Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase II, Phase I Treatment Active Under 55 NCI MSKCC-06125 NCT00423514

Objectives

Primary

1. 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)
2. Determine the 1-year disease-free survival of patients treated with this regimen. (Phase II)
3. Determine the efficacy of this regimen, in terms of antileukemic potential and relapse rate, in these patients.

Secondary

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

Entry Criteria

Disease Characteristics:

• Histologically or cytologically confirmed diagnosis of 1 of the following:
  • Acute lymphoblastic OR myeloid leukemia, meeting 1 of the following criteria:
    • In third or subequent remission
    • Refractory or relapsed disease with blasts > 5% but blasts in bone marrow < 25% at the time of transplant
  • Acute undifferentiated or biphenotypic leukemia, meeting 1 of the following criteria:
    • In second or subsequent remission
    • Refractory or relapsed disease with blasts > 5% but blasts in bone marrow < 25% at the time of transplant
  • Infantile acute leukemia, meeting 1 of the following criteria:
    • In first remission with 11q23 gene rearrangement
    • In second or greater remission with germline 11q23
    • Refractory or relapsed disease with blasts > 5% but blasts in bone marrow < 25% at the time of transplant
  • Myelodysplastic syndromes (MDS), meeting 1 of the following criteria:
    • Primary MDS with excess blasts
    • Secondary MDS of any stage
    • Juvenile myelomonocytic leukemia
  • Chronic myelogenous leukemia
    • In second or greater chronic phase, accelerated phase, or blastic phase



• 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 ≥ 5 or 6 of HLA-A, -B, and -DRB1 alleles
  • Unrelated donor meeting 1 of the following criteria:
    • 10 of 10 alleles matched
    • 8 or 9 of 10 alleles matched with the mismatch at 1 HLA-A, -B, or -DRB1 allele OR 2 HLA-A, -B, -C, -DRB1, or -DQB1 alleles (must be matched at 1 allele for each locus)

Prior/Concurrent Therapy:

• No hydroxyurea within the past 2 weeks
• No allogeneic or autologous stem cell transplantation within the past 6 months
• No prior gemtuzumab ozogamicin

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

Expected Enrollment

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

Outcomes

Relapse of leukemia
Overall and disease-free survival

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

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 receive tacrolimus IV continuously over 24 hours or orally every 8-12 hours beginning on day -1. Patients with matched related donors and without GVHD continue tacrolimus for 60 days followed by a taper until day 168. Patients with matched unrelated donors and without GVHD continue on tacrolimus for 168 days followed by a taper until day 360. Patients also receive mycophenolate mofetil (MMF) IV or orally 3 times daily on days -1 to 30 (if there is acute GVHD requiring systemic therapy by day 30, MMF is discontinued 7 days after control of GVHD).



• Allogeneic hematopoietic stem cell transplantation (HSCT): Patients undergo allogeneic HSCT (bone marrow or peripheral blood stem cells) on day 0. Patients also receive filgrastim (G-CSF) IV or subcutaneously beginning on day 7 and continuing until blood counts recover.



• Maintenance therapy: Patients with acute leukemia receive cytarabine intrathecally (IT) at 2 months after HSCT and then once a month for 5 months. 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.

Trial Contact Information

Trial Lead Organizations

Memorial Sloan-Kettering Cancer Center

Farid Boulad, MD, Principal investigator		Ph: 212-639-6684; 800-525-2225 Email: bouladf@mskcc.org
Esperanza B. Papadopoulos, MD, Principal investigator		Ph: 212-639-8276; 800-525-2225 Email: papadope@mskcc.org

U.S.A.
New York
	New York
	Memorial Sloan-Kettering Cancer Center
		Farid Boulad, MD	Ph:  212-639-6684 800-525-2225
			Email: bouladf@mskcc.org

Registry Information
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
Trial Start Date		2006-11-20
Trial Completion Date		2010-11-22 (estimated)
Registered in ClinicalTrials.gov		NCT00423514
Date Submitted to PDQ		2006-11-29
Information Last Verified		2008-09-12
NCI Grant/Contract Number		CA08748