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Reduced-Intensity Conditioning Before Donor Stem Cell Transplant in Treating Patients With High-Risk Hematologic Malignancies

Primary Purpose

Acute Myeloid Leukemia With FLT3/ITD Mutation, Acute Myeloid Leukemia With Gene Mutations, Acute Myeloid Leukemia With Inv(3) (q21.3;q26.2); GATA2, MECOM

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Fludarabine phosphate
Busulfan
Total-Body Irradiation
Therapeutic Allogeneic Lymphocytes
Cyclophosphamide
Allogeneic Hematopoietic Stem Cell Transplantation
Peripheral Blood Stem Cell Transplantation
Tacrolimus
Mycophenolate Mofetil
Laboratory Biomarker Analysis
Sponsored by
Sidney Kimmel Cancer Center at Thomas Jefferson University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia With FLT3/ITD Mutation

Eligibility Criteria

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

Inclusion Criteria:

  1. Any patient with a high-risk hematologic or oncologic diagnosis in which allogeneic HSCT is thought to be beneficial, and in whom front-line therapy has already been applied. High risk is defined as:

    1. Acute myeloid leukemia with high risk features as defined by:

      • Age greater than or equal to 60
      • Secondary AML (prior therapy or hematologic malignancy)
      • Normal cytogenetics but FLT3/ITD positive
      • Any relapse or primary refractory disease
      • Greater than 3 cytogenetic abnormalities or any one of the following cytogenetic abnormalities: -5/del(5q), -7/del(7q), Abn(9q),(11q),(3q),(21q),(17p),t(6;9), t(6;11), t(11;19), +8,del(12p),inv(3),t(10;11),-17, 11q 23
      • Any single autosomal monosomy
    2. Acute lymphoid leukemia in 1st or 2nd morphological remission. ALL with any morphological evidence of disease will not be eligible.
    3. Myelodysplasia (MDS) other than refractory anemia (RA), refractory anemia with rare sideroblasts (RARS), or isolated 5q- syndrome subtypes.
    4. Hodgkin's or Non-Hodgkin's lymphoma in 2nd or greater remission or with persistent disease.
    5. Myeloma with evidence of persistent disease after front-line therapy.
    6. Chronic myeloid leukemia (CML) resistant to signal transducer inhibitor (STI) therapy
    7. Myelofibrosis and CMML
    8. Essential Thrombocytopenia or Polycythemia Vera with current or past evidence of evolution to acute leukemia
    9. Any hematological malignancy not cited above which is thought to be high-risk with increased chance of post HSCT relapse. Patients in this category require specific approval of the PI and the TJU BMT attending physician group for entrance.
    10. Any hematological malignancy or dyscrasia not cited above which is thought to be high-risk with increased chance of post HSCT relapse.
    11. Any patient who has an aggressive disease that would normally be treated on a myeloablative study, but is prevented from doing so by factors in their past medical history. Examples are patients with previous treatment with radiation therapy precluding TBI, or a past history of myeloablative therapy, precluding a 2nd myeloablative regimen.
    12. Patients with aplastic anemia may be treated on this protocol, with outcomes reported descriptively.
  2. Patients must have a related donor who is at least a 4 antigen match at the Human Leukocyte Antigen (HLA)-A; B; C; DR loci. Patients with only a 1 out of 8 mismatch in the GVH direction will be classified in the matched related category
  3. Patients must adequate organ function:

    1. Left ventricular end diastolic function (LVEF) of >50%
    2. Diffusion Lung Capacity of Oxygen (DLCO) >50% of predicted corrected for hemoglobin
    3. Adequate liver function as defined by a serum bilirubin <1.8, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 2.5X upper limit of normal
    4. Creatinine Clearance of ≥ 60 mL/min 4) Patients must have adequate KPS and HCT-CI scores:
    1. Patients < age 60 years must have a KPS of ≥80% and an HCT-CI score of 5 or less
    2. Patients aged 60 to 65 years must have a KPS of ≥80% and an HCT-CI score of 4 or less
    3. Patients aged 66 to 69 years must have a KPS of 90% and an HCT-CI score of 3 or less
    4. Patients aged 70 years or more must have a KPS of 90% and an HCT-CI score of 2 or less (Patients with greater than the allowable HCT-CI points for age can be enrolled for trial with approval of the PI and at least 1 Co-I not on the primary care team of the patient). This is an adjustment to account for healthy patients who meet the spirit of the protocol but have histories that result in higher than guideline HCT-CI points. An examples 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 5) Patients must be willing to use contraception if they have childbearing potential 6) Patient or patient's guardian is able to give informed consent

Exclusion Criteria:

  1. HIV positive
  2. Active involvement of the central nervous system with malignancy
  3. Pregnancy
  4. Patients with life expectancy of < 6 months for reasons other than their underlying hematologic/oncologic disorder
  5. Patients who have received alemtuzumab or ATG within 8 weeks of the transplant admission.
  6. Patients with evidence of another malignancy, exclusive of a skin cancer that requires only local treatment, should not be enrolled on this protocol

Sites / Locations

  • Thomas Jefferson University

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (RIC and allogeneic PBSCT)

Arm Description

REDUCED INTENSITY CONDITIONING: Patients receive fludarabine phosphate IV on days -15 to -12, busulfan IV on days -14 to -13, DLI on day -6, and cyclophosphamide IV on days -3 and -2. Patients also undergo TBI on day -10. TRANSPLANT: Patients undergo allogeneic PBSCT on day 0. GVHD PROPHYLAXIS: Patients receive tacrolimus IV on days -1 to 42 followed by taper and mycophenolate mofetil IV BID on days -1 to 28

Outcomes

Primary Outcome Measures

Disease-free survival (DFS)
This hypothesis will be rejected if the 95% confidence interval for year DFS rate computed from the estimated Kaplan-Meier survival curves will be entirely above 0.35.

Secondary Outcome Measures

Overall survival
Will be analyzed and reported descriptively.
Overall survival
Will be analyzed and reported descriptively.
Incidence of regimen related toxicity graded according to the National Cancer Institute Common Toxicity Criteria version 4.0
Will be analyzed and reported descriptively
Immune reconstitution
Will be analyzed and reported descriptively.
Incidence and degree of graft versus host disease
Will be analyzed and reported descriptively.
Engraftment rates
Will be analyzed and reported descriptively.

Full Information

First Posted
January 2, 2013
Last Updated
January 4, 2023
Sponsor
Sidney Kimmel Cancer Center at Thomas Jefferson University
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT01760655
Brief Title
Reduced-Intensity Conditioning Before Donor Stem Cell Transplant in Treating Patients With High-Risk Hematologic Malignancies
Official Title
A Two Step Approach to Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation for High Risk Hematologic Malignancies
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Completed
Study Start Date
December 24, 2012 (Actual)
Primary Completion Date
April 15, 2022 (Actual)
Study Completion Date
December 5, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Sidney Kimmel Cancer Center at Thomas Jefferson University
Collaborators
National Cancer Institute (NCI)

4. Oversight

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

5. Study Description

Brief Summary
This phase II trial studies reduced-intensity conditioning before donor stem cell transplant in treating patients with high-risk hematologic malignancies. Giving low-doses of chemotherapy and total-body irradiation before a donor stem cell transplant helps 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). Giving an infusion of the donor's T cells (donor lymphocyte infusion) before the transplant may help increase this effect.
Detailed Description
PRIMARY OBJECTIVES: I. To compare the rate of disease-free survival (DFS) at 1 year post hematopoietic stem cell transplant (HSCT) in patients undergoing HSCT treated on this successor Thomas Jefferson University (TJU) 2 Step reduced intensity conditioning (RIC) haploidentical regimen and compare it with that of the initial 2 Step RIC regimen. SECONDARY OBJECTIVES: I. To assess the 100 day regimen-related mortality (RRM) in patients undergoing HSCT on this treatment protocol. II. To determine the incidence and severity of graft-versus-host disease (GVHD) in patients undergoing treatment on this regimen. III. To evaluate engraftment rates and lymphoid reconstitution in patients treated on this trial. IV. To assess overall survival at 1 and 3 years past HSCT in patients treated on this trial. OUTLINE: REDUCED INTENSITY CONDITIONING: Patients receive fludarabine phosphate intravenously (IV) on days -15 to -12, busulfan IV on days -14 to -13, donor lymphocyte infusion (DLI) on day -6, and cyclophosphamide IV on days -3 and -2. Patients also undergo total-body irradiation (TBI) on day -10. TRANSPLANT: Patients undergo allogeneic peripheral blood stem cell transplant (PBSCT) on day 0. GVHD PROPHYLAXIS: Patients receive tacrolimus IV on days -1 to 42 followed by taper and mycophenolate mofetil IV twice daily (BID) on days -1 to 28. After completion of study treatment, patients are followed up periodically.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia With FLT3/ITD Mutation, Acute Myeloid Leukemia With Gene Mutations, Acute Myeloid Leukemia With Inv(3) (q21.3;q26.2); GATA2, MECOM, Acute Myeloid Leukemia With t(6;9) (p23;q34.1); DEK-NUP214, Aplastic Anemia, Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Chronic Myelomonocytic Leukemia, Follicular Lymphoma, Hodgkin Lymphoma, Myelodysplastic Syndrome, Myelofibrosis, Myeloid Leukemia, Non-Hodgkin Lymphoma, Plasma Cell Myeloma, Polycythemia Vera, Recurrent Adult Acute Myeloid Leukemia, Recurrent Childhood Acute Myeloid Leukemia, Refractory Acute Myeloid Leukemia, Secondary Acute Myeloid Leukemia, Therapy-Related Acute Myeloid Leukemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
62 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (RIC and allogeneic PBSCT)
Arm Type
Experimental
Arm Description
REDUCED INTENSITY CONDITIONING: Patients receive fludarabine phosphate IV on days -15 to -12, busulfan IV on days -14 to -13, DLI on day -6, and cyclophosphamide IV on days -3 and -2. Patients also undergo TBI on day -10. TRANSPLANT: Patients undergo allogeneic PBSCT on day 0. GVHD PROPHYLAXIS: Patients receive tacrolimus IV on days -1 to 42 followed by taper and mycophenolate mofetil IV BID on days -1 to 28
Intervention Type
Drug
Intervention Name(s)
Fludarabine phosphate
Other Intervention Name(s)
2-F-ara-AMP, 75607-67-9, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, 2-fluoro-9-(5-O-phosphono-beta-D-arabinofuranosyl), Beneflur, Fludara, Fludarabine-5'-Monophosphate, SH T 586
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Busulfan
Other Intervention Name(s)
1, 4-Bis[methanesulfonoxy]butane, 1,4-Bis(methanesulfonoxy)butane, 1,4-Bitanediol Dimethanesulfonate Esters, 1,4-Butanediol Dimethylsulfonate, 1,4-Di(methanesulfonyloxy)butane, 1,4-Di(methylsulfonyloxy)butane, 55-98-1, BUS, Bussulfam, Busulfanum, Busulfex, Busulphan, CB 2041, CB-2041, Glyzophrol, GT 41, GT-41, Joacamine, Methanesulfonic Acid Tetramethylene Ester, Methanesulfonic acid, tetramethylene ester, Mielucin, Misulban, Misulfan, Mitosan, Myeleukon, Myeloleukon, Myelosan, Mylecytan, Myleran, Sulfabutin, Tetramethylene Bis(methanesulfonate), Tetramethylene bis[methanesulfonate], WR-19508
Intervention Description
Given IV
Intervention Type
Radiation
Intervention Name(s)
Total-Body Irradiation
Other Intervention Name(s)
TBI, SCT_TBI, TOTAL BODY IRRADIATION, Whole Body, Whole Body Irradiation, Whole-Body Irradiation
Intervention Description
Undergo TBI
Intervention Type
Biological
Intervention Name(s)
Therapeutic Allogeneic Lymphocytes
Other Intervention Name(s)
Allogeneic Lymphocytes
Intervention Description
Undergo DLI
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
(-)-Cyclophosphamide, 1-bis(2-chloroethyl)-amino-1-oxo-2-aza-5-oxaphosphoridin monohydrate, 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrate, 2-[bis(b-chloroethyl)amino]-1-oxa-3-aza-2-phosphacyclohexane-2-oxide monohydrate, 2-[di(chloroethyl)amino]-1-oxa-3-aza-2-phosphacyclohexane 2-oxide monohydrate, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, 6055-19-2, bis(2-chloroethyl)phosphamide cyclic propanolamide ester monohydrate, Bis(2-chloroethyl)phosphoramide cyclic propanolamide ester monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, N,N-bis(2-chloroethyl)-N',O-propylenephosphoric acid ester diamide monohydrate, N,N-bis(2-chloroethyl)-N'-(3-hydroxypropyl)phosphorodiamidic acid intramolecular ester monohydrate, N,N-bis(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine 2-oxide monohydrate, N,N-bis(b-chloroethyl)-N',O-trimethylenephosphoric acid ester diamide monohydrate, N,N-bis(beta-chloroethyl)-N',O-propylenephosphoric acid ester diamide monohydrate, N,N-bis(beta-chloroethyl)-N',O-trimethylenephosphoric acid ester diamide monohydrate, Neosar, Revimmune, Syklofosfamid, WR- 138719
Intervention Description
Given IV
Intervention Type
Procedure
Intervention Name(s)
Allogeneic Hematopoietic Stem Cell Transplantation
Other Intervention Name(s)
Allogeneic, Allogeneic Hematopoietic Cell Transplantation, allogeneic stem cell transplantation, HSC, HSCT, Stem Cell Transplantation
Intervention Description
Undergo allogeneic PBSCT
Intervention Type
Procedure
Intervention Name(s)
Peripheral Blood Stem Cell Transplantation
Other Intervention Name(s)
PBPC transplantation, PBSCT, Peripheral Blood, Peripheral Blood Progenitor Cell Transplantation, PERIPHERAL BLOOD STEM CELL TRANSPLANT, peripheral stem cell support, Peripheral Stem Cell Transplant, peripheral stem cell transplantation
Intervention Description
Undergo allogeneic PBSCT
Intervention Type
Drug
Intervention Name(s)
Tacrolimus
Other Intervention Name(s)
109581-93-3, FK 506, Fujimycin, Hecoria, Prograf, Protopic
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Mycophenolate Mofetil
Other Intervention Name(s)
115007-34-6, 128794-94-5, Cellcept, MMF
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Disease-free survival (DFS)
Description
This hypothesis will be rejected if the 95% confidence interval for year DFS rate computed from the estimated Kaplan-Meier survival curves will be entirely above 0.35.
Time Frame
1 year post hematopoietic stem cell transplant (HSCT)
Secondary Outcome Measure Information:
Title
Overall survival
Description
Will be analyzed and reported descriptively.
Time Frame
1 year post HSCT
Title
Overall survival
Description
Will be analyzed and reported descriptively.
Time Frame
3 years post HSCT
Title
Incidence of regimen related toxicity graded according to the National Cancer Institute Common Toxicity Criteria version 4.0
Description
Will be analyzed and reported descriptively
Time Frame
Up to 1 year
Title
Immune reconstitution
Description
Will be analyzed and reported descriptively.
Time Frame
Up to 1 year
Title
Incidence and degree of graft versus host disease
Description
Will be analyzed and reported descriptively.
Time Frame
Up to 1 year
Title
Engraftment rates
Description
Will be analyzed and reported descriptively.
Time Frame
Up to 1 year

10. Eligibility

Sex
All
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: By definition, patients with hematological malignancies or dyscrasias that require HSCT as part of cure-directed therapy are by definition high-risk and can be treated on this protocol; examples of high risk patients include but are not limited to: Acute myeloid leukemia with high risk features as defined by: Age greater than or equal to 60 Secondary acute myeloid leukemia (AML) (prior therapy or hematologic malignancy) Normal cytogenetics but fms-related tyrosine kinase 3 (FLT3)/internal tandem duplication (ITD) positive Any relapse or primary refractory disease Greater than 3 cytogenetic abnormalities or any one of the following cytogenetic abnormalities: -5/del(5q), -7/del(7q), Abn(9q), (11q), (3q), (21q), (17p), t(6;9), t(6;11), t(11;19), +8, del(12p), inv(3), t(10;11), -17, 11q 23 Any single autosomal monosomy Acute lymphoid leukemia in 1st or 2nd morphological remission; ALL with any morphological evidence of disease will not be eligible Myelodysplasia (MDS) other than refractory anemia (RA), refractory anemia with rare sideroblasts (RARS), or isolated 5q- syndrome subtypes Hodgkin's or Non-Hodgkin's lymphoma in 2nd or greater remission or with persistent disease Myeloma with evidence of persistent disease after front-line therapy Chronic myeloid leukemia (CML) resistant to signal transducer inhibitor (STI) therapy Myelofibrosis and chronic myelomonocytic leukemia (CMML) Essential thrombocytopenia or polycythemia vera with current or past evidence of evolution to acute leukemia Patients with chronic lymphocytic leukemia (CLL), follicular non-Hodgkin lymphoma (NHL), or other lymphoid malignancies who have highly adverse cytogenetics (such as p53 deletion), are chemo-insensitive, are not responsive to highly effective novel treatments such as chimeric antigen receptor T-lymphocytes (CART) or Ibrutinib, or who have transformed disease Any hematological malignancy not cited above which is thought to be high-risk with increased chance of post HSCT relapse Any patient who has an aggressive disease that would normally be treated on a myeloablative study, but is prevented from doing so by factors in their past medical history; examples are patients with previous treatment with radiation therapy precluding TBI, or a past history of myeloablative therapy, precluding a 2nd myeloablative regimen Patients with aplastic anemia may be treated on this protocol, with outcomes reported descriptively Patients must have a related donor who is at least a 2-4/8 antigen mismatch at the human leukocyte antigen (HLA)-A; B; C; DR loci; patients with only a 1 out of 8 mismatch in the GVH direction will be classified in the matched related category Left ventricular end diastolic function (LVEF) of >= 50% Diffusion lung capacity of oxygen (DLCO) >= 50% of predicted corrected for hemoglobin Serum bilirubin =< 1.8 Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 2.5 x upper limit of normal Creatinine clearance of >= 60 mL/min Patients < age 60 years must have a Karnofsky performance status (KPS) of >= 80% and a hematopoietic cell transplant comorbidity index (HCT-CI) score of 5 or less Patients aged 60 to 65 years must have a KPS of >= 80% and an HCT-CI score of 4 or less Patients aged 66 to 69 years must have a KPS of 90% and an HCT-CI score of 3 or less Patients aged 70 years or more must have a KPS of 90% and an HCT-CI score of 2 or less * (Patients with greater than the allowable HCT-CI points for age can be enrolled for trial with approval of the principal investigator [PI] and at least 1 co-investigator [Co-I] not on the primary care team of the patient) this is an adjustment to account for healthy patients who meet the spirit of this protocol but have histories that result in higher than guideline HCT-CI 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 Patients must be willing to use contraception if they have childbearing potential Patient or patient's guardian is able to give informed consent Exclusion Criteria: Human immunodeficiency virus (HIV) positive Active involvement of the central nervous system with malignancy; this can be documented as a normal neurological exam and/or a negative cerebrospinal fluid (CSF) analysis Pregnancy Patients with life expectancy of =< 6 months for reasons other than their underlying hematologic/oncologic disorder Patients who have received alemtuzumab or ATG within 8 weeks of the transplant admission Patients with evidence of another malignancy, exclusive of a skin cancer that requires only local treatment, should not be enrolled on this protocol
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Dolores Grosso, RN, CRNP, DNP
Organizational Affiliation
Thomas Jefferson University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Neal Flomenberg, MD
Organizational Affiliation
Thomas Jefferson University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Thomas Jefferson University
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19107
Country
United States

12. IPD Sharing Statement

Links:
URL
http://hospitals.jefferson.edu/
Description
Thomas Jefferson University Hospital

Learn more about this trial

Reduced-Intensity Conditioning Before Donor Stem Cell Transplant in Treating Patients With High-Risk Hematologic Malignancies

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