Patients with refractory hematologic malignancies including those who develop recurrent disease after allogeneic hematopoietic stem cell transplantation (HSCT) have a dismal prognosis. Historically, both regimen-related mortality and disease recurrence have been significant causes of treatment failure in this heavily pre-treated patient population. The investigators institution has utilized mismatched family member donors for these patients for several reasons: (1) Only 30% of patients have matched related donors available; (2) transplantation can be performed more rapidly since the time to unrelated donor trans-plantation averages 3 to 4 months; (3) the alloimmune reactivity of natural killer (NK) cells following haploidentical HSCT has been shown to reduce relapse rates in certain patient groups; and, (4) no other curative treatment options are available. In the present trial, the investigators propose a novel conditioning regimen using clofarabine in an effort to enhance cytotoxicity while simultaneously reducing regimen related toxicity. In this phase I trial, the goal is to determine the maximum tolerated dose (MTD) of clofarabine when used in combination with melphalan and thiotepa pre-transplant.
The primary objective of this trial is to determine the maximum tolerated dose of clofarabine in combination with thiotepa and melphalan as a conditioning regimen for a haploidentical stem cell transplant with an engineered graft depleted of CD3+ cells. Study participants will children and young adults with refractory hematologic malignancies. Secondary objectives include the following: * To describe the one-year overall survival (OS) and event-free survival (EFS) rates in these study participants. * To determine the time to hematopoietic recovery and donor cell engraftment following this study treatment. * To estimate the cumulative incidence of relapse in study participants. * To estimate the incidence of overall grade II-IV and grade III-IV acute GVHD and the rate of chronic GVHD. * To estimate the incidence and describe the causes of non-hematologic regimen-related toxicity and regimen-related mortality in the first 100 days post HSCT. * To explore the biologic significance of soluble interleukin-2 (IL-2) receptor, tumor necrosis factor (TNF), and lymphocyte reconstitution (qualitative and quantitative, V beta spectratyping, TREC
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
34
One dose intravenously every 24 hrs for five days total. Dose level 1 Clofarabine 40 mg/m2/day intravenous Dose level 2 Clofarabine 45 mg/m2/day intravenous Dose Level 3 Clofarabine 50 mg/m2/day intravenous
Haploidentical Hematopoietic Stem Cell Transplantation (two infusions, one on day 0 and the other on day +1)
Start at 0.0125 mg/kg intravenous once a day, taper dose down incrementally and discontinue after 17 days total Muromonab-CD3
5 mg/kg/day intravenous every 12 hours (2 doses total)
60mg/m2 intravenous every 12 hours for 2 doses total.
Mycophenolate mofetil 600 mg/m2 intravenous two times a day (continue for approximately 2 months or as clinically indicated)
375 mg/m2 intravenous for 1 dose total
G-CSF 5 mcg/kg/day subcutaneous or intravenous until ANC greater than 2.000/mm3 for 2 consecutive days and then as clinically indicated.
St. Jude Children's Research Hospital
Memphis, Tennessee, United States
To determine the MTD and DLT of clofarabine in combination with thiotepa and melphalan as a conditioning regimen for a haploidentical HSCT with an engineered graft depleted of CD3+ cells obtained by negative selection with OKT3 on the CliniMACS system.
Time frame: 30 days
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