Clinical Trials /

Clofarabine and Melphalan Before Donor Stem Cell Transplant in Treating Patients With Myelodysplasia, Acute Leukemia in Remission, or Chronic Myelomonocytic Leukemia

NCT01885689

Description:

This phase II trial studies how well clofarabine and melphalan before a donor stem cell transplant works in treating patients with a decrease in or disappearance of signs and symptoms of myelodysplasia or acute leukemia (disease is in remission), or chronic myelomonocytic leukemia. Giving chemotherapy, such as clofarabine and melphalan, 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. When the healthy stem cells from a donor are infused into a patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Giving clofarabine and melphalan before transplant may help prevent the cancer from coming back after transplant, and they may cause fewer side effects than standard treatment.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Clofarabine and Melphalan Before Donor Stem Cell Transplant in Treating Patients With Myelodysplasia, Acute Leukemia in Remission, or Chronic Myelomonocytic Leukemia
  • Official Title: Phase II Study of Clofarabine and High-Dose Melphalan Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation for Myelodysplasia or Acute Leukemia in Remission

Clinical Trial IDs

  • ORG STUDY ID: 13130
  • SECONDARY ID: NCI-2013-01193
  • NCT ID: NCT01885689

Conditions

  • Adult Acute Lymphoblastic Leukemia in Remission
  • Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
  • Adult Acute Myeloid Leukemia in Remission
  • Myelodysplastic Syndrome
  • Secondary Myelodysplastic Syndrome
  • Chronic Myelomonocytic Leukemia
  • Therapy-Related Myelodysplastic Syndrome

Interventions

DrugSynonymsArms
clofarabineCAFdA, Clofarex, ClolarTreatment (clofarabine, melphalan, transplant)
melphalanAlkeran, CB-3025, L-PAM, L-phenylalanine mustard, L-SarcolysinTreatment (clofarabine, melphalan, transplant)
tacrolimusFK 506, PrografTreatment (clofarabine, melphalan, transplant)
sirolimusAY 22989, Rapamune, rapamycin, SLMTreatment (clofarabine, melphalan, transplant)

Purpose

This phase II trial studies how well clofarabine and melphalan before a donor stem cell transplant works in treating patients with a decrease in or disappearance of signs and symptoms of myelodysplasia or acute leukemia (disease is in remission), or chronic myelomonocytic leukemia. Giving chemotherapy, such as clofarabine and melphalan, 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. When the healthy stem cells from a donor are infused into a patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Giving clofarabine and melphalan before transplant may help prevent the cancer from coming back after transplant, and they may cause fewer side effects than standard treatment.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Following a patient safety lead-in, determine the anti-tumor activity of clofarabine given
      in combination with high-dose melphalan as assessed by 2-year progression-free survival
      (PFS).

      II. Estimate overall survival (OS), cumulative incidence (CI) of relapse/progression and
      non-relapse mortality (NRM) at 100 days, 1 year and 2 years.

      III. Summarize toxicities/complications by organ and severity, including acute and chronic
      graft-vs-host disease (GVHD), and infection.

      OUTLINE:

      CONDITIONING REGIMEN: Patients receive clofarabine intravenously (IV) over 2 hours on days -9
      to -5 and melphalan IV over 30 minutes on day -4.

      TRANSPLANT: Patients undergo allogeneic hematopoietic stem cell transplant on day 0.

      GVHD PROPHYLAXIS: Beginning on day -3, patients receive tacrolimus IV or orally (PO) and
      sirolimus PO once daily with taper per City of Hope standard operating procedure.

      After completion of study treatment, patients are followed up once weekly for 60 days, at
      100, and 180 days, at one year, and then yearly for up to 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (clofarabine, melphalan, transplant)ExperimentalCONDITIONING REGIMEN: Patients receive clofarabine IV over 2 hours on days -9 to -5 and melphalan IV over 30 minutes on day -4. TRANSPLANT: Patients undergo allogeneic hematopoietic stem cell transplant on day 0. GVHD PROPHYLAXIS: Beginning on day -3, patients receive tacrolimus IV or PO and sirolimus PO once daily with taper per City of Hope standard operating procedure.
  • clofarabine
  • melphalan
  • tacrolimus
  • sirolimus

Eligibility Criteria

        Inclusion Criteria:

          -  Patients in 1st or 2nd remission with acute myeloid leukemia (AML) or acute
             lymphoblastic leukemia (ALL), who are eligible for stem cell transplant. Remission
             defined as no circulating blasts, < 5% blasts in the bone marrow, normalization of
             previously detected cytogenetic abnormalities, no extramedullary disease

          -  High risk myelodysplastic syndrome (MDS)

               -  Intermediate II and high risk by International Prognostic Scoring System (IPSS)

               -  Intermediate, high, or very high by World Health Organization (WHO)
                  classification-based Prognostic Scoring System (WPSS)

               -  Transfusion dependent

               -  Therapy-related MDS or MDS evolved from previous hematological disorder
                  (excepting myelofibrosis)

          -  Patients with chronic myelomonocytic leukemia (CMML) are allowed to be enrolled

          -  Patients with MDS that has evolved to AML must be in remission

          -  Patients must not be eligible for full ablative regimens by the attending physician

          -  Patients with AML or MDS arising from myeloproliferative neoplasm can be enrolled
             after principal investigator (PI) approval on case to case basis, depends on the
             spleen size and degree of bone marrow fibrosis

          -  Performance status of >= 70% on the Karnofsky scale

          -  Women of child-bearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control or abstinence) prior to study entry and
             for six months following duration of study participation; should a woman become
             pregnant or suspect she is pregnant while participating on the trial, she should
             inform her treating physician immediately

          -  Bone marrow and peripheral blood studies must be available for confirmation of
             diagnosis; cytogenetics, flow cytometry, and molecular studies (such as Flt-3 status)
             will be obtained as per standard practice

          -  Bone marrow aspirates/biopsies should be performed within 28 (+ 4 day window) days
             from registration to confirm disease remission status

          -  A pretreatment measured creatinine clearance (absolute value) of >= 60 mL/minute

          -  Patients must have a serum bilirubin =< 2.0 mg/dl

          -  Patients must have serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate
             pyruvate transaminase (SGPT) =< 2.5 times the institutional upper limit of normal

          -  Ejection fraction measured by echocardiogram or multi gated acquisition scan (MUGA) >
             50%

          -  Diffusing capacity of the lung for carbon monoxide (DLCO) or forced expiratory volume
             in 1 second (FEV1) > 45% predicted

          -  Availability of a human leukocyte antigen (HLA) matched (6/6) sibling donor or 8/8
             matched unrelated donor; Donors with mismatch at HLA-A, HLA-B, HLA-C, and HLA-DR will
             be reviewed by matched unrelated donor (MUD) committee and allowed if their mismatch
             with the recipient does not require additional GVHD prophylaxis (other than tacrolimus
             and sirolimus), donors with mismatch at HLA-DQ or HLA-DPB are eligible; donor
             evaluation according to City of Hope (COH) standard operating procedure (SOP)

          -  Donor stem cell source can be either peripheral blood or bone marrow

          -  All patients must have a psychosocial evaluation prior to transplant as per COH SOP

          -  All subjects must have the ability to understand and the willingness to sign a written
             informed consent

          -  ALL or AML patients who received chemotherapy (induction or consolidation) can proceed
             to transplant once bone marrow cellularity is > 10 % with no evidence of leukemia

        Exclusion Criteria:

          -  Patients who have received a prior autologous or allogeneic transplant are excluded

          -  Patients with significant hepatic dysfunction (not meeting liver function tests [LFT]
             eligibility criteria)

          -  Patients with MDS evolved into AML that is not in remission

          -  Patients with acute promyelocytic leukemia

          -  Patients with myeloproliferative neoplasms

          -  Patients with suspected or proven central nervous system (CNS) leukemia; (diagnostic
             lumbar puncture not required before enrollment)

          -  Uncontrolled intercurrent illness including, but not limited to ongoing or active or
             poorly controlled infection, symptomatic congestive heart failure, unstable angina
             pectoris, cardiac arrhythmia, poorly controlled pulmonary disease or psychiatric
             illness/social situations that would limit compliance with study requirements

          -  Pregnant and lactating women are excluded from this study

          -  Patients who do not agree to practice effective forms of contraception

          -  Human immunodeficiency virus (HIV)-positive patients are excluded from this study

          -  Patients are excluded if they are hepatitis B surface antigen (sAg), hepatitis B (Hep
             B) core antibody (cAb), or hepatitis C (Hep C) positive. Patients with Hepatitis B cAB
             positive and Hepatitis B PCR negative are eligible if they started prophylactic
             treatment prior to registration to trial

          -  Patients who have received radiation therapy as part of their leukemia treatment may
             be ineligible and individual cases must be presented to the study principal
             investigator (PI) for determination of eligibility

          -  Any psychiatric, social or compliance issues that, in the treating physician's
             opinion, will interfere with completion of the transplant treatment and follow up

          -  Medical or psychiatric reasons which make the donor unlikely to tolerate or cooperate
             with filgrastim (G-CSF) therapy or leukapheresis or bone marrow harvest

          -  Known allergies to clofarabine, melphalan, sirolimus or tacrolimus

          -  Patients with other active malignancies (besides AML, ALL, MDS) requiring treatment or
             where there is concern of progression are ineligible for this study; however, patients
             with previously treated skin cancer, early stage cervical or prostate cancer may be
             eligible if there is no evidence of residual disease

          -  Cord blood as a donor source is not acceptable

          -  Subjects, who in the opinion of the investigator, may not be able to comply with the
             safety monitoring requirements of the study
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival
Time Frame:From start of treatment to the date of death, disease relapse/progression, or last follow-up whichever occurs first, assessed at 2 years
Safety Issue:
Description:Calculated using the Kaplan-Meier product-limit method.

Secondary Outcome Measures

Measure:Overall survival
Time Frame:From start of treatment until death, or last follow-up, whichever comes first, assessed up to 5 years
Safety Issue:
Description:Calculated using the Kaplan-Meier product-limit method.
Measure:Cumulative incidence of relapse/progression
Time Frame:From start of treatment, assessed up to 5 years
Safety Issue:
Description:Calculated as competing risks using the Gray method.
Measure:Cumulative incidence of non-relapse mortality defined as death occurring in a patient from causes other than relapse or progression
Time Frame:From start of treatment until non-disease death, assessed up to 5 years
Safety Issue:
Description:Calculated as competing risks using the Gray method.
Measure:Overall toxicity graded using the Bearman scale and CTCAE v4.03
Time Frame:Up to 100 days post-transplant
Safety Issue:
Description:Toxicity information recorded will include the type, severity, and the probable association with the study regimen. Tables will be constructed to summarize the observed incidence by severity and type of toxicity.
Measure:Incidence and severity of acute GVHD of grades 2-4 and 3-4 according to the consensus grading
Time Frame:Up to 100 days post-transplant
Safety Issue:
Description:The first day of acute GVHD onset at a certain grade will be used to calculate cumulative incidence curves for that GVHD grade.
Measure:Incidence and severity of chronic GVHD scored according to National Institute of Health (NIH) consensus staging
Time Frame:After 100 days post-transplant
Safety Issue:
Description:The first day of chronic GVHD onset will be used to calculate cumulative incidence curves.
Measure:Microbiologically documented infection
Time Frame:Up to 100 days post-transplant
Safety Issue:
Description:Reported by site of disease, date of onset, severity and resolution, if any.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:City of Hope Medical Center

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