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

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

Brief Summary

      This clinical 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) after the transplant may help increase this
      effect.
    

Detailed Description

      PRIMARY OBJECTIVE:

      1. 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:

        1. To assess the 100 day regimen-related mortality (RRM) in patients undergoing HSCT on
           this treatment protocol.

        2. To determine the incidence and severity of graft-versus-host disease (GVHD) in patients
           undergoing treatment on this regimen.

        3. To evaluate engraftment rates and lymphoid reconstitution in patients treated on this
           trial.

        4. 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)
      over 60 minutes on days -15 to -12, thiotepa IV over 2 hours on days -15 to -13, donor
      lymphocyte infusion (DLI) on day -6, and cyclophosphamide IV over 2 hours 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.
    

Study Phase

Phase 2

Study Type

Interventional

Primary Outcome

Disease-free survival (DFS)

Secondary Outcome

 Overall survival

Condition

Accelerated Phase Chronic Myelogenous Leukemia

Intervention

Fludarabine phosphate

Study Arms / Comparison Groups

 Treatment (RIC and stem cell transplant)

Description:  REDUCED INTENSITY CONDITIONING: Patients receive fludarabine phosphate IV on days -15 to -12, thiotepa IV over 2 hours on days -15 to -13, donor lymphocyte infusion (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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Status

Drug

Estimated Enrollment

72

Start Date

December 24, 2012

Completion Date

September 2021

Primary Completion Date

July 2021

Eligibility Criteria

        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
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Dolores Grosso, RN, CRNP, DNP, 215-955-8874, 

Location Countries

United States

Location Countries

United States

NCT ID

NCT01760655

Organization ID

12D.501

Secondary IDs

2012-67

Responsible Party

Sponsor

Study Sponsor

Sidney Kimmel Cancer Center at Thomas Jefferson University

Study Sponsor

Dolores Grosso, RN, CRNP, DNP, Principal Investigator, Thomas Jefferson University

Verification Date

June 2021