Clofarabine With Cytarabine for Patients With Minimal Residual Disease Positive Leukemia

Study Overview
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Brief Summary
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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.

Detailed Description
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Recent studies have demonstrated that even low levels of minimum residual disease (MRD) (>0.01% abnormal blasts) after aggressive re-induction therapy indicate a relatively poor outcome in relapsed acute lymphoblastic leukemia (ALL) patients, including those who proceed to allogeneic stem cell transplant (alloSCT). A similarly poor prognosis was seen in pediatric acute myelogenous leukemia patients with sub-morphologic disease prior to alloSCT. Studies to identify therapies that can eliminate persistent leukemia, have low toxicity profiles and can serve as a bridge to transplant are needed. This study will test the ability of clofarabine + cytarabine to eliminate minimal residual disease (MRD) in acute myelogenous leukemia and acute lymphoblastic leukemia 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.

Official Title
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Clofarabine With Cytarabine for MRD Positive Leukemia

Conditions
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Minimal Residual Disease, Leukemia, Lymphoblastic, Acute, Leukemia, Myelogenous, Acute

Intervention / Treatment
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* Drug: Clofarabine
* Drug: Cytarabine intravenous
* Drug: Methotrexate
* Drug: Intrathecal (IT) Cytarabine


Participation Criteria
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Eligibility Criteria
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A. INCLUSION CRITERIA Patients must be ≥1 and ≤ 21 years of age when enrolled onto this study. 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. 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 Performance Level Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for patients ≤16 years of age. Patient must have adequate venous access. Prior Therapy Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study. At least 21 days must have elapsed from prior chemotherapy, at least 7 days must have elapsed since receiving biological therapy. It must be at least 45 days from any higher dose cytarabine therapy (>1 gm/ m2/day). Patients on steroid taper must be on less than 0.5mg/kg/day with plans to continue taper and discontinue the steroids. Renal and Hepatic Function Patient must have adequate renal and hepatic functions as indicated by the following laboratory values: 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. Conjugated (direct) serum bilirubin ≤ 1.5 x ULN for age. Alanine transaminase (ALT) ≤ 2.5 × ULN for age. Alkaline phosphatase ≤ 2.5 × ULN for age. Serum amylase ≤ 1.5 ULN for age. Serum Lipase is ≤ ULN for age. Patient must have a shortening fraction > 28% by echocardiogram or an ejection fraction > 50% by MUGA Reproductive Function Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed 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. 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: Patients with previous HSCT within previous 180 days. Patients who have had prior treatment with clofarabine. Patients with CNS2 or CNS 3 disease or bulky chloromatous disease. Patients with Down Syndrome. 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. 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). Use of investigational agents within 30 days of planned treatment on this protocol. Patient is receiving or plans to receive concomitant chemotherapy, radiation therapy, immunotherapy or other anti-cancer therapy other than is specified in the protocol. Pregnant or lactating patients. 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. 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: 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. 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. 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).

Ages Eligible for Study
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Minimum Age: 1 Year
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: Single Arm<br>A maximum of two courses of the following regimen will be administered. Clofarabine: 20 mg/m2/day intravenously (IV) over 2 hours (given at hours 0 to 2) on days 1 through 5. Cytarabine intravenous: 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. Intrathecal (IT) cytarabine: is optional for acute myelogenous leukemia (AML) patients. | Drug: Clofarabine<br>* 20 mg/m2/day intravenously (IV) over 2 hours (given at hours 0 to 2) on days 1 through 5.<br>* Other names: Cl-F-ara-A;Drug: Cytarabine intravenous<br>* 1 gram/m2/day intravenously (IV) over 2 hours to be given 4 hours after the initiation of clofarabine on days 1 through 5.<br>* Other names: Cytosar;Drug: Methotrexate<br>* 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<br>* Other names: Amethopterin;Drug: Intrathecal (IT) Cytarabine<br>* 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<br>* Other names: Cytosar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Minimal Residual Disease (MRD) | To be assessed in acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL) patients whose bone marrows exhibit complete remission by morphology. Patient's bone marrow will be evaluated for the amount of minimal residual disease (MRD) present after treatment on courses 1 and 2. | Sample collected between Days 22-36 of courses 1 and 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Dose-Limiting Toxicity (DLT) | Treatment related toxicities that preclude proceeding to HSCT by day 56 of the treatment course. | Beginning with the first dose of investigational product until day 56 of treatment course, an average of 1 year | 
| Occurrence of Toxicity During Hematopoietic Cell Transplant (HCT) for Patients Who Achieve Remission and Proceed to Transplant | After the patient completes therapy on this protocol, data will continue to be collected regarding whether the patient proceeded to HCT. Toxicity and adverse event information will be collected. | Every 3 months for life following completion of protocol therapy. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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relapse, relapsed, refractory, Minimal Residual disease, MRD, MRD positive, MRD+, ALL, Acute lymphoblastic leukemia, AML, Acute myelogenous leukemia, Relapsed AML