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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

Primary Purpose

Acute Myeloid Leukemia in Remission, Adult Acute Lymphoblastic Leukemia in Complete Remission, Chronic Myelogenous Leukemia, BCR-ABL1 Positive in Remission

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Allogeneic Hematopoietic Stem Cell Transplantation
Cyclophosphamide
Fludarabine Phosphate
Laboratory Biomarker Analysis
Melphalan Hydrochloride
Mycophenolate Mofetil
Sirolimus
Total-Body Irradiation
Sponsored by
Roswell Park Cancer Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia in Remission

Eligibility Criteria

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

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

Sites / Locations

  • Roswell Park Cancer Institute

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Prevention (chemotherapy, TBI, cyclophosphamide)

Arm Description

CONDITIONING REGIMEN: 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. 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.

Outcomes

Primary Outcome Measures

Extensive chronic graft versus host disease (GVHD)
Will be analyzed for each stratum. Will examine in a post-hoc analysis potential chronic GVHD rates of response by human leukocyte antigen (HLA) matching status.

Secondary Outcome Measures

Clinical response 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.
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.
Cumulative incidence of relapse
Will be analyzed in a descriptive fashion with means +/- standard deviations or frequency counts.
Engraftment rate assessed as per bone marrow transplant (BMT) standard of care
Will be analyzed in a descriptive fashion with means +/- standard deviations or frequency counts.
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.
Progression free survival (PFS) 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.
Treatment-related mortality rates
Will be analyzed in a descriptive fashion with means +/- standard deviations or frequency counts.

Full Information

First Posted
June 16, 2017
Last Updated
June 7, 2023
Sponsor
Roswell Park Cancer Institute
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1. Study Identification

Unique Protocol Identification Number
NCT03192397
Brief Title
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
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
August 9, 2017 (Actual)
Primary Completion Date
February 23, 2024 (Anticipated)
Study Completion Date
February 23, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Roswell Park Cancer Institute

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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, Graft Versus Host Disease, Hodgkin Lymphoma, Minimal Residual Disease, Myelodysplastic Syndrome, Myeloproliferative Neoplasm, Non-Hodgkin Lymphoma, Plasma Cell Myeloma, Severe Aplastic Anemia, Waldenstrom Macroglobulinemia

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
35 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Prevention (chemotherapy, TBI, cyclophosphamide)
Arm Type
Experimental
Arm Description
CONDITIONING REGIMEN: 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. 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.
Intervention Type
Procedure
Intervention Name(s)
Allogeneic Hematopoietic Stem Cell Transplantation
Other Intervention Name(s)
allogeneic stem cell transplantation, HSC, HSCT
Intervention Description
Undergo allogeneic hematopoietic stem cell transplant
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Fludarabine Phosphate
Other Intervention Name(s)
2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Drug
Intervention Name(s)
Melphalan Hydrochloride
Other Intervention Name(s)
Alkeran, Alkerana, Evomela
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Mycophenolate Mofetil
Other Intervention Name(s)
Cellcept, MMF
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Sirolimus
Other Intervention Name(s)
Rapamune
Intervention Description
Given IV and PO
Intervention Type
Radiation
Intervention Name(s)
Total-Body Irradiation
Other Intervention Name(s)
TOTAL BODY IRRADIATION, Whole-Body Irradiation
Intervention Description
Undergo TBI
Primary Outcome Measure Information:
Title
Extensive chronic graft versus host disease (GVHD)
Description
Will be analyzed for each stratum. Will examine in a post-hoc analysis potential chronic GVHD rates of response by human leukocyte antigen (HLA) matching status.
Time Frame
Up to 365 days
Secondary Outcome Measure Information:
Title
Clinical response assessed as per bone marrow transplant (BMT) standard of care
Description
Will utilize either straight Kaplan-Meier based estimators or extensions of nonparametric survival models to account for competing risks.
Time Frame
Up to 4 years
Title
Cumulative incidence of grade III-IV acute graft versus host disease (GVHD)
Description
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.
Time Frame
Up to 4 years
Title
Cumulative incidence of relapse
Description
Will be analyzed in a descriptive fashion with means +/- standard deviations or frequency counts.
Time Frame
Up to 4 years
Title
Engraftment rate assessed as per bone marrow transplant (BMT) standard of care
Description
Will be analyzed in a descriptive fashion with means +/- standard deviations or frequency counts.
Time Frame
Up to 4 years
Title
Overall survival assessed as per bone marrow transplant (BMT) standard of care
Description
Will utilize either straight Kaplan-Meier based estimators or extensions of nonparametric survival models to account for competing risks.
Time Frame
Up to 4 years
Title
Progression free survival (PFS) assessed as per bone marrow transplant (BMT) standard of care
Description
Will utilize either straight Kaplan-Meier based estimators or extensions of nonparametric survival models to account for competing risks.
Time Frame
At 1 year
Title
Treatment-related mortality rates
Description
Will be analyzed in a descriptive fashion with means +/- standard deviations or frequency counts.
Time Frame
Up to 4 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Maureen Ross
Organizational Affiliation
Roswell Park Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Roswell Park Cancer Institute
City
Buffalo
State/Province
New York
ZIP/Postal Code
14263
Country
United States

12. IPD Sharing Statement

Learn more about this trial

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

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