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Safety and Efficacy of Pentostatin and Low Dose TBI With Allogenic Peripheral Blood Stem Cell Transplant

This study has been completed.
Sponsor:
Collaborator:
Astex Pharmaceuticals
Information provided by:
University of Nebraska
ClinicalTrials.gov Identifier:
NCT00571662
First received: December 11, 2007
Last updated: December 2, 2010
Last verified: December 2010
History of Changes
  Purpose

This is a continuation of a pilot study which is now regarded as a phase II trial with a plan to enroll an additional 40 patients (20 related and 20 unrelated donor transplants) with hematological malignancy assessing the safety and efficacy of a minimally myelosuppressive regimen with pentostatin and low-dose total body irradiation (TBI) followed by allogeneic peripheral blood stem cell transplantation (alloPSCT).


Condition Intervention Phase
Acute Myelogenous Leukemia
Acute Lymphocytic Leukemia
Chronic Myelogenous Leukemia
Chronic Lymphocytic Leukemia
Myelodysplastic Syndromes
Multiple Myeloma
Non-Hodgkins Lymphoma
Hodgkins Disease
Peripheral T-Cell Lymphoma
 Drug: Pentostatin
Radiation: Total-body irradiation (TBI)
Drug: Cyclosporine A (CsA)
Drug: Mycophenolate Mofetil (MMF)
Drug: G-CSF
 Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Allogeneic Peripheral Blood Stem Cell Transplantation With Minimally Myelosuppressive Regimen of Pentostatin and Low-dose Total-body Irradiation

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by University of Nebraska:

Primary Outcome Measures:
  • Percent of Participants With Chimerism: Full Donor Chimerism Defined as >95% Donor CD3+ Cell in Blood as Assessed by DNA Fingerprinting [ Time Frame: days +28 and +70 ] [ Designated as safety issue: No ]
    the efficacy of the regimen as determined by engraftment rate and establishment of donor hematopoietic chimerism at day +28 and day +70.


Secondary Outcome Measures:
  • Toxicity [ Time Frame: Duration of treatment ] [ Designated as safety issue: Yes ]
    determination of regimen related toxicity of the combination of Pentostatin and low dose total body irradiation. Treatment related toxicity will be graded using NCI CTC Version 2.0 and GVHD using the standard GVHD grading system.

  • Immune Effects [ Time Frame: pretransplant and post transplant days28,70,100 and 12, and 24 months ] [ Designated as safety issue: Yes ]
    kinetics of hematologic and immunologic reconstitution after allogeneic transplantation

  • Incidence of Acute and Chronic Graft-versus-host Disease [ Time Frame: twice weekly until day 100 up to 1 year post transplant ] [ Designated as safety issue: Yes ]
    Incidence of acute and chronic graft-versus-host disease.Acute GVHD usually occurs during the first three months following transplant. Chronic GVHD usually develops after the third month post-transplant.

  • Responses to Therapy [ Time Frame: every 6 mo. up to 2 years ] [ Designated as safety issue: No ]
    event-free and overall survival at 12 months


Enrollment: 76
Study Start Date: December 2000
Study Completion Date: December 2008
Primary Completion Date: December 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort I
Pentostatin to be administered intravenously on days - 10, -9, and -8 at a dose of 4mg/m2/day
 Drug: Pentostatin
4 mg/m^2 intravenous(IV)once a day(QD)x3days (days -10, -9, -8)
Other Name: Nipent
Radiation: Total-body irradiation (TBI)
TBI will consist of 2.0 GY at 8-12cGy/min via 6MV photons delivered AP/PA fields, without lung blocks or via lateral fields with lucite compensator along the head and neck region. TLD (thermal luminescent dosimetry) will be used to verify dose uniformity. TBI will be given on day -1.
Drug: Cyclosporine A (CsA)
CsA will be given at 2.0 mg/kg intravenous (IV) Q 12hrs on days -1,0,and+1 (total 6 doses) then converted to oral at 2 mg/kg by mouth (PO) twice a day (BID) until day+80, then tapered 10% per week over approximately 3 months if no GVHD for related donor transplants. For unrelated CsA will be given at same dose and schedule until day+100 then tapered by 10% per week if no GVHD
Other Name: Neoral
Drug: Mycophenolate Mofetil (MMF)
MMF 15 mg/kg by mouth twice a day (PO BID) will be given from day 0-27 then stopped without tapering for related donor transplants. For unrelated donor transplants MMF will be given at same dose until day+40 then tapered over 2months. in absence of GVHD. Doses will be rounded to nearest 250 mg.
Drug: G-CSF
10 mcg/kg/day subcutaneously for at least 4 consecutive days.
Other Name: Leukine

Detailed Description:

This is a pilot study which began with a plan to enroll 50 patients (20 related and 30 unrelated donor transplants) with hematological malignancy assessing the safety and efficacy of a minimally myelosuppressive regimen with Pentostatin and low-dose total body irradiation (TBI) followed by allogeneic peripheral blood stem cell transplantation (alloPSCT). Patients with persistent or progressive malignancy after transplantation will be treated with GM-CSF (cytokine therapy) to assess its toxicity and potential therapeutic efficacy. Patients with persistent or progressive disease who fail or do not qualify for the cytokine therapy portion of the study will become candidates for donor leukocyte infusions.

The purpose of this protocol remains a pilot study which is now regarded as a phase II trial with a plan to enroll 40 ADDITIONAL patients (20 related and 20 unrelated donor transplants) with hematological malignancy assessing the safety and efficacy of a modified version of the original preparative regimen of Pentostatin and low-dose total body irradiation (TBI) followed by allogeneic peripheral blood stem cell transplantation (alloPSCT). Patients who fail will become candidates for donor-leukocyte infusion (DLI).

Primary Objectives

  1. To determine the safety of treating hematological malignancies by establishing donor hematopoietic chimerism using pentostatin and low-dose total body irradiation followed by allogeneic peripheral blood stem cell transplantation.
  2. To determine the immunomodulatory effects of pentostatin as part of the conditioning regimen for allogeneic peripheral blood stem cell transplantation.

Secondary Objectives

  1. To determine the incidence of infections after using a minimally myelosuppressive conditioning regimen.
  2. To determine the kinetics of hematological and immunological reconstitution after allotransplantation with a minimally myelosuppressive conditioning regimen.
  3. To determine the incidence of chronic GVHD after using allogeneic peripheral blood stem cell transplantation with a minimally myelosuppressive preparative regimen.
  4. To evaluate the role of the preparative regimen and donor source (related versus unrelated) on inflammatory cytokine profiles.
  5. To evaluate blood and where possible, biopsy specimens for a recently identified nuclear protein (molecular weight 44/46) in mononuclear cells obtained from study subjects.

Interventions, evaluation, and follow up will include:

Pentostatin 4 mg/m^2/d intravenously once a day x 3 days will be administered with 1000 cc NS hydration before and after pentostatin ten days prior to stem cell infusion (days -10, -9, and -8). Total-body irradiation (TBI): TBI 2.0 Gy will be given on day -1. Antiemetics will be given as needed. Patients will receive one liter normal saline over 2 hours pre TBI. A bone marrow biopsy and aspiration with cytogenetics and flow cytometry will be performed on Day +28, Day +70 and 6, 12, 18 and 24 months following the transplant to monitor hematologic recovery. DNA fingerprinting will also be conducted at the same time at 3, 4, 5, 6, 12, 18, and 24 months to determine chimerism.

  Eligibility

Ages Eligible for Study:   19 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Age 19-75 years

  1. Patients who relapse after autologous stem cell transplantation.
  2. Patients who are candidates for an autologous or conventional allogeneic stem cell transplantation from a disease standpoint but who do not qualify functionally (from the point of view of organ function, or performance status) for a myeloablative protocol.
  3. Any patient, where in the opinion of the primary treating oncologist, nonmyleoablative therapy would be the treatment option in the best patients interest providing the patient fits all other eligibility criteria for this protocol.

Identification of a matched related or unrelated stem cell donor

Diseases:

Acute myelogenous leukemia first complete remission with high-risk cytogenetics>second complete remission minimal residual disease (<10% blasts*). Acute lymphocytic leukemia first complete remission with high-risk cytogenetics >second complete remission minimal residual disease (<10% blasts*). Chronic myelogenous leukemia first chronic phase, accelerated phase (<10% blasts*)blast phase with minimal residual disease (<10% blasts*)second chronic phase. Chronic lymphocytic leukemia recurrence after the front line regimen (related donor transplant), chemorefractory disease (unrelated donor transplant),T-CLL in partial remission or any minimal residual disease. Myelodysplastic syndromes refractory anemia with or without ringed sideroblasts,RAEB, RAEB-T, and CMML (< than 10% blasts*). *both in peripheral blood and bone marrow

Multiple myeloma - after receiving at least one regimen of prior chemotherapy

Non-Hodgkin's Lymphomas:

Small Lympho(plasma)cytic Lymphoma (B-SLL, B-LPL): recurrence after a front line regimen (related donor transplant), or chemorefractory disease (related or unrelated donor transplant). Follicular Low-Grade Lymphoma, Marginal Zone Lymphomas (splenic, nodal, or extranodal/MALT type): chemorefractory disease or > 2 prior regimens. Mantle Cell Lymphoma: first complete or partial remission, refractory disease, or failed prior ASCT. Diffuse Large B-cell Lymphoma, Follicular Large cell Lymphoma, Peripheral T-cell Lymphoma, Anaplastic Large Cell Lymphoma: refractory disease, or failed prior ASCT. Burkitt or Acute Lymphoblastic Lymphomas: high-risk disease in remission, chemosensitive persistent or recurrent disease. Cutaneous T-cell Lymphomas: (Mycosis Fungoides, Sezary Syndrome): chemorefractory disease of > 2 prior regimens

Hodgkins Disease: refractory or persistent disease and not candidate for ASCT, or failed prior ASCT.

Peripheral T-cell Lymphoma

Exclusion Criteria:

  • Age > 75 years and < 19 years
  • progressive disease within 8 weeks of prior therapy or within 12 weeks after prior autologous stem cell transplantation
  • Active CNS malignancy (patients with known positive CSF cytology or parenchymal lesions visible by CT or MRI)
  • Fertile men or women unwilling to use appropriate contraceptive techniques during and for 12 months following treatment
  • Females who are pregnant
  • Patients who are HIV seropositive
  • Active uncontrolled infection or immediate life-threatening condition at the time of enrollment

  • Significant Organ dysfunction:

    1. Calculated Creatinine Clearance <55ml/min
    2. cardiac ejection fraction <40%, NYHA class II or greater cardiac disease.
    3. DLCO < 40% , FEV1/FVC ratio <50% predicted, or receiving supplementary continuous oxygen
    4. total bilirubin > 2x upper limit of normal (unless due to Gilberts disease or malignancy), ALT and AST 4x the upper limit of normal
  • Karnofsky score <60%
  • Patients with uncontrolled medical illnesses (e.g., uncontrolled systemic hypertension, diabetes)

Donor Inclusion Criteria:

  • HLA genotypically matched relative
  • siblings or first-degree relatives matched at HLA-A, B, or DR loci (6 antigen match) are acceptable donors
  • HLA matched unrelated volunteer donor
  • unrelated donor matched at HLA-A, B, or DR loci (6 antigen match) are acceptable donors
  • One antigen mismatch related or unrelated donor will also be acceptable, molecular typing needs to be used at each H LA-A, B, or DR loci in case of mismatched unrelated donor.

Donor Exclusion Criteria:

  • Identical twin
  • Pregnancy
  • HIV positive
  • Serious Allergy to G-CSF
  • Current serious systemic illness
  • Failure to meet the UNMC or NMDP criteria for donors
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00571662

Locations
United States, Nebraska
University of Nebraska Medical Center, Section of Oncology/Hematology
Omaha, Nebraska, United States, 68198
Sponsors and Collaborators
University of Nebraska
Astex Pharmaceuticals
Investigators
Principal Investigator: Gregory Bociek, M.D. University of Nebraska
  More Information

No publications provided

Responsible Party: Gregory Bociek, M.D. Principal Investigator, University of Neberask Medical Center
ClinicalTrials.gov Identifier: NCT00571662     History of Changes
Other Study ID Numbers: 389-00, IRB389-00
Study First Received: December 11, 2007
Results First Received: October 19, 2010
Last Updated: December 2, 2010
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Hodgkin Disease
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Lymphoma
Lymphoma, Non-Hodgkin
Multiple Myeloma
Neoplasms, Plasma Cell
Myelodysplastic Syndromes
Preleukemia
Lymphoma, T-Cell
 Lymphoma, T-Cell, Peripheral
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias

ClinicalTrials.gov processed this record on May 23, 2013