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Intensity Modulated Total Marrow Irradiation, Fludarabine Phosphate, and Melphalan in Treating Patients With Relapsed Hematologic Cancers Undergoing a Second Donor Stem Cell Transplant

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ClinicalTrials.gov Identifier: NCT02333162
Recruitment Status : Recruiting
First Posted : January 7, 2015
Last Update Posted : May 1, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
University of Chicago

Brief Summary:
This phase I trial studies the side effects and the best dose of intensity modulated total marrow irradiation (IMTMI) when given together with fludarabine phosphate and melphalan in treating patients with cancers of the blood (hematologic) that have returned after a period of improvement (relapsed) undergoing a second donor stem cell transplant. IMTMI is a type of radiation therapy to the bone marrow that may be less toxic and may also reduce the chances of cancer to return. Giving fludarabine phosphate, melphalan, and IMTMI before a donor stem cell transplant may help stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets.

Condition or disease Intervention/treatment Phase
Previously Treated Myelodysplastic Syndrome Recurrent Adult Acute Lymphoblastic Leukemia Recurrent Adult Acute Myeloid Leukemia Recurrent Hematologic Malignancy Drug: Fludarabine Phosphate Drug: Melphalan Radiation: Intensity-Modulated Radiation Therapy Radiation: Total Marrow Irradiation Procedure: Allogeneic Hematopoietic Stem Cell Transplantation Procedure: Peripheral Blood Stem Cell Transplantation Procedure: Allogeneic Bone Marrow Transplantation Drug: Tacrolimus Drug: Mycophenolate Mofetil Other: Laboratory Biomarker Analysis Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. The determine the maximum tolerated dose (MTD) of intensity-modulate total marrow irradiation (IMTMI) in combination with fludarabine (fludarabine phosphate)/melphalan as conditioning for second allogeneic stem cell transplantation for patients with hematologic malignancies.

SECONDARY OBJECTIVES:

I. To determine the overall toxicity and day 100 transplant related mortality after second allogeneic hematopoietic stem cell transplantation conditioned with increasing doses of intensity-modulate total marrow irradiation (IMTMI) in combination with fludarabine/melphalan.

II. To determine the time to neutrophil and platelet engraftment after second allogeneic hematopoietic stem cell transplantation conditioned with increasing doses of intensity-modulate total marrow irradiation (IMTMI) in combination with fludarabine/melphalan.

III. To determine the overall survival (OS) and event-free-survival (EFS) in patients with hematologic undergoing second allogeneic hematopoietic stem cell transplant (HSCT) after conditioning with fludarabine/melphalan and IMTMI.

OUTLINE: This is a dose-escalation study of IMTMI.

CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes daily on days -7 to -3 and melphalan IV on day -2. Patients also undergo IMTMI twice daily (BID) for 2 to 5 days between days -7 to -3.

TRANSPLANT: Patients undergo allogeneic peripheral blood stem cell transplant (PBSCT) or bone marrow transplant (BMT) on day 0.

GRAFT-VERSUS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients receive tacrolimus IV continuously over 24 hours or orally (PO) BID on days -2 to 180 with taper thereafter and mycophenolate mofetil IV every 8 hours or PO on days 0-28 (for matched donors) or days 0-40 (for alternative donors) with taper to day 60.

After completion of treatment, patients are followed up periodically for 1 year and then yearly for 2 years.


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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 Phase I Study of Intensity Modulated Total Marrow Irradiation (IMTMI) in Addition to Fludarabine/Melphalan Conditioning for Allogeneic Transplantation for Advanced Hematologic Malignancies
Actual Study Start Date : December 5, 2014
Estimated Primary Completion Date : December 1, 2020
Estimated Study Completion Date : December 1, 2022


Arm Intervention/treatment
Experimental: Treatment (IMTMI, combination chemotherapy, PBSCT or BMT)

CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes daily on days -7 to -3 and melphalan IV on day -2. Patients also undergo IMTMI BID for 2 to 5 days between days -7 to -3.

TRANSPLANT: Patients undergo allogeneic PBSCT or BMT on day 0.

GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously over 24 hours or PO BID on days -2 to 180 with taper thereafter and mycophenolate mofetil IV every 8 hours or PO on days 0-28 (for matched donors) or days 0-40 (for alternative donors) with taper to day 60.

Drug: Fludarabine Phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • SH T 586

Drug: Melphalan
Given IV
Other Name: Alkeran

Radiation: Intensity-Modulated Radiation Therapy
Undergo IMTMI
Other Names:
  • IMRT
  • Intensity Modulated RT
  • Intensity-Modulated Radiotherapy

Radiation: Total Marrow Irradiation
Undergo IMTMI

Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic PBSCT
Other Names:
  • HSC
  • HSCT

Procedure: Peripheral Blood Stem Cell Transplantation
Undergo allogeneic PBSCT
Other Names:
  • PBPC transplantation
  • Peripheral Blood Progenitor Cell Transplantation
  • Peripheral Stem Cell Support
  • Peripheral Stem Cell Transplantation

Procedure: Allogeneic Bone Marrow Transplantation
Undergo allogeneic BMT
Other Names:
  • Allo BMT
  • Allogeneic BMT

Drug: Tacrolimus
Given IV or PO
Other Names:
  • Advagraf
  • FK 506

Drug: Mycophenolate Mofetil
Given IV or PO
Other Names:
  • Cellcept
  • MMF

Other: Laboratory Biomarker Analysis
Correlative studies




Primary Outcome Measures :
  1. MTD of conditioning regimen defined as any grade III or higher dose-limiting toxicity, graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 30 days post second allo-SCT ]

Secondary Outcome Measures :
  1. Overall incidence of adverse events, graded according to the NCI CTCAE version 4.0 [ Time Frame: Up to 2 years ]
  2. Transplant related mortality [ Time Frame: Day 100 ]
  3. Time to neutrophil engraftment [ Time Frame: First day in which the ANC is > 500/mm^3 for 3 consecutive days ]
  4. Time to platelet engraftment [ Time Frame: First day the platelet count is > 20,000/mm^3 without transfusion support for 7 consecutive days ]
  5. overall survival (OS) [ Time Frame: Up to 2 years ]
  6. event-free-survival (EFS) [ Time Frame: Up to 2 years ]


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with the following diseases: acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MDS) undergoing second allogeneic (allo)-stem cell transplant (SCT) using the same donor or different donor for disease relapse; patients with other hematologic malignancies, including acute lymphoblastic leukemia (ALL), will be at the discretion of the investigators
  • Karnofsky performance status of 70 or above
  • Life expectancy is not severely limited by concomitant illness
  • Adequate cardiac and pulmonary function; patients with decreased left ventricular ejection fraction (LVEF) =< 40% or diffusion capacity of carbon monoxide (DLCO) =< 50% of predicted will be evaluated by cardiology or pulmonary prior to enrollment on this protocol
  • Serum creatinine =<1.5 mg/dL or creatinine clearance > 50 ml/min; some patients with minor deviations may be accepted on protocol after discussion with the principal investigator (PI)
  • Serum bilirubin =< 2.0 mg/dl; some patients with minor deviations may be accepted on protocol after discussion with the PI
  • Serum glutamic oxaloacetic transaminase (SGPT) < 5 x upper limit of normal; some patients with minor deviations may be accepted on protocol after discussion with the PI
  • No evidence of chronic active hepatitis or cirrhosis
  • Human immunodeficiency virus (HIV)-negative
  • Patient is not pregnant
  • Patient or guardian able to sign informed consent
  • DONOR: Since these patients already had first allo-SCT; in the majority time, the same matched donor has been used for second allo-SCT; if the patients have multiple donors, alternative matched (8/8 or 10/10) donor could be used for the second allo-SCT; the donor could be matched related donors or matched unrelated donors from registry
  • DONOR: If more than one potential volunteer unrelated donor is considered suitable, further selection of the most suitable donor will be prioritized as follows or will follow our institutional guideline from our stem cell transplant standard operating procedure (SOP):

    • Age of donor (18-24 > 25-34 > 35-44 > 45+)
    • Sex of donor (male > female, nulliparous female > parous, multiparous female)
    • Cytomegalovirus (CMV) status, if recipient is CMV seronegative (CMV- > CMV+

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): NCT02333162


Locations
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United States, Illinois
University of Chicago Comprehensive Cancer Center Recruiting
Chicago, Illinois, United States, 60637
Contact: Hongtao Liu    773-834-0589    hliu2@medicine.bsd.uchicago.edu   
Principal Investigator: Hongtao Liu         
Sponsors and Collaborators
University of Chicago
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Hongtao Liu University of Chicago Comprehensive Cancer Center

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Responsible Party: University of Chicago
ClinicalTrials.gov Identifier: NCT02333162     History of Changes
Other Study ID Numbers: IRB14-0709
NCI-2014-02469 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
IRB14-0709 ( Other Identifier: University of Chicago Comprehensive Cancer Center )
P30CA014599 ( U.S. NIH Grant/Contract )
First Posted: January 7, 2015    Key Record Dates
Last Update Posted: May 1, 2019
Last Verified: April 2019

Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid, Acute
Neoplasms
Myelodysplastic Syndromes
Preleukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Leukemia, Myeloid
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Tacrolimus
Fludarabine phosphate
Melphalan
Mycophenolic Acid
Fludarabine
Vidarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antimetabolites, Antineoplastic