T2007-002 Clofarabine, Etoposide, Cyclophosphamide in Relapsed Acute Myelogenous Leukemia (AML)

Study Overview
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Brief Summary
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Clofarabine is a drug approved by the FDA (Food and Drug Administration) for treating children (age 1-21) with leukemia. This research study will use clofarabine with two other cancer fighting drugs. Clofarabine will be used together with etoposide (VePesid®, VP-16) and cyclophosphamide (Cytoxan®).

Detailed Description
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Clofarabine, etoposide and cyclophosphamide have been used together in a phase I study to find out the highest doses of these drugs that can be safely given to children with relapsed or refractory leukemia. This study is a phase II study which will use the drugs to study how well these drugs work against AML. This study will also examine the safety of this drug combination.

Official Title
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T2007-002 A Phase II Study of Clofarabine With Etoposide and Cyclophosphamide in Relapsed/Refractory AML (IND 104,650)

Conditions
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Relapsed Acute Myelogenous Leukemia

Intervention / Treatment
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* Drug: Clofarabine
* Drug: Etoposide
* Drug: Cyclophosphamide
* Drug: Filgrastim
* Drug: Cytarabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: patients must be ≥ 1 and ≤ 21 years of age at the of study entry. Diagnosis: Patients must have a diagnosis of first or second relapse or refractory acute myelogenous leukemia (AML) according to WHO classification with ≥ 5% blasts in the bone marrow, with or without extramedullary disease. Patients may have CNS 1 or CNS 2 disease but not CNS 3. Performance Level: Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for patients ≤ 16 years of age. Prior Therapy: Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study. Patient has not received more than 2 previous induction attempts. (Frontline therapy is included in this count). Patients must have adequate venous access. At least 1 year must have elapsed since hematopoietic stem cell transplant (HSCT) and patients must not have active GVHD. Reproductive Function 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 and for a minimum of 6 months after study treatment. 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. 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. Total bilirubin <1.5 x ULN for age and conjugated/direct serum bilirubin ≤ ULN for age if total bilirubin is elevated. Aspartate transaminase (AST)/alanine transaminase (ALT) ≤ 2.5 × ULN. Alkaline phosphatase ≤ 2.5 × ULN. Exclusion Criteria: Patients with Down Syndrome. Prior treatment with Clofarabine. 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 who have a history of cirrhosis of the liver or who are positive for hepatitis B core antibody (anti-HBc) or have a positive test for hepatitis C antibody (anti-HCV). Patient has received TBI. If it has been less than 1 year since the patient had a HSCT. Infection Criteria 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). Positive blood culture within 48 hours of study registration. Patient required supplemental oxygen or vasopressors within 48 hours of study (Oxygen after anesthesia for procedures is ok). Patient is receiving or plans to receive concomitant 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 planned drug initiation with the exception of hydroxyurea or intrathecal therapy given with the diagnostic lumbar puncture. Have any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart, kidney, liver, or other organ system that may place the patient at undue risk to undergo treatment. 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.

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 - Clofarabine with Chemo<br>All patients receive the same treatment regimen consisting of clofarabine, etoposide, cyclophosphamide, cytarabine, and filgrastim. Up to 4 courses of therapy may be given. | Drug: Clofarabine<br>* 40 mg/m2/day IV over 2 hours (given at hours 0 to 2) on days 1 through 5.<br>* Other names: Clolar;Drug: Etoposide<br>* 100 mg/m2/day IV over 2 hours (given at hours 2 to 4) on days 1 through 5.<br>* Other names: Etopophos;Drug: Cyclophosphamide<br>* 440 mg/m2/day IV as a 30-60 minute infusion (given at hours 4 to 5) on days 1 through 5.<br>* Other names: Cytoxan;Drug: Filgrastim<br>* Administered in Courses 1 and 2 only. 5 micrograms/kg/day IV or SC will begin on Day 6 and end when the ANC is > 1000 x 2 days.<br>* Other names: Granulocyte Colony Stimulating Factor;Drug: Cytarabine<br>* Given intrathecally on day 1 at the dose defined by age 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: AraC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Achievement of Complete Remission (CR) at Reinduction | Disease response assessed after chemotherapy from bone marrow aspirates/biopsies and complete blood count. | Between Days 22-36 or on Day 43 and weekly thereafter if peripheral counts haven't recovered | 
| Death | Number of participants who died. | From the first dose of study therapy until 30 days after last therapy dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, relapsed, relapse, refractory, Acute myelogenous leukemia, Relapsed AML