Chemotherapy, Total Body Irradiation, and Post-Transplant Cyclophosphamide in Reducing Rates of Graft Versus Host Disease in Patients With Hematologic Malignancies Undergoing Donor Stem Cell Transplant

A Phase Ib/2 Trial of Fludarabine/Melphalan/Total Body Irradiation With Post Transplant Cyclophosphamide as Graft Versus Host Disease Prophylaxis in Matched-Related and Matched-Unrelated Allogeneic Hematopoietic Cell Transplantation

This phase Ib/2 trial studies how well chemotherapy, total body irradiation, and post-transplant cyclophosphamide work in reducing rates of graft versus host disease in patients with hematologic malignancies undergoing a donor stem cell transplant. Drugs used in the chemotherapy, such as fludarabine phosphate and melphalan hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy and total-body irradiation before a donor stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer 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. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells (called graft versus host disease). Giving cyclophosphamide after the transplant may stop this from happening.

Study Overview

• Status: Active, not recruiting
• Conditions: Hodgkin Lymphoma; Waldenstrom Macroglobulinemia; Non-Hodgkin Lymphoma; Myelodysplastic Syndrome; Plasma Cell Myeloma; Myeloproliferative Neoplasm; Minimal Residual Disease; Graft Versus Host Disease; Severe Aplastic Anemia; Acute Myeloid Leukemia in Remission; Adult Acute Lymphoblastic Leukemia in Complete Remission; Chronic Myelogenous Leukemia, BCR-ABL1 Positive in Remission; Chronic Myelomonocytic Leukemia in Remission
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Drug: Cyclophosphamide; Radiation: Total-Body Irradiation; Drug: Fludarabine Phosphate; Drug: Mycophenolate Mofetil; Drug: Melphalan Hydrochloride; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Sirolimus

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the cumulative incidence of extensive chronic graft versus host disease (GVHD) at 1 year after transplantation utilizing the novel conditioning/GVHD prophylactic regimen for patients undergoing allogeneic hematopoietic cell transplantation, in patients who do not progress before day 100.

SECONDARY OBJECTIVES:

I. To evaluate clinical response, engraftment rate, progression-free survival (PFS) at one year and, overall survival (OS).

II. To determine the cumulative incidence of relapse. III. To evaluate the day 100 transplant-related mortality rate. IV. To determine the cumulative incidence of grade III-IV acute GVHD.

OUTLINE: This is a dose-escalation study of melphalan hydrochloride.

CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -5 to -2 and melphalan hydrochloride IV over 30 minutes on day -2. Patients undergo total body irradiation (TBI) on day -1.

STEM CELL INFUSION: Patients undergo allogeneic hematopoietic stem cell transplant on day 0.

GVHD PROPHYLAXIS REGIMEN: Patients receive cyclophosphamide IV over 2 hours on days 3-4, mycophenolate mofetil IV over 2 hours on days 5-35, and tacrolimus IV and then orally (PO) once tolerated on days 5-180 with a taper beginning on day 100.

After completion of study treatment, patients are followed up for 12 months and then annually thereafter.

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• The patient must have a diagnosis of one of the following (one must be yes):

  • Acute myeloid leukemia (AML)
  • Acute lymphoblastic leukemia (ALL)
  • Chronic lymphoblastic leukemia (CLL)
  • Chronic myelogenous leukemia (CML) (chronic phase intolerant or unresponsive to tyrosine kinase inhibitors, accelerated phase, history of blast crisis)
  • Myelodysplastic syndrome (MDS)
  • Non-Hodgkin lymphoma (NHL)
  • Hodgkin lymphoma (HL) (received and failed frontline therapy or failed autologous transplantation or inability to collect enough peripheral blood stem cells [PBSC] for autologous hematopoietic cell transplant [auto-HCT])
  • Multiple myeloma (MM)
  • Severe aplastic anemia

• Histocompatible donor identified:

  • Related donor matched 5/6 or better (A, B, DRB1)
  • Unrelated donor matched 7/8 or better (A, B, C and DRB1)
• Patients with severe aplastic anemia do not have disease requirements; however, if the patient has a mismatched donor, the patient must have had prior therapy with ATG.

The following are eligible for study inclusion:

• Patients with MDS/MPN only require <5% myeloblast on bone marrow evaluation.
• Patients with AML, ALL or CLL may be in CRi, patients with MM may be in VGPR

• Patients with NHL/HL must be in CR

  • Have a Karnofsky performance status score of > 50%
  • Diffusing capacity of the lung for carbon monoxide (DLCO) > 40% predicted, corrected for hemoglobin and/or alveolar ventilation
  • Left ventricular ejection fraction > 40%
  • Bilirubin =< 3 x upper limit of normal
  • Liver alkaline phosphatase =< 3 x upper limit of normal
  • Serum glutamic-oxaloacetic transaminase (SGOT) or serum glutamate pyruvate transaminase (SGPT) =< 3 x upper limit of normal
  • Calculated creatinine clearance > 40 cc/min by the modified Cockroft-Gault formula
  • Patient must be cleared pre-transplant by Radiation Oncology to be able to receive 400 cGy
  • Participants of child-bearing potential must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
  • Patients who have failed a prior autologous or allogeneic transplant are eligible; however, at least 6 months must have elapsed between the start of this reduced intensity conditioning regimen and the last transplant if patient had a prior autologous or myeloablative allogeneic bone marrow transplant (BMT)
  • At least 2 weeks since prior radiation treatment and/or surgery. Appropriate washout of prior chemotherapy per BMT standard of care. If medication is not on the list, go by physician discretion
  • Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure

Exclusion Criteria:

• Moderate to severe myelofibrosis within 60 days prior to transplant
• Presence of human leukocyte antigen (HLA) antibodies to the donor within 60 days prior to transplant
• Patients who in the opinion of the treating physician are unlikely to comply with the restrictions of allogeneic stem cell transplantation based on formal psychosocial screening. (i.e., serious, uncontrolled psychiatric illness/social situations that would limit compliance with study requirements)
• Uncontrolled diabetes mellitus, cardiovascular disease, active serious infection or other condition which, in the opinion of treating physician, would make this protocol unreasonably hazardous for the patient
• Known human immunodeficiency virus (HIV) positive
• Pregnant or nursing female participants
• Unwilling or unable to follow protocol requirements
• Any condition which in the Investigator's opinion deems the participant an unsuitable candidate to receive study intervention

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: <=50 years of age Cohort A; CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes on days -5 to -2 and 50mg/m2 melphalan hydrochloride IV over 30 minutes on day -2. Patients undergo TBI on day -1. STEM CELL INFUSION: Patients undergo allogeneic hematopoietic stem cell transplant on day 0. GVHD PROPHYLAXIS REGIMEN: Patients receive cyclophosphamide IV over 2 hours on days 3-4, mycophenolate mofetil IV over 2 hours on days 5-35, and sirolimus IV and then PO once tolerated on days 5-180 with a taper beginning on day 100.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Radiation: Total-Body Irradiation; Undergo TBI; Other Names: Whole-Body Irradiation; TOTAL BODY IRRADIATION; Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; Fludara; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; SH T 586; Drug: Mycophenolate Mofetil; Given IV; Other Names: Cellcept; MMF; Drug: Melphalan Hydrochloride; Given IV; Other Names: Alkeran; Evomela; Alkerana; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Undergo allogeneic hematopoietic stem cell transplant; Other Names: HSC; HSCT; allogeneic stem cell transplantation; Drug: Sirolimus; Given IV and PO; Other Names: Rapamune
Experimental: <=50 years of age Cohort B; Patients receive fludarabine phosphate IV over 30 minutes on days -5 to -2 and melphalan hydrochloride IV over 30 minutes on day -2. Patients undergo TBI on day -1. Patients recieve 75 mg/m2 Melphalan STEM CELL INFUSION: Patients undergo allogeneic hematopoietic stem cell transplant on day 0. GVHD PROPHYLAXIS REGIMEN: Patients receive cyclophosphamide IV over 2 hours on days 3-4, mycophenolate mofetil IV over 2 hours on days 5-35, and sirolimus IV and then PO once tolerated on days 5-180 with a taper beginning on day 100.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Radiation: Total-Body Irradiation; Undergo TBI; Other Names: Whole-Body Irradiation; TOTAL BODY IRRADIATION; Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; Fludara; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; SH T 586; Drug: Mycophenolate Mofetil; Given IV; Other Names: Cellcept; MMF; Drug: Melphalan Hydrochloride; Given IV; Other Names: Alkeran; Evomela; Alkerana; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Undergo allogeneic hematopoietic stem cell transplant; Other Names: HSC; HSCT; allogeneic stem cell transplantation; Drug: Sirolimus; Given IV and PO; Other Names: Rapamune
Experimental: >50 years of age Cohort A -25 mg/m2 Melphalan; Following the administration of Fludarabine 40 mg/m2/day on Days -5 to -2.75 mg/m2 Patients receive 25 mg/m2 Melphalan STEM CELL INFUSION: Patients undergo allogeneic hematopoietic stem cell transplant on day 0. GVHD PROPHYLAXIS REGIMEN: Patients receive cyclophosphamide IV over 2 hours on days 3-4, mycophenolate mofetil IV over 2 hours on days 5-35, and sirolimus IV and then PO once tolerated on days 5-180 with a taper beginning on day 100.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Radiation: Total-Body Irradiation; Undergo TBI; Other Names: Whole-Body Irradiation; TOTAL BODY IRRADIATION; Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; Fludara; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; SH T 586; Drug: Mycophenolate Mofetil; Given IV; Other Names: Cellcept; MMF; Drug: Melphalan Hydrochloride; Given IV; Other Names: Alkeran; Evomela; Alkerana; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Undergo allogeneic hematopoietic stem cell transplant; Other Names: HSC; HSCT; allogeneic stem cell transplantation; Drug: Sirolimus; Given IV and PO; Other Names: Rapamune
Experimental: >50 years of age Cohort B 50 mg/m2 Melphalan; Following the administration of Fludarabine 40 mg/m2/day on Days -5 to -2, Patients receive 50 mg/m2 Melphalan STEM CELL INFUSION: Patients undergo allogeneic hematopoietic stem cell transplant on day 0. GVHD PROPHYLAXIS REGIMEN: Patients receive cyclophosphamide IV over 2 hours on days 3-4, mycophenolate mofetil IV over 2 hours on days 5-35, and sirolimus IV and then PO once tolerated on days 5-180 with a taper beginning on day 100.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Radiation: Total-Body Irradiation; Undergo TBI; Other Names: Whole-Body Irradiation; TOTAL BODY IRRADIATION; Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; Fludara; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; SH T 586; Drug: Mycophenolate Mofetil; Given IV; Other Names: Cellcept; MMF; Drug: Melphalan Hydrochloride; Given IV; Other Names: Alkeran; Evomela; Alkerana; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Undergo allogeneic hematopoietic stem cell transplant; Other Names: HSC; HSCT; allogeneic stem cell transplantation; Drug: Sirolimus; Given IV and PO; Other Names: Rapamune
Experimental: >50 years of age Cohort C .75 mg/m2 Melphalan; Following the administration of Fludarabine 40 mg/m2/day on Days -5 to -2, patients receive 75 mg/m2 Melphalan STEM CELL INFUSION: Patients undergo allogeneic hematopoietic stem cell transplant on day 0. GVHD PROPHYLAXIS REGIMEN: Patients receive cyclophosphamide IV over 2 hours on days 3-4, mycophenolate mofetil IV over 2 hours on days 5-35, and sirolimus IV and then PO once tolerated on days 5-180 with a taper beginning on day 100.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Radiation: Total-Body Irradiation; Undergo TBI; Other Names: Whole-Body Irradiation; TOTAL BODY IRRADIATION; Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; Fludara; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; SH T 586; Drug: Mycophenolate Mofetil; Given IV; Other Names: Cellcept; MMF; Drug: Melphalan Hydrochloride; Given IV; Other Names: Alkeran; Evomela; Alkerana; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Undergo allogeneic hematopoietic stem cell transplant; Other Names: HSC; HSCT; allogeneic stem cell transplantation; Drug: Sirolimus; Given IV and PO; Other Names: Rapamune

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Extensive Chronic Graft Versus Host Disease (GVHD)	Percentage of chronic GVHD of response by human leukocyte antigen (HLA) matching by cohort	Up to 365 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Response Assessed as Per Bone Marrow Transplant (BMT) Standard of Care	Patients who achieved a clinical response will be summarized descriptively using frequency counts	Up to 4 years
Cumulative Incidence of Grade III-IV Acute Graft Versus Host Disease (GVHD)	Will be analyzed in a descriptive fashion with means +/- standard deviations or frequency counts. Will examine in a post-hoc analysis potential chronic GVHD rates of response by human leukocyte antigen (HLA) matching status.	Up to 4 years
Cumulative Incidence of Relapse	Will be analyzed in a descriptive fashion with frequency counts.	Up to 4 years
Engraftment Rate Assessed as Per Bone Marrow Transplant (BMT) Standard of Care	Will be analyzed in a descriptive fashion with frequency counts.	Up to 4 years
Overall Survival Assessed as Per Bone Marrow Transplant (BMT) Standard of Care	Will utilize either straight Kaplan-Meier based estimators or extensions of nonparametric survival models to account for competing risks.	Up to 4 years
1-Year Progression Free Survival (PFS) Rate Assessed as Per Bone Marrow Transplant (BMT) Standard of Care	Will utilize either straight Kaplan-Meier based estimators or extensions of nonparametric survival models to account for competing risks.	At 1 year
Treatment-related Mortality Rates	Count of participants that died by cohort.	All-Cause Mortality monitored/assessed up to 4 years. Adverse Events monitored/assessed from the start date of the conditioning regimen (Day -5) until 30 days after stem cell infusion will be reported, up to 12 months.

Collaborators and Investigators

• Sponsor: Roswell Park Cancer Institute
• Investigators: Principal Investigator: Maureen Ross, Roswell Park Cancer Institute

Study record dates

Study Major Dates

• Study Start (Actual): August 9, 2017
• Primary Completion (Actual): August 21, 2023
• Study Completion (Estimated): May 21, 2027

Study Registration Dates

• First Submitted: June 16, 2017
• First Submitted That Met QC Criteria: June 16, 2017
• First Posted (Actual): June 20, 2017

Study Record Updates

• Last Update Posted (Actual): April 14, 2026
• Last Update Submitted That Met QC Criteria: April 1, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Bone Marrow Failure Disorders; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Neoplasms; Chronic Disease; Disease Attributes; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Neoplastic Processes; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma; Leukemia, Myeloid; Bone Marrow Diseases; Neoplasms, Plasma Cell; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders; Anemia; Leukemia; Pathological Conditions, Signs and Symptoms; Hemic and Lymphatic Diseases; Neoplasm, Residual; Multiple Myeloma; Lymphoma, Non-Hodgkin; Myelodysplastic Syndromes; Myeloproliferative Disorders; Hodgkin Disease; Anemia, Aplastic; Graft vs Host Disease; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Waldenstrom Macroglobulinemia; Amino Acids, Peptides, and Proteins; Organic Chemicals; Investigative Techniques; Therapeutics; Fatty Acids; Lipids; Hydrocarbons; Acids, Acyclic; Carboxylic Acids; Amino Acids; Macrolides; Lactones; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Radiotherapy; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Caproates; Sirolimus; Cyclophosphamide; Melphalan; Mycophenolic Acid; fludarabine phosphate; Whole-Body Irradiation
• Other Study ID Numbers: I 44417 (Other Identifier: Roswell Park Cancer Institute); NCI-2017-01069 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No