized prior to transplant will be made in each center prior to enrolling the patient in the study. Patients should be off treatment with investigational for at least 4 weeks and have recovered from all toxicities. Exclusion Criteria: Pregnancy HIV positive > 20% myeloblasts in the peripheral blood or bone marrow LVEF < 45% DLCO < 50% of predicted ECOG performance status ≥ 3 Chronic active hepatitis or cirrhosis Chronic renal insufficiency
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
John Mascarenhas, MD
Organizational Affiliation
Icahn School of Medicine at Mount Sinai
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Giovanni Barosi, MD
Organizational Affiliation
Myeloproliferative Disorders-Research Consortium
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Damiano Rondelli, MD
Organizational Affiliation
Myeloproliferative Disorders-Research Consortium
Official's Role
Study Chair
Facility Information:
Facility Name
University of Illinois at Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States
Facility Name
Johns Hopkins
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21205
Country
United States
Facility Name
Roswell Park Cancer Institute
City
Buffalo
State/Province
New York
ZIP/Postal Code
14263
Country
United States
Facility Name
Icahn School of Medicine at Mount Sinai
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
Facility Name
Weill Cornell Medical College
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
Ohio State Univesity
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Facility Name
University of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States
Facility Name
Princess Margaret Hospital
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G2M9
Country
Canada
Facility Name
University of Florence
City
Florence
State/Province
IL
ZIP/Postal Code
60302
Country
Italy
Facility Name
Ospedali Riuniti di Bergamo
City
Bergamo
ZIP/Postal Code
24128
Country
Italy
Facility Name
University of San Martino
City
San Martino
Country
Italy
Facility Name
Regionala etikprovningsnamnden Goteborg
City
Goteborg
ZIP/Postal Code
60302
Country
Sweden

12. IPD Sharing Statement

Citations:
PubMed Identifier
24963042
Citation
Rondelli D, Goldberg JD, Isola L, Price LS, Shore TB, Boyer M, Bacigalupo A, Rambaldi A, Scarano M, Klisovic RB, Gupta V, Andreasson B, Mascarenhas J, Wetzler M, Vannucchi AM, Prchal JT, Najfeld V, Orazi A, Weinberg RS, Miller C, Barosi G, Silverman LR, Prosperini G, Marchioli R, Hoffman R. MPD-RC 101 prospective study of reduced-intensity allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis. Blood. 2014 Aug 14;124(7):1183-91. doi: 10.1182/blood-2014-04-572545. Epub 2014 Jun 24.
Results Reference
result

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Study of Fludarabine Based Conditioning for Allogeneic Stem Cell Transplantation for Myelofibrosis

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