Clofarabine With Cytarabine for Patients With Minimal Residual Disease Positive Leukemia
Condition: Minimal Residual Disease; Leukemia, Lymphoblastic, Acute; Leukemia, Myelogenous, Acute
MeSH terms: Leukemia; Neoplasm, Residual; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Intervention: Clofarabine; Cytarabine intravenous; Methotrexate; Intrathecal (IT) Cytarabine
Intervention description: 20 mg/m2/day intravenously (IV) over 2 hours (given at hours 0 to 2) on days 1 through 5.; 1 gram/m2/day intravenously (IV) over 2 hours to be given 4 hours after the initiation of clofarabine on days 1 through 5.; Methotrexate to be given intrathecally (IT) to all acute lymphoblastic leukemia (ALL) patients on day 1 at the dose defined by age below:
8 mg for patients age 1-1.99
10 mg for patients age 2-2.99
12 mg for patients 3-8.99 years of age
15 mg for patients >9 years of age; Intrathecal (IT) cytarabine is optional for acute myelogenous leukemia (AML) patients.
If intrathecal cytarabine is to be given, it must be given at least 72 hours but not more than 7 days prior to the initiation of intravenous cytarabine.
Dose should be given according to age as defined below:
30 mg for patients age 1-1.99
50 mg for patients age 2-2.99
70 mg for patients >3 years of age
Intervention MeSH terms: Cytarabine; Methotrexate; Clofarabine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 2.0
Sex: All
Minimum age: 1 Year
Maximum age: 21 Years
Healthy volunteers: No
Keywords: relapsed; relapse; refractory; Minimal Residual disease; MRD; MRD positive; MRD+; ALL; Acute lymphoblastic leukemia; AML; Acute myelogenous leukemia; Relapsed AML

Summary:

      This study will test the ability of clofarabine + cytarabine to eliminate minimal residual
      disease (MRD) in acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL)
      patients whose bone marrows exhibit complete remission by morphology. The toxicity profile of
      this regimen will be evaluated in addition to toxicity experienced by patients who proceed to
      stem cell transplant. Overall length of remission will also be collected.
    

Eligibility criteria:

        A. INCLUSION CRITERIA

          1. Patients must be ≥1 and ≤ 21 years of age when enrolled onto this study.

          2. Diagnosis

               -  Patients must have a diagnosis of relapsed or refractory AML or ALL and,

               -  Patient must have an M1 marrow based upon a recovered marrow with less than 5%
                  blasts by conventional morphology and,

               -  Patient must have minimal residual disease (MRD) detected by either
                  multidimensional or conventional flow cytometry greater than 0.1% and less than
                  5% following any re-induction attempt and

               -  Patients must be CNS 1.

          3. Patient must have an ANC >500/μL off cytokine support for at least 24 hours and
             platelets >50,000 K/μL without platelet transfusion in the past seven days

          4. Performance Level Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for
             patients ≤16 years of age.

          5. Patient must have adequate venous access.

          6. Prior Therapy

               1. Patients must have fully recovered from the acute toxic effects of all prior
                  chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

               2. At least 21 days must have elapsed from prior chemotherapy, at least 7 days must
                  have elapsed since receiving biological therapy.

               3. It must be at least 45 days from any higher dose cytarabine therapy (>1 gm/
                  m2/day).

               4. Patients on steroid taper must be on less than 0.5mg/kg/day with plans to
                  continue taper and discontinue the steroids.

          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 normal calculated creatinine clearance as calculated below:

                    -  Pediatric Population (age <18): Calculated creatinine clearance ≥ 90
                       ml/min/1.73m2 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.

                    -  Adult Population (age ≥18): 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.

               2. Conjugated (direct) serum bilirubin ≤ 1.5 x ULN for age.

               3. Alanine transaminase (ALT) ≤ 2.5 × ULN for age.

               4. Alkaline phosphatase ≤ 2.5 × ULN for age.

               5. Serum amylase ≤ 1.5 ULN for age.

               6. Serum Lipase is ≤ ULN for age.

          8. Patient must have a shortening fraction > 28% by echocardiogram or an ejection
             fraction > 50% by MUGA

          9. Reproductive Function

               1. Female patients of childbearing potential must have a negative urine or serum
                  pregnancy test confirmed 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.

         10. Patient must agree to submission of blood and bone marrow for MPF assessment of MRD to
             TACL centralized lab.

        B. EXCLUSION CRITERIA

        Patients will be excluded if they meet any of the following criteria:

          1. Patients with previous HSCT within previous 180 days.

          2. Patients who have had prior treatment with clofarabine.

          3. Patients with CNS2 or CNS 3 disease or bulky chloromatous disease.

          4. Patients with Down Syndrome.

          5. Patients with a previous history of veno-occlusive disease (VOD) or findings
             consistent with a diagnosis of VOD, defined as: conjugated serum bilirubin >1.4 mg/dL
             AND unexplained weight gain greater than 10% of baseline weight or ascites AND
             hepatomegaly or right upper quadrant pain without another explanation, OR reversal of
             portal vein flow on ultrasound, OR pathological confirmation of VOD on liver biopsy.

          6. 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).

          7. Use of investigational agents within 30 days of planned treatment on this protocol.

          8. Patient is receiving or plans to receive concomitant chemotherapy, radiation therapy,
             immunotherapy or other anti-cancer therapy other than is specified in the protocol.

          9. Pregnant or lactating patients.

         10. Any significant concurrent disease, illness, psychiatric disorder or social issue that
             would compromise patient safety or compliance, interfere with consent, study
             participation, follow up, or interpretation of study results.

         11. Have had a diagnosis of another malignancy, unless the patient has been disease-free
             for at least 3 years following the completion of curative intent therapy with the
             following exceptions:

               1. Patients with treated non-melanoma skin cancer, in situ carcinoma, or cervical
                  intraepithelial neoplasia, regardless of the disease-free duration, are eligible
                  for this study if definitive treatment for the condition has been completed.

               2. Patients with organ-confined prostate cancer with no evidence of recurrent or
                  progressive disease based on prostate-specific antigen (PSA) values are also
                  eligible for this study if hormonal therapy has been initiated or a radical
                  prostatectomy has been performed.

         12. Patient has active acute (greater than grade II) or active chronic extensive GVHD.
             Patients who are on a tapering dose of immunosuppressants will be permitted (tapering
             calcineurin inhibitor and/or less than 0.5 mg/kg/day of steroids).