Haploidentical Hematopoietic Stem Cell Transplantation Using A Novel Clofarabine Containing Conditioning Regimen For Patients With Refractory Hematologic Malignancies

Study Overview
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Brief Summary
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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.

Detailed Description
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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

Official Title
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Haploidentical Hematopoietic Stem Cell Transplantation Using A Novel Clofarabine Containing Conditioning Regimen For Patients With Refractory Hematologic Malignancies

Conditions
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Hematologic Malignancies

Intervention / Treatment
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* Drug: Clofarabine
* Procedure: Stem Cell Transplantation, Hematopoietic
* Other: OKT3
* Drug: Thiotepa
* Drug: Melphalan
* Drug: Mycophenolate mofetil
* Drug: Rituximab
* Other: G-CSF


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age less than or equal to 21 years old; may be greater than 21 years old if a previously treated St. Jude patient and within 3 years of completion of most recent prior disease specific therapy. One of the following refractory hematologic malignancies (chemoresistant relapse or primary induction failure) or diagnoses: ALL AML (>25% blasts in the bone marrow) secondary AML/MDS CML in accelerated phase or blast crisis juvenile myelomonocytic leukemia (JMML) myelodysplastic syndrome (MDS) Hodgkin or non-Hodgkin lymphoma (NHL) with residual or recurrent disease following autologous HSCT, who are unable to undergo autologous HSCT due to chemo-resistant disease or inability to have an acceptable quantity of tumor-free stem cells collected (> 1 x 108 TNC/kg marrow or > 1 x 106 CD34+/kg PBS patients with a hematologic malignancy who have undergone prior allogeneic HSCT or who have a co-morbid condition that in the medical opinion of medical faculty (Division of Bone Marrow Transplantation and Cellular Therapy) makes standard myeloablation prohibitive Does not have any other active malignancy other than the one for which this transplant is indicated Cardiac shortening fraction greater than or equal to 25% For pediatric patients, creatinine clearance greater than or equal to 90 ml/min/1.73 m2 according to the Schwartz formula for estimated GFR (ml/min/1.73m2) = k*height (cm)/serum creatinine (mg/dL). k is a proportionality constant that varies with age and is a function of urinary creatinine clearance per unit of body size; 0.45 up to 12 months of age; 0.55 children and adolescent girls; and 0.70 for adolescent boys For adolescent or adult patients, serum creatinine 1.0 mg/dL; if serum creatinine 1.0 mg/dL, then the estimated glomerular filtration rate (GFR) must be 60 mL/min/1.73 m2 as calculated by the Modification of Diet in Renal Disease equation where predicted GFR (ml/min/1.73 m2) = 186 x (serum creatinine)-1.154 x (age in years)-0.023 x (0.742 if patient is female) x (1.212 if patient is black) Forced vital capacity (FVC) greater than or equal to 40% of predicted value or pulse oximetry greater than or equal to 92% on room air. Karnofsky or Lansky (age-dependent) performance score of greater than or equal to 50 (See APPENDIX A) Does not have active acute or active chronic GVHD defined as requiring medical therapy. Does not have active acute bronchiolitis obliterans (BO) or bronchiolitis obliterans organizing pneumonia (BOOP). Has a suitable HLA partially matched family member donor available for stem cell donation Bilirubin less than or equal to 1.5 times the upper limit of normal for age. Alanine aminotransferase (ALT) less than or equal to 1.5 times the upper limit of normal for age. Aspartate aminotransferase (AST) less than or equal to 1.5 times the upper limit of normal for age. Not pregnant (confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment). Not lactating Inclusion criteria (stem cell donor): Partially HLA-matched family member. At least 18 years of age. HIV negative Not pregnant (confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment). Not lactating

Ages Eligible for Study
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Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: Clofarabine<br>* 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<br>Procedure: Stem Cell Transplantation, Hematopoietic<br>* Haploidentical Hematopoietic Stem Cell Transplantation (two infusions, one on day 0 and the other on day +1)<br>Other: OKT3<br>* Start at 0.0125 mg/kg intravenous once a day, taper dose down incrementally and discontinue after 17 days total Muromonab-CD3<br>* Other names: Orthoclone OKT3;Drug: Thiotepa<br>* 5 mg/kg/day intravenous every 12 hours (2 doses total)<br>Drug: Melphalan<br>* 60mg/m2 intravenous every 12 hours for 2 doses total.<br>Drug: Mycophenolate mofetil<br>* Mycophenolate mofetil 600 mg/m2 intravenous two times a day (continue for approximately 2 months or as clinically indicated)<br>* Other names: CellCept;Drug: Rituximab<br>* 375 mg/m2 intravenous for 1 dose total<br>* Other names: Rituxin;Other: G-CSF<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. |  | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stem Cell Transplantation, Hematopoietic, Peripheral Blood Stem Cell Transplantation, Maximal Tolerated Dose, Clofarabine, Hematological Malignancies, Apheresis