Clofarabine, Cytarabine, and Filgrastim in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia, Advanced Myelodysplastic Syndrome, and/or Advanced Myeloproliferative Neoplasm

Study Overview
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Brief Summary
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This phase II trial is studying how well giving clofarabine and cytarabine together with filgrastim works in treating patients with newly diagnosed acute myeloid leukemia (AML), advanced myelodysplastic syndrome (MDS), and/or advanced myeloproliferative neoplasm. Drugs used in chemotherapy, such as clofarabine and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving the drugs in different doses may kill more cancer cells. Colony stimulating factors, such as filgrastim, may increase the number of immune cells found in bone marrow or peripheral blood and may help the immune system recover from the side effects of chemotherapy.

Detailed Description
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PRIMARY OBJECTIVES: I. To assess the complete remission (CR) rate of this regimen as compared with 7 + 3 standard induction with the 90 mg/m^2/dose of daunorubicin (historical control) in previously untreated patients with AML or advanced MDS or advanced myeloproliferative neoplasm less than age 65. SECONDARY OBJECTIVES: I. To determine the event free survival (EFS), overall survival (OS) and treatment related mortality of this regimen. II. To assess the toxicity of this regimen in previously untreated patients. III. To determine whether 3 consolidation chemotherapy cycles consisting of G-CSF (filgrastim), clofarabine, and cytarabine (GCLAC) can be administered with prompt recovery of blood counts. OUTLINE: INDUCTION THERAPY: Patients receive filgrastim subcutaneously (SC) daily beginning the day prior to chemotherapy and continuing until blood counts recover. Patients receive clofarabine intravenously (IV) over 1 hour followed by cytarabine IV over 2 hours daily for 5 days. CONSOLIDATION THERAPY: Patients receive filgrastim SC daily for 5 days beginning the day prior to chemotherapy. Patients receive clofarabine IV over 1 hour followed by cytarabine IV over 2 hours daily for 4 days. Treatment with induction therapy may continue for up to 2 courses and treatment with consolidation therapy may continue for up to 3 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 2 years and then annually for 5 years.

Official Title
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Phase 2 Study Of Clofarabine With High Dose Cytarabine And G-CSF Priming In Adult Patients Less Than Age 65 With Newly Diagnosed Acute Myeloid Leukemia Or Advanced Myelodysplastic Syndrome and/or Advanced Myeloproliferative Neoplasm

Conditions
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Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(15;17)(q22;q12), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Chronic Myelomonocytic Leukemia, de Novo Myelodysplastic Syndromes, Refractory Anemia With Excess Blasts, Untreated Adult Acute Myeloid Leukemia, Myeloproliferative Neoplasm With 10% Blasts or Higher

Intervention / Treatment
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* Biological: filgrastim
* Drug: clofarabine
* Drug: cytarabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of acute myeloid leukemia by World Health Organization (WHO) criteria (except acute promyelocytic leukemia), or myelodysplastic syndrome, RAEB-2 by WHO classification or advanced myeloproliferative neoplasm with >= 10% blasts in the bone marrow or peripheral blood, including chronic myelomonocytic leukemia (CMML)-2 by WHO classification Eastern Cooperative Oncology Group (ECOG) Performance Status 0 - 2 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 m^2 as calculated by the Modification of Diet in Renal Disease equation Serum bilirubin =< 1.5 x upper limit of normal (ULN) unless elevation is thought to be due to Gilbert's syndrome, hemolysis, or hepatic infiltration by the hematologic malignancy Aspartate transferase (AST)/alanine transferase (ALT) =< 2.5 x ULN unless elevation is thought to be due to hepatic infiltration by the hematologic malignancy Alkaline phosphatase =< 2.5 x ULN Capable of understanding the investigational nature, potential risks and benefits of the study, and able to provide valid informed consent Female patients of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to enrollment Male and female patients must use an effective contraceptive method during the study and for a minimum of 90 days after study treatment Exclusion Criteria: Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol with the exception of intrathecal chemotherapy administered on days that are not concurrent with clofarabine and cytarabine No prior induction chemotherapy for AML; treatment with hydroxyurea is permitted; treatment with imides or hypomethylating agents for preceding hematological disorders is permitted 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 Patients with significant organ compromise due to systemic fungal, bacterial, viral, or other infection Pregnant or lactating patients Any significant concurrent illness, condition, or psychiatric disorder 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 including the following: 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 Prior allogeneic stem cell transplant

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 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: Treatment (chemotherapy and colony stimulating factor)<br>INDUCTION THERAPY: Patients receive filgrastim SC daily beginning the day prior to chemotherapy and continuing until blood counts recover. Patients receive clofarabine IV over 1 hour followed by cytarabine IV over 2 hours daily for 5 days. CONSOLIDATION THERAPY: Patients receive filgrastim SC daily for 5 days beginning the day prior to chemotherapy. Patients receive clofarabine IV over 1 hour followed by cytarabine IV over 2 hours daily for 4 days. Treatment with induction therapy may continue for up to 2 courses and treatment with consolidation therapy may continue for up to 3 courses in the absence of disease progression or unacceptable toxicity. | Biological: filgrastim<br>* Given SC<br>* Other names: Neupogen;Drug: clofarabine<br>* Given IV<br>* Other names: Clolar;Drug: cytarabine<br>* Given IV<br>* Other names: cytosine arabinoside;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rates of Complete Remission and Complete Remission With Incomplete Recovery of Counts | With 50 patients, the rates of these endpoints will be estimated with a standard error of 5 to 7 percentage points, depending on the observed rates. Complete remission is defined as less than 5% blast cells present in the bone marrow and count recovery (absolute neutrophil count greater than 1000/microL and platelet count greater than 100,000/microL). Complete remission with incomplete recovery of counts is defined as less than 5% blast cells present in the bone marrow without compete count recovery (absolute neutrophil count less than 1000/microL and platelet count less than 100,000/microL). | Up to 5 years | 
| Duration of Remission | With 50 patients, the rates of these endpoints will be estimated with a standard error of 5 to 7 percentage points, depending on the observed rates. Remission is defined as less than 5% blasts in the bone marrow, no appearance of blasts in the peripheral blood, and no extramedullary disease (appearance of leukemic cells in other tissues). | Up to 5 years | 
| Time to Progression | With 50 patients, the rates of these endpoints will be estimated with a standard error of 5 to 7 percentage points, depending on the observed rates. | Up to 5 years | 
| Event Free Survival | Number of patients in remission at a median follow up of 15 months. | Up to 5 years | 
| Treatment-related Mortality (TRM) | Treatment-related mortality (TRM) data was not collected. | Up to 5 years | 
| Overall Survival | With 50 patients, the rates of these endpoints will be estimated with a standard error of 5 to 7 percentage points, depending on the observed rates. | Up to 5 years |