Clofarabine and Low Dose Total Body Irradiation as a Preparative Regimen for Stem Cell Transplant in Leukemia.

Study Overview
=================
Brief Summary
-----------------
Stem cell transplant is an important therapeutic option for pediatric patients with relapsed or refractory leukemia. Although, full myeloablative transplants are widely used for patients with acute leukemia, myeloablative chemo-radiotherapy may not be feasible in some specific settings. These settings include 1) patients with pre-existing health issues and organ toxicities; 2) patients who have relapsed post-ablative transplant and need a second stem cell transplant; and 3) leukemia patients with advanced disease who have been heavily pre-treated. Clofarabine, a new purine nucleoside anti-metabolite, has the advantage of significant antileukemic activity in addition to its possible immuno-suppressive properties. In this study we plan to determine the maximum feasible dose (MFD) of Clofarabine in combination with total body irradiation that can achieve durable donor engraftment without causing excessive toxicity.

Official Title
-----------------
Phase I Feasibility Study of Clofarabine and Low Dose Total Body Irradiation (TBI) as a Non-myeloablative Preparative Regimen for Stem Cell Transplantation (SCT) for Hematologic Malignancies

Conditions
-----------------
Leukemia Lymphoblastic, Acute, Acute Myeloid Leukemia, Neoplasm Recurrent

Intervention / Treatment
-----------------
* Drug: Clofarabine
* Radiation: Total Body Irradiation
* Other: Stem Cell Infusion
* Drug: Cyclosporins
* Drug: Mycophenolate mofetil


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must be greater than or equal to 1 and less than or equal to 21 years of age at the of study entry. Patients must have a diagnosis of ALL or AML. ALL patients must be in clinical remission defined as BM morphology <5% blasts and CNS 1 status. AML patients must be in M1 (<5% blasts) or M2 (<20% blasts) marrow status with CNS 1 status. Patient must have an ANC greater than or equal to 750/ul. Patient must have one of the appropriate donor types as described below: HLA identical sibling donor. Complete matched unrelated donor, (matched at A, B, C, DR B1 and DQ, B1 at the allelic level based on high resolution typing for Class I and II antigens, 10/10 match). 1 allelic mis-matched unrelated donor (antigen mis-matches are not allowed). The stem cell source from the donor must be one of the following: Bone Marrow or Peripheral blood stem cells (PBSC) from a matched related donor. PBSC from an unrelated donor. (Bone marrow is not acceptable for unrelated donors) Karnofsky > 50% for patients > 10 years of age and Lansky > 50% for patients less than or equal to 10 years of age. Female patients of childbearing potential must have a negative serum pregnancy test confirmed within 2 weeks prior to enrollment. Female patients with infants must agree not to breastfeed their infants while on this study. Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study. Patients must have a calculated creatinine clearance ≥ 70mL/min/m2 as calculated by the Schwartz formula for estimated glomerular filtration rate (GFR) where GFR (ml/min/1.73 m2) = k * Height (cm)/serum creatinine (mg/dl). K is a proportionality constant which varies with age and is a function of urinary creatinine excretion per unit of body size; 0.45 up to 12 months of age; 0.55 children and adolescent girls; and 0.70 adolescent boys. Total serum bilirubin < 2 mg/dL. Aspartate transaminase (AST) and alanine transaminase (ALT) less than or equal to 5 × ULN. Patient must have a shortening fraction (SF) > 25%. If the SF is <25%, patient must have an ejection fraction (EF) by MUGA of >30%. Patient must have pulmonary function as defined below: DLCO >30% FVC/TLC >30% FEV1 > 30% of predicted Patient is not on continuous oxygen If patient is not old enough or unable to comply with pulmonary function tests, they must have a pulse ox >92% in room air and not be on continuous oxygen. Patient must have signed informed consent Exclusion Criteria: Patients will be excluded if they have evidence of an active, progressive invasive infection. All patients with existing infections at the time study entry should be discussed with the study chair. Patients may have stable invasive infections and still be eligible. Patients with infections that are responsive to medical or surgical treatment as shown by radiographic and or microbial assessment may still be eligible. Patients will be excluded if they have an active, uncontrolled systemic fungal, bacterial, viral or other infection. All patients with existing infections at the time of study entry should be discussed with the study chair. •An active uncontrolled infection is defined as exhibiting ongoing signs and symptoms related to the infection (fevers, positive blood cultures, chills, tachycardia, etc) despite appropriate antibiotics or other treatment. Patient has a diagnosis of CML or MDS. Patient has CNS 2 or CNS 3 status. Patient is HIV positive. Current or planned treatment with chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol. Use of investigational agents within 30 days or any anticancer therapy within 2 weeks before study entry. Have any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart, kidney (including dialysis patients), liver, or other organ system that may place the patient at undue risk to undergo treatment. Patients with a systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment). Any significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance, study participation, follow up, or interpretation of study results.

Ages Eligible for Study
-----------------
Minimum Age: 1 Year
Maximum Age: 21 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: A<br>Stratum A are those patients with related stem cell donors. | Drug: Clofarabine<br>* Clofarabine will be given as an intravenous infusion over 2 hours on days -6 though -2. The dose of Clofarabine will be assigned at study entry.<br>* Other names: Clolar;Radiation: Total Body Irradiation<br>* Low dose (2 Gy) TBI will be administered from a linear accelerator at ≤ 20 cGy/min on day 0 according to institutional guidelines.<br>* Other names: TBI;Other: Stem Cell Infusion<br>* Patients will be infused with 'unmanipulated' hematopoietic stem cells from a related or unrelated donor on day 0 of the treatment regimen according to institutional practice guidelines.<br>Drug: Cyclosporins<br>* Cyclosporin (CSP) should be started on day -1 after completion of Clofarabine. CSP levels should be maintained between 300-400 ng/ml. Age ≤ 6 years old: 6 mg/kg IV QD. in divided doses (e.g. 2 mg/kg q8hrs). Age > 6 years old: 3 mg/kg IV QD in divided doses (1.5mg/kg q12hrs)<br>* Other names: CSA;Drug: Mycophenolate mofetil<br>* Mycophenolate mofetil (MMF) will be at 15 mg/kg, based on adjusted body weight, every 8 hours (45 mg/kg/day; max.3g/day) PO, or IV if indicated, from the evening of day 0 (i.e. first dose 4-6 hours following stem cell infusion) to day +40 post-transplant.<br>* Other names: MMF;|
| Active Comparator: B<br>Stratum B are those patients with unrelated stem cell donors. | Drug: Clofarabine<br>* Clofarabine will be given as an intravenous infusion over 2 hours on days -6 though -2. The dose of Clofarabine will be assigned at study entry.<br>* Other names: Clolar;Radiation: Total Body Irradiation<br>* Low dose (2 Gy) TBI will be administered from a linear accelerator at ≤ 20 cGy/min on day 0 according to institutional guidelines.<br>* Other names: TBI;Other: Stem Cell Infusion<br>* Patients will be infused with 'unmanipulated' hematopoietic stem cells from a related or unrelated donor on day 0 of the treatment regimen according to institutional practice guidelines.<br>Drug: Cyclosporins<br>* Cyclosporin (CSP) should be started on day -1 after completion of Clofarabine. CSP levels should be maintained between 300-400 ng/ml. Age ≤ 6 years old: 6 mg/kg IV QD. in divided doses (e.g. 2 mg/kg q8hrs). Age > 6 years old: 3 mg/kg IV QD in divided doses (1.5mg/kg q12hrs)<br>* Other names: CSA;Drug: Mycophenolate mofetil<br>* Mycophenolate mofetil (MMF) will be at 15 mg/kg, based on adjusted body weight, every 8 hours (45 mg/kg/day; max.3g/day) PO, or IV if indicated, from the evening of day 0 (i.e. first dose 4-6 hours following stem cell infusion) to day +40 post-transplant.<br>* Other names: MMF;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the maximum feasible dose of Clofarabine that can be given in combination with 2Gy total body irradiation as a non-myeloablative preparative regimen for allogeneic stem cell transplantation in pediatric patients with relapsed leukemia. |  | Day 100 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the rate of engraftment in both matched related donor (MRD) and matched unrelated donor (MUD) settings using this novel preparative regimen. |  | Day 100 | 
| To assess the transplant related mortality (TRM) at day +100, associated with this non-myeloablative regimen. |  | Day 100 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ALL, AML, Recurrence, Relapsed, Stem Cell Transplant, Non-myeloablastive