Reduced Intensity Chemotherapy and Radiation Therapy Before Donor Stem Cell Transplant in Treating Patients With Hematologic Malignancies

Sponsor

Sidney Kimmel Cancer Center at Thomas Jefferson University (Other)

Overall Status

Recruiting

CT.gov ID

NCT02566304

Collaborator

(none)

Enrollment

Location

Arm

91.6

Anticipated Duration (Months)

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This clinical trial studies the use of reduced intensity chemotherapy and radiation therapy before donor stem cell transplant in treating patients with hematologic malignancies. Giving low doses of chemotherapy, such as cyclophosphamide and fludarabine phosphate, before a donor stem cell transplant may help stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Reducing the intensity of the chemotherapy and radiation may also reduce the side effects of the donor stem cell transplant.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia Acute Myeloid Leukemia in Remission Aplastic Anemia Chronic Myelomonocytic Leukemia Hodgkin Lymphoma Indolent Non-Hodgkin Lymphoma Malignant Neoplasm Myelodysplastic Syndrome Myeloproliferative Neoplasm Plasma Cell Myeloma Refractory Anemia Refractory Anemia With Excess Blasts Refractory Anemia With Ring Sideroblasts Refractory Cytopenia With Multilineage Dysplasia Refractory Cytopenia With Multilineage Dysplasia and Ring Sideroblasts	Drug: Fludarabine Radiation: Total-Body Irradiation Biological: T Cell-Depleted Donor Lymphocyte Infusion Drug: Cyclophosphamide Procedure: Peripheral Blood Stem Cell Transplantation Procedure: Allogeneic Hematopoietic Stem Cell Transplantation Drug: Tacrolimus Drug: Mycophenolate mofetil Other: Laboratory Biomarker Analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

To demonstrate efficacy of this approach over the historical 2 step reduced intensity conditioning (RIC) approaches in the "vulnerable" population defined as: patients with hematopoietic cell transplant (HCT)-co-morbidity index (CI)/age scores >= 2, but no more than a score of 5 as based on the Sorror et al. data.

SECONDARY OBJECTIVES:

To compare the non-relapse mortality (NRM) and relapse related mortality (RRM) rates at 1 year for patients treated on this study to the that of patients undergoing haploidentical RIC hematopoietic stem cell transplantation (HSCT) as reported in the literature and as observed in the 2 step RIC trials.
To determine the incidence and severity of graft-versus-host disease (GVHD) in patients undergoing treated on the Thomas Jefferson University (TJU) RIC 2 step approach.
To evaluate engraftment rates and lymphoid reconstitution in patients treated on the TJU RIC 2 step approach.

OUTLINE:

RIC: Patients receive fludarabine phosphate intravenously (IV) over 60 minutes on days -10 to -8 and cyclophosphamide IV over 2 hours on days -3 and -2. Patients also undergo total body irradiation (TBI) followed by a donor lymphocyte infusion (DLI) on day -6.

TRANSPLANT: Patients undergo cluster of differentiation (CD)34+ peripheral blood stem cell transplant on day 0.

GVHD PROPHYLAXIS: Patients receive tacrolimus orally (PO) beginning day -1 with a taper initiated on day 42 and mycophenolate mofetil IV twice daily (BID) on days -1 to 28 in the absence of GVHD.

After completion of study treatment, patients are followed up for 1 year.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

35 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Two Step Approach to Non-Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation for Patients With Hematologic Malignancies

Actual Study Start Date :

Nov 13, 2015

Anticipated Primary Completion Date :

May 1, 2023

Anticipated Study Completion Date :

Jul 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: RIC HSCT, GVHD prophylaxis RIC: Patients receive fludarabine phosphate IV on days -10 to -8 and cyclophosphamide IV on days -3 and -2. Patients also undergo TBI followed by a DLI on day -6. TRANSPLANT: Patients undergo CD34+ peripheral blood stem cell transplant on day 0. GVHD PROPHYLAXIS: Patients receive tacrolimus PO beginning day -1 with a taper initiated on day 42 and mycophenolate mofetil IV BID on days -1 to 28 in the absence of GVHD.	Drug: Fludarabine Given IV Other Names: Fludarabine phosphate Fludara Radiation: Total-Body Irradiation Undergo TBI Biological: T Cell-Depleted Donor Lymphocyte Infusion Undergo DLI Drug: Cyclophosphamide Given IV Other Names: Endoxan Cytoxan Neosar Procytox Revimmune Cycloblastin Cytophosphane CP Procedure: Peripheral Blood Stem Cell Transplantation Undergo PBSC transplant Procedure: Allogeneic Hematopoietic Stem Cell Transplantation Undergo PBSC transplant Drug: Tacrolimus Given PO Other Names: FK-506 Fujimycin Prograf Advograf Protopic Drug: Mycophenolate mofetil Given IV Other Names: Mycophenolic acid MMF CellCept Myfortic Other: Laboratory Biomarker Analysis Correlative studies

Arm

Intervention/Treatment

Experimental: RIC HSCT, GVHD prophylaxis

RIC: Patients receive fludarabine phosphate IV on days -10 to -8 and cyclophosphamide IV on days -3 and -2. Patients also undergo TBI followed by a DLI on day -6. TRANSPLANT: Patients undergo CD34+ peripheral blood stem cell transplant on day 0. GVHD PROPHYLAXIS: Patients receive tacrolimus PO beginning day -1 with a taper initiated on day 42 and mycophenolate mofetil IV BID on days -1 to 28 in the absence of GVHD.

Drug: Fludarabine

Given IV

Other Names:

Fludarabine phosphate

Fludara

Radiation: Total-Body Irradiation

Undergo TBI

Biological: T Cell-Depleted Donor Lymphocyte Infusion

Undergo DLI

Drug: Cyclophosphamide

Given IV

Other Names:

Endoxan

Cytoxan

Neosar

Procytox

Revimmune

Cycloblastin

Cytophosphane

Procedure: Peripheral Blood Stem Cell Transplantation

Undergo PBSC transplant

Procedure: Allogeneic Hematopoietic Stem Cell Transplantation

Undergo PBSC transplant

Drug: Tacrolimus

Given PO

Other Names:

FK-506

Fujimycin

Prograf

Advograf

Protopic

Drug: Mycophenolate mofetil

Given IV

Other Names:

Mycophenolic acid

MMF

CellCept

Myfortic

Other: Laboratory Biomarker Analysis

Correlative studies

Outcome Measures

Primary Outcome Measures

Overall Survival (OS) [At 1 year post HSCT]
OS will be estimated using Kaplan-Meier curves. The 1-year OS rate and corresponding 95% confidence interval will be estimated from the Kaplan-Meier curve for the OS.

Secondary Outcome Measures

Relapse Related Mortality (RRM) [At 1 year post HSCT]
Will be reported descriptively. RRM may also be estimated using Kaplan Meier curves and/or cumulative incidence analyses.
Non-Relapse Mortality (NRM) [At 1 year post HSCT]
Will be reported descriptively. NRM may also be estimated using Kaplan Meier curves and/or cumulative incidence analyses.
Incidence and severity of GVHD [Up to 1 year post HSCT]
Will be reported descriptively
Engraftment rates [Up to 1 year post HSCT]
Will be reported descriptively
Lymphoid reconstitution [Up to 1 year post HSCT]
Lymphoid reconstitution will be evaluated monthly to every other month during the first year post HSCT and will be reported descriptively.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients treated on this study will have:
Acute myeloid leukemia in morphologic complete remission (CR) not requiring treatment for their disease for 4 weeks
A history of acute myeloid leukemia (AML) with < 10% residual blasts (use highest count on staging studies) after induction therapy and persisting with < 10% blasts for at least 8 weeks without reinduction and at the time of HSCT
Refractory anemia (RA) or refractory anemia with ring sideroblasts (RARS) or isolated 5q-
Refractory anemia with excess blasts (RAEB)-1, refractory cytopenia with multilineage dysplasia (RCMD)+/-ringed sideroblasts (RS), or myelodysplastic syndrome (MDS) not otherwise specified (NOS) with stable disease for at least 3 months
RAEB-2 must demonstrate chemo-responsiveness; chemo-responsiveness is defined as a persistent blast percentage decrease by at least 5 percentage points to therapy and there must be =< 10% blasts (use highest count on staging studies) after treatment and at the time of transplant
Hodgkin or Indolent non-Hodgkin's lymphoma
Myeloma with < 5% plasma cells in the marrow
Myeloproliferative disorders (excludes chronic myelomonocytic leukemia [CMML])
Aplastic anemia
A hematological or oncological disease (not listed) in which allogeneic HSCT is thought to be beneficial, and the disease is chemoresponsive
Patients without clear manifestation of their disease status in terms of stage and/or responsiveness should be discussed with the principal investigator (PI) and enrollment analysis should be documented in the study records
Patients must have a related donor who is human leukocyte antigen (HLA) mismatched at 2, 3, or 4 antigens at the HLA-A; B; C; DR loci in the graft-versus-host disease (GVHD) direction; (patients with related donors who are HLA identical or are a 1-antigen mismatch may be treated on this therapeutic approach, but will have their outcomes will not be part of the statistical aims of the study); the HLA matched related category includes patients with a syngeneic donor
Patients must have had front line therapy for their disease
LVEF (left ventricular end diastolic function) of >= 45%
DLCO (diffusing capacity of the lung for carbon monoxide) >= 45% of predicted corrected for hemoglobin, FEV-1 (forced expiratory volume at 1 second) >= 50% of predicted
Serum bilirubin =< 1.8
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 2.5 X upper limit of normal
Creatinine clearance of >= 60 mL/min
HCT-CI/age score =< 5 points (patients with greater than 5 points will be allowed for trial with approval of the PI and the co-PI or his designee; this is an adjustment to account for healthy patients who meet the spirit of this protocol but have histories that result in higher than HCT-CI 5 points; an example is a patient with a solid tumor malignancy in their remote history [adds 3 points to HCT-CI total] where the treatment for the malignancy occurred years to decades before and there has been complete recovery of toxicities)
Karnofsky performance status (KPS) >= 90% patients older than 70 years, KPS >= 80% patients younger than 70 years
Patients must be willing to use contraception if they have childbearing potential

Exclusion Criteria:

Performance status < 90% in patients 70 years old or greater, < 80% in patients less than age 70 years
HCT-CI/age score > 5 points (patients with greater than 5 points will be allowed for trial with approval of the principal investigator and the co-principal investigator or his designee; this is an adjustment to account for healthy patients who meet the spirit of this protocol but have histories that result in higher than HCT-CI 5 points; an example is a patient with a solid tumor malignancy in their remote history [adds 3 points to HCT-CI total] where the treatment for the malignancy occurred years to decades before and there has been complete recovery of toxicities)
A diagnosis of chronic myelomonocytic leukemia (CMML), unless in morphologic CR
Human immunodeficiency virus (HIV) positive
Active involvement of the central nervous system with malignancy
Inability to obtain informed consent from patient or surrogate
Pregnancy
Patients with life expectancy of =< 6 months for reasons other than their underlying hematologic/oncologic disorder
Patients who have received alemtuzumab or antithymocyte globulin within 8 weeks of the transplant admission; the absence of these therapies in the medical record will serve as documentation that they were not given
Patients with evidence of another malignancy, exclusive of a skin cancer that requires only local treatment, should not be enrolled on this protocol