Clofarabine and Low Dose Total Body Irradiation as a Preparative Regimen for Stem Cell Transplant in Leukemia.
Condition: Leukemia Lymphoblastic, Acute; Acute Myeloid Leukemia; Neoplasm Recurrent
MeSH terms: Leukemia; Leukemia, Lymphoid
Intervention: Clofarabine; Total Body Irradiation; Stem Cell Transplantation; Cyclosporine; Mycophenolate Mofetil
Intervention description: 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 (30, 40 or 52 mg/m2).; Low dose (2 Gy) TBI will be administered from a linear accelerator at ≤ 20 cGy/min on day "0" according to institutional guidelines.; 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.; Cyclosporine is given IV based on body weight at:
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)
Cyclosporine should be started on day -1 after completion of Clofarabine. Levels should be maintained between 300-400 ng/ml.; MMF will be at 15 mg/kg, based on adjusted body weight, q 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. Oral doses will be rounded to the nearest 250 mg (capsules are 250 mg). MMF is also available in oral suspension form. MMF will be given until day +40 post transplant and then tapered by 10% per week to be discontinued by day +90.
Intervention MeSH terms: Cyclosporine; Mycophenolic Acid; Clofarabine; Cyclosporins
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 18.0
Sex: All
Minimum age: 1 Year
Maximum age: 21 Years
Healthy volunteers: No
Keywords: ALL; AML; Recurrence; Relapsed; Stem Cell Transplant; Non-myeloablative

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.
    

Eligibility criteria:

        Inclusion Criteria

        Since this is a Phase 1 study, any patient who is a candidate for a non-myeloablative SCT
        because he/she cannot tolerate the standard myeloablative preparative therapy is eligible
        for this trial. Briefly, the following groups of patients will be targeted and are eligible
        for this trial:

          -  Patients with presence of organ system dysfunction or severe systemic infections that
             significantly increase the risk of TRM with standard myeloablative regimens.

          -  History of previous myeloablative allogeneic or autologous transplantation.

          -  Heavily pre-treated leukemia patients, eg. Patients in CR after failure of ≥2 prior
             regimens.(eg. ALL CR ≥ 3).

          -  Combination of toxicities or co-morbidities that leads the investigator to feel that
             the child is at high risk (>50%) of TRM with standard ablative regimens.

        The eligibility criteria listed below are interpreted literally and cannot be waived.

          1. Age: Patients must be >1 and < 21 years of age at the of study entry.

          2. Diagnosis

               1. 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.

               2. Patient must have an ANC > 750/ul.

          3. Donor Selection: Patient must have one of the appropriate donor types as described
             below:

               1. HLA identical sibling donor.

               2. 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).

               3. 1 allelic mis-matched unrelated donor (antigen mis-matches are not allowed).

          4. Stem Cell Source: The stem cell source from the donor must be one of the following:

               1. Bone Marrow or Peripheral blood stem cells (PBSC) from a matched related donor.

               2. PBSC from an unrelated donor. (Bone marrow is not acceptable for unrelated
                  donors)

          5. Performance Level: Karnofsky > 50% for patients > 10 years of age and Lansky > 50% for
             patients < 10 years of age.

          6. Reproductive Function

               1. Female patients of childbearing potential must have a negative serum pregnancy
                  test confirmed within 2 weeks prior to enrollment.

               2. Female patients with infants must agree not to breastfeed their infants while on
                  this study.

               3. Male and female patients of child-bearing potential must agree to use an
                  effective method of contraception approved by the investigator during the study.

          7. Renal and Hepatic Function: Patient must have adequate renal and hepatic functions as
             indicated by the following laboratory values:

               1. 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.

               2. Total serum bilirubin < 2 mg/dL.

               3. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 5 × ULN.

          8. Cardiac Function: Patient must have a shortening fraction (SF) > 25%. If the SF is
             <25%, patient must have an ejection fraction (EF) by MUGA of >30%. 3.3.9 Pulmonary
             Function Patient must have pulmonary function as defined below:

               1. DLCO >30%

               2. FVC/TLC >30%

               3. FEV1 > 30% of predicted

               4. 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.

          9. Patients with prior exposure to Clofarabine are eligible.

         10. Informed Consent: Patients and/or their parents or legal guardians must be capable of
             understanding the investigational nature, potential risks and benefits of the study.
             All patients and/or their parents or legal guardians must sign a written informed
             consent. Age appropriate assent will be obtained per institutional guidelines. To
             allow non-English speaking patients to participate in this study, bilingual health
             services will be provided in the appropriate language when feasible.

         11. Protocol Approval: All institutional, FDA, and OHRP requirements for human studies
             must be met.

        Exclusion Criteria

        Patients will be excluded if they meet any of the following criteria:

          1. Infection

               1. 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.

               2. 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.

          2. Patient has a diagnosis of CML or MDS.

          3. Patient has CNS 2 or CNS 3 status.

          4. Patient is HIV positive.

          5. Current or planned treatment with chemotherapy, radiation therapy, or immunotherapy
             other than as specified in the protocol.

          6. Use of investigational agents within 30 days or any anticancer therapy within 2 weeks
             before study entry.

          7. 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.

          8. 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).

          9. 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.