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

A Phase I Study of Intensity Modulated Total Marrow Irradiation (IMTMI) in Addition to Fludarabine/Melphalan Conditioning for Allogeneic Transplantation for Advanced Hematologic Malignancies

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.

Study Overview

• Status: Suspended
• Conditions: Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Hematologic Malignancy
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Drug: Melphalan; Drug: Fludarabine Phosphate; Drug: Tacrolimus; Drug: Mycophenolate Mofetil; Procedure: Peripheral Blood Stem Cell Transplantation; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Procedure: Allogeneic Bone Marrow Transplantation; Radiation: Intensity-Modulated Radiation Therapy; Radiation: Total Marrow Irradiation

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.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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+

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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.

Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Melphalan; Given IV; Other Names: Alkeran; Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; SH T 586; Drug: Tacrolimus; Given IV or PO; Other Names: FK 506; Advagraf; Drug: Mycophenolate Mofetil; Given IV or PO; Other Names: Cellcept; MMF; 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 Hematopoietic Stem Cell Transplantation; Undergo allogeneic PBSCT; Other Names: HSC; HSCT; Procedure: Allogeneic Bone Marrow Transplantation; Undergo allogeneic BMT; Other Names: Allo BMT; Allogeneic BMT; Radiation: Intensity-Modulated Radiation Therapy; Undergo IMTMI; Other Names: IMRT; Intensity Modulated RT; Intensity-Modulated Radiotherapy; Radiation: Total Marrow Irradiation; Undergo IMTMI

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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	Up to 30 days post second allo-SCT

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: University of Chicago
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Hongtao Liu, University of Chicago Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): December 5, 2014
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: January 5, 2015
• First Submitted That Met QC Criteria: January 6, 2015
• First Posted (Estimated): January 7, 2015

Study Record Updates

• Last Update Posted (Actual): March 30, 2026
• Last Update Submitted That Met QC Criteria: March 24, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Leukemia, Myeloid; Leukemia, Lymphoid; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Hematologic Neoplasms; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Amino Acids, Peptides, and Proteins; Organic Chemicals; Therapeutics; Fatty Acids; Lipids; Surgical Procedures, Operative; Hydrocarbons; Acids, Acyclic; Carboxylic Acids; Transplantation; Amino Acids; Macrolides; Lactones; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Radiotherapy; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Radiotherapy, Conformal; Radiotherapy, Computer-Assisted; Caproates; Stem Cell Transplantation; Hematopoietic Stem Cell Transplantation; Melphalan; Mycophenolic Acid; Tacrolimus; fludarabine phosphate; Radiotherapy, Intensity-Modulated; Peripheral Blood Stem Cell Transplantation
• Other Study ID Numbers: IRB14-0709 (Other Identifier: University of Chicago Comprehensive Cancer Center); P30CA014599 (U.S. NIH Grant/Contract); NCI-2014-02469 (Registry Identifier: CTRP (Clinical Trial Reporting Program))