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

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2014 by City of Hope Medical Center
Sponsor:
Collaborator:
Information provided by (Responsible Party):
City of Hope Medical Center
ClinicalTrials.gov Identifier:
NCT01885689
First received: June 21, 2013
Last updated: November 11, 2014
Last verified: November 2014
  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. 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.


Condition Intervention Phase
Adult Acute Lymphoblastic Leukemia in Remission
Adult Acute Megakaryoblastic Leukemia (M7)
Adult Acute Minimally Differentiated Myeloid Leukemia (M0)
Adult Acute Monoblastic Leukemia (M5a)
Adult Acute Monocytic Leukemia (M5b)
Adult Acute Myeloblastic Leukemia With Maturation (M2)
Adult Acute Myeloblastic Leukemia Without Maturation (M1)
Adult Acute Myeloid Leukemia in Remission
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
Adult Acute Myeloid Leukemia With Del(5q)
Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
Adult Acute Myelomonocytic Leukemia (M4)
Adult Erythroleukemia (M6a)
Adult Pure Erythroid Leukemia (M6b)
Previously Treated Myelodysplastic Syndromes
Secondary Acute Myeloid Leukemia
Drug: clofarabine
Drug: melphalan
Procedure: allogeneic hematopoietic stem cell transplantation
Other: laboratory biomarker analysis
Drug: tacrolimus
Drug: sirolimus
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: Phase II Study of Clofarabine and High-Dose Melphalan Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation for Myelodysplasia or Acute Leukemia in Remission

Resource links provided by NLM:


Further study details as provided by City of Hope Medical Center:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    Calculated using the Kaplan-Meier product-limit method.


Secondary Outcome Measures:
  • Overall survival [ Time Frame: From start of treatment until death, or last follow-up, whichever comes first, assessed up to 5 years ] [ Designated as safety issue: No ]
    Calculated using the Kaplan-Meier product-limit method.

  • Cumulative incidence of relapse/progression [ Time Frame: From start of treatment, assessed up to 5 years ] [ Designated as safety issue: No ]
    Calculated as competing risks using the Gray method.

  • 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 ] [ Designated as safety issue: No ]
    Calculated as competing risks using the Gray method.

  • Overall toxicity graded using the Bearman scale and CTCAE v4.0 [ Time Frame: Up to 100 days post-transplant ] [ Designated as safety issue: Yes ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    The first day of acute GVHD onset at a certain grade will be used to calculate cumulative incidence curves for that GVHD grade.

  • Incidence and severity of chronic GVHD scored according to National Institute of Health (NIH) consensus staging [ Time Frame: After 100 days post-transplant ] [ Designated as safety issue: No ]
    The first day of chronic GVHD onset will be used to calculate cumulative incidence curves.

  • Microbiologically documented infection [ Time Frame: Up to 100 days post-transplant ] [ Designated as safety issue: No ]
    Reported by site of disease, date of onset, severity and resolution, if any.


Estimated Enrollment: 77
Study Start Date: January 2014
Estimated Primary Completion Date: December 2021 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (clofarabine, melphalan, transplant)

CONDITIONING REGIMEN: Patients receive clofarabine IV over 2 hours on days -9 to -5 and melphalan IV over 20 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.

Drug: clofarabine
Given IV
Other Names:
  • CAFdA
  • Clofarex
  • Clolar
Drug: melphalan
Given IV
Other Names:
  • Alkeran
  • CB-3025
  • L-PAM
  • L-phenylalanine mustard
  • L-Sarcolysin
Procedure: allogeneic hematopoietic stem cell transplantation
Undergo allogeneic hematopoietic stem cell transplant
Other: laboratory biomarker analysis
Correlative studies
Drug: tacrolimus
Given IV or PO
Other Names:
  • FK 506
  • Prograf
Drug: sirolimus
Given PO
Other Names:
  • AY 22989
  • Rapamune
  • rapamycin
  • SLM

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 20 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 on 30, 100, and 180 days, and then yearly for 5 years.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients in 1st or 2nd remission with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) (no circulating blasts, < 5% myeloblasts in the bone marrow, normalization of previously detected cytogenetic abnormalities, no extramedullary disease )
  • High risk myelodysplastic syndrome (MDS) (not myeloproliferative neoplasms)

    • 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 MDS that has evolved to AML must be in remission
  • Patient must not be eligible for full ablative regimens by the attending physician
  • 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 fms-related tyrosine kinase 3 [Flt-3] status) will be obtained as per standard practice
  • Bone marrow aspirates/biopsies should be performed within 14 +/- 7 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 an human leukocyte antigen (HLA) matched (6/6) sibling donor or 8/8 matched unrelated donor (no mismatch allowed in HLA-A, HLA-B, HLA-C and HLA-DR, donors with mismatch HLA-DQ or HLA-DPH are eligible)
  • Donor stem cell source can be either peripheral blood or bone marrow
  • All patients must have a psychosocial evaluation prior to transplant as per City of Hope (COH) standard operating procedure (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 myelofibrosis or AML evolved from myelofibrosis
  • 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 or 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 antigen (cAg), Hep B core antibody (cAb), or hepatitis C (Hep C) positive
  • 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
  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: NCT01885689

Locations
United States, California
City of Hope Medical Center Recruiting
Duarte, California, United States, 91010
Contact: Samer K. Khaled, MD    800-826-4673    skhaled@coh.org   
Principal Investigator: Samer K. Khaled         
Sponsors and Collaborators
City of Hope Medical Center
Investigators
Principal Investigator: Samer Khaled City of Hope Medical Center
  More Information

No publications provided

Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT01885689     History of Changes
Other Study ID Numbers: 13130, NCI-2013-01193
Study First Received: June 21, 2013
Last Updated: November 11, 2014
Health Authority: United States: Federal Government

Additional relevant MeSH terms:
Myelodysplastic Syndromes
Preleukemia
Acute Disease
Leukemia
Leukemia, Erythroblastic, Acute
Leukemia, Lymphoid
Leukemia, Megakaryoblastic, Acute
Leukemia, Monocytic, Acute
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Bone Marrow Diseases
Disease Attributes
Hematologic Diseases
Immune System Diseases
Immunoproliferative Disorders
Lymphatic Diseases
Lymphoproliferative Disorders
Myelodysplastic-Myeloproliferative Diseases
Myeloproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Pathologic Processes
Precancerous Conditions
Clofarabine
Melphalan
Sirolimus
Tacrolimus

ClinicalTrials.gov processed this record on November 19, 2014