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

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

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®).

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.

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.