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

Sponsor

Memorial Sloan Kettering Cancer Center (Other)

Overall Status

Completed

CT.gov ID

NCT00423514

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

Arm

174.9

Actual Duration (Months)

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	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

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

42 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (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

Actual Study Start Date :

Nov 20, 2006

Actual Primary Completion Date :

Jun 18, 2021

Actual Study Completion Date :

Jun 18, 2021

Arms and Interventions

Arm	Intervention/Treatment
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

Arm

Intervention/Treatment

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

Outcome Measures

Primary Outcome Measures

Relapse of leukemia [1 year]
Overall and disease-free survival [1 year]

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 [1 year]

Eligibility Criteria

Criteria

Ages Eligible for Study:

0 Years to 54 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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