Clofarabine, Melphalan, and Thiotepa Followed By a Donor Stem Cell Transplant in Treating Patients With High-Risk and/or Advanced Hematologic Cancer or Other Disease

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by Memorial Sloan-Kettering Cancer Center
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier:
NCT00423514
First received: January 16, 2007
Last updated: June 5, 2014
Last verified: June 2014
  Purpose

RATIONALE: Giving chemotherapy, such as clofarabine, melphalan, and thiotepa, before a donor stem cell transplant helps stop the growth of cancer or abnormal cells. It also helps stop the patient's immune system from rejecting the donor's stem 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 also make an immune response against the body's normal cells. Giving tacrolimus and mycophenolate mofetil before the transplant may stop this from happening.

PURPOSE: This phase I/II trial is studying the side effects and best dose of clofarabine when given together with melphalan and thiotepa, followed by a donor stem cell transplant and to see how well it works in treating patients with high-risk and/or advanced hematologic cancer or other disease.


Condition Intervention Phase
Graft Versus Host Disease
Leukemia
Myelodysplastic Syndromes
Biological: filgrastim
Drug: clofarabine
Drug: melphalan
Drug: mycophenolate mofetil
Drug: tacrolimus
Drug: thiotepa
Procedure: allogeneic bone marrow transplantation
Procedure: allogeneic hematopoietic stem cell transplantation
Procedure: peripheral blood stem cell transplantation
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/II Dose Escalation Trial of Clofarabine, in Addition to Melphalan and Thiotepa as Myeloablative Regimen Followed by an Allogeneic Unmodified Hematopoietic Stem Cell Transplant From HLA-Compatible Related or Unrelated Donors for the Treatment of High Risk and/or Advanced Hematologic Malignancies

Resource links provided by NLM:


Further study details as provided by Memorial Sloan-Kettering Cancer Center:

Primary Outcome Measures:
  • Relapse of leukemia [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • Overall and disease-free survival [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Early post-transplant regimen-related severe morbidity (grade III to IV nonhematologic toxicity) and mortality as measured by the NCI Cancer Therapy Evaluation Program CTCAE v 3.0 [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 42
Study Start Date: November 2006
Estimated Study Completion Date: November 2015
Estimated Primary Completion Date: November 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: cytoreduction regimen & stem cell transplant
This is a single arm phase I/II clinical trial to assess efficacy (the antileukemic potential and relapse rate), and safety (peri-transplant morbidity and mortality) of a novel cytoreduction regimen in preparation for allogeneic hematopoietic stem cell transplantation (HSCT).
Biological: filgrastim Drug: clofarabine Drug: melphalan Drug: mycophenolate mofetil Drug: tacrolimus Drug: thiotepa Procedure: allogeneic bone marrow transplantation Procedure: allogeneic hematopoietic stem cell transplantation Procedure: peripheral blood stem cell transplantation

Detailed Description:

OBJECTIVES:

Primary

  • Determine the maximum tolerated dose of clofarabine when administered with melphalan and thiotepa followed by allogeneic stem cell transplantation in patients with high-risk and/or advanced hematologic malignancies. (Phase I)
  • Determine the 1-year disease-free survival of patients treated with this regimen. (Phase II)
  • Determine the efficacy of this regimen, in terms of antileukemic potential and relapse rate, in these patients.

Secondary

  • Evaluate the incidence and severity of nonhematologic toxicity of this regimen in these patients.
  • Evaluate the incidence and severity of graft-versus-host disease in patients treated with this regimen.

OUTLINE: This is a phase I, dose-escalation study of clofarabine followed by an open-label, phase II study. Patients are stratified according to HLA-compatible donor type (related vs unrelated).

  • Cytoreductive therapy: Patients receive clofarabine IV over 2 hours once daily on days -9 to -5, thiotepa IV over 4 hours on day -4, and melphalan IV over 30 minutes once daily on days -3 and -2.

Cohorts of 3-6 patients receive escalating doses of clofarabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

  • Graft-versus-host disease (GVHD) prophylaxis: Patients who undergo bone marrow or peripheral blood stem cell transplantation receive tacrolimus IV continuously over 24 hours or orally every 8-12 hours beginning on day -3 and methotrexate IV on days 1, 3, 6, and 11. Patients who undergo UCB transplantation receive tacrolimus IV continuously over 24 hours or orally every 8-12 hours beginning on day -3 and mycophenolate mofetil (MMF) IV or orally 2 or 3 times daily on days -3 to 45 followed by a taper until day 100 (unless there are signs of acute GVHD). Patients who undergo UCB transplantation without GVHD continue tacrolimus for 6 months followed by a taper and discontinued 1 year after transplantation.
  • Allogeneic hematopoietic stem cell transplantation (HSCT) or allogeneic umbilical cord blood (UCB) transplantation: Patients undergo allogeneic HSCT (bone marrow or peripheral blood stem cells) or double UCB transplantation on day 0. Patients also receive filgrastim (G-CSF) IV or subcutaneously beginning on day 7 and continuing until blood counts recover.
  • Maintenance therapy: Approximately 2 months after transplantation patients with ALL, M4 or M5 AML, and those transplanted with AML in bone marrow relapse receive cytarabine intrathecally (IT) monthly for up to 5 doses. Patients with a history of CNS leukemia receive cytarabine IT once monthly during months 2-12 after HSCT.

After completion of study therapy, patients are followed periodically for at least 4 years.

PROJECTED ACCRUAL: A total of 42 patients will be accrued for this study.

  Eligibility

Ages Eligible for Study:   up to 54 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Histologically or cytologically confirmed diagnosis of 1 of the following:

    • Acute myelogenous leukemia, meeting 1 of the following criteria:

      • In first complete remission (CR), meeting 1 of the following criteria:

        • Poor risk [no t(15,17), inv 16, or t(8,21)]
        • Not a candidate for total body irradiation (TBI)
        • Any infant in first CR
      • In second CR, meeting the following criteria:

        • All patients
      • In more than second CR OR relapsed/refractory disease, meeting the following criteria:

        • All patients
        • Blast percentage > 5% and < 25% in bone marrow (BM) at the time of stem cell transplantation (SCT)
    • Acute lymphoblastic leukemia, meeting 1 of the following criteria:

      • In first CR, meeting 1 of the following criteria:

        • Poor risk [t(9;22), t(4;11) AND no CR after 7-28 days of induction]
        • Not a candidate for TBI
        • Any infant in first CR
      • In second CR, meeting the following criteria:

        • All patients
      • In more than second CR OR relapsed/refractory disease, meeting the following criteria:

        • All patients
        • Blast percentage > 5% and < 25% in BM at the time of SCT
      • Acute undifferentiated or biphenotypic leukemia, meeting the following criteria:

        • All patients
        • Blast percentage > 5% and < 25% in BM at the time of SCT
      • Chronic myelogenous leukemia, meeting the following criteria:

        • All patients
        • In first chronic phase
      • Myelodysplastic syndrome, meeting 1 of the following criteria:

        • Primary high risk disease

          • Stage > RAEB1
        • Secondary high risk disease

          • All patients
          • Any stage
        • Juvenile myelomonocytic leukemia

          • All patients
  • No doubling of peripheral blast counts within a period of 2 weeks
  • No active CNS disease
  • HLA-compatible donor available meeting 1 of the following criteria:

    • Related donor

      • Genotypically or phenotypically matched at ≥ 7 or 8 of HLA-A, -B, -C and -DRB1 alleles
    • Unrelated donor meeting 1 of the following criteria:

      • 8 of 8 alleles matched
      • For patients < 18 years old only: 7 or 8 alleles matched with the mismatch at only 1 HLA-A, -B, -C, or -DRB1 allele
  • Two HLA-compatible unrelated cord blood (UCB) units available meeting the following criteria:

    • HLA-matched minimally at 4 of 6 HLA-A, HLA-B, and DRB1 allele

      • HLA-A and HLA-B matched at intermediate resolution by molecular technique
      • DRB1 allele matched at high resolution by molecular technique
    • Both matched UCB units with cryopreserved nucleated cell dose ≥ 1.5 x 10^7/kg

PATIENT CHARACTERISTICS:

  • Karnofsky OR Lansky performance status 70-100%
  • SGOT < 2 times upper limit of normal
  • Bilirubin < 1.5 mg/dL (unless there is liver disease involvement)
  • Creatinine normal OR creatinine clearance > 60 mL/min
  • LVEF > 50% at rest OR shortening fraction ≥ 29%
  • Patients with asymptomatic pulmonary disease with no prior risk factors OR symptomatic pulmonary disease with diffusion capacity > 50% of predicted (corrected for hemoglobin) are eligible
  • No active uncontrolled viral, bacterial, or fungal infection
  • No known HIV I or II positivity
  • No known human T-cell lymphotrophic virus I or II positivity
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

  • No hydroxyurea within the past 2 weeks
  • No allogeneic or autologous stem cell transplantation within the past 6 months
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00423514

Contacts
Contact: Farid Boulad, M.D. 212-639-6684
Contact: Esperanza Papadopoulos, M.D. 212-639-8276

Locations
United States, New York
Memorial Sloan-Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Farid Boulad, MD    212-639-6684      
Contact: Esperanza Papadopoulos, MD    212-639-8276      
Principal Investigator: Faird Boulad, MD         
Sponsors and Collaborators
Memorial Sloan-Kettering Cancer Center
Investigators
Principal Investigator: Farid Boulad, MD Memorial Sloan-Kettering Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT00423514     History of Changes
Other Study ID Numbers: 06-125, MSKCC-06125
Study First Received: January 16, 2007
Last Updated: June 5, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Memorial Sloan-Kettering Cancer Center:
graft versus host disease
adult acute lymphoblastic leukemia in remission
adult acute myeloid leukemia in remission
childhood acute lymphoblastic leukemia in remission
childhood chronic myelogenous leukemia
recurrent childhood acute myeloid leukemia
accelerated phase chronic myelogenous leukemia
acute undifferentiated leukemia
adult acute myeloid leukemia with 11q23 (MLL) abnormalities
blastic phase chronic myelogenous leukemia
juvenile myelomonocytic leukemia
previously treated myelodysplastic syndromes
recurrent adult acute lymphoblastic leukemia
recurrent adult acute myeloid leukemia
relapsing chronic myelogenous leukemia
secondary acute myeloid leukemia
secondary myelodysplastic syndromes
childhood acute myeloid leukemia in remission
de novo myelodysplastic syndromes
recurrent childhood acute lymphoblastic leukemia
chronic phase chronic myelogenous leukemia
adult acute myeloid leukemia with inv(16)(p13;q22)
adult acute myeloid leukemia with t(15;17)(q22;q12)
adult acute myeloid leukemia with t(16;16)(p13;q22)
adult acute myeloid leukemia with t(8;21)(q22;q22)
childhood myelodysplastic syndromes

Additional relevant MeSH terms:
Graft vs Host Disease
Leukemia
Myelodysplastic Syndromes
Preleukemia
Immune System Diseases
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Melphalan
Thiotepa
Clofarabine
Mycophenolic Acid
Mycophenolate mofetil
Tacrolimus
Lenograstim
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Myeloablative Agonists
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Enzyme Inhibitors
Antibiotics, Antineoplastic
Antimetabolites, Antineoplastic

ClinicalTrials.gov processed this record on July 31, 2014