Clofarabine and Cytarabine in Treating Older Patients With AML or High-Risk MDS

Study Overview
=================
Brief Summary
-----------------
This phase I/II trial studied the side effects and best dose of clofarabine when given together with cytarabine and to see how well they work in treating older patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS) that have relapsed or not responded to treatment.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To estimate the maximum tolerated dose (MTD) of oral clofarabine when given with LDAC (cytarabine) in patients age >= 60 with previously treated AML or high risk MDS. SECONDARY OBJECTIVES: I. To determine the response rate, disease-free survival (DFS), and overall survival (OS) after therapy with oral clofarabine and LDAC for previously treated AML or high-risk MDS. OUTLINE: This is a phase I, dose-escalation study of clofarabine followed by a phase II study. Patients receive clofarabine orally (PO) once daily (QD) on days 1-5 and low-dose cytarabine subcutaneously (SC) twice daily (BID) on days 1-10 or SC QD on days 1-14. Treatment repeats every 21-28 days for up to 4 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 3 years.

Official Title
-----------------
Study of Oral Clofarabine Plus Low-dose Cytarabine in Previously Treated AML and High-Risk MDS Patients at Least 60 Years of Age

Conditions
-----------------
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(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Myelodysplastic Syndrome With Isolated Del(5q), Previously Treated Myelodysplastic Syndromes, Recurrent Adult Acute Myeloid Leukemia

Intervention / Treatment
-----------------
* Drug: clofarabine
* Drug: cytarabine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of 1st relapse or refractory AML; or patients with high risk MDS (10-19% blasts) who have received previous therapy 1st remission must have been < 1 year Must not have received previous ara-C (cytarabine) or clofarabine Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 Not candidates for standard 7 + 3 regimen (Ara-C and an anthracycline), high dose Ara-C, or hematopoietic stem-cell transplantation Serum creatinine =< 1.0 mg/dL; if serum creatinine > 1.0 mg/dL, then the estimated glomerular filtration rate (GFR) must be > 50 L/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) Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN 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 should use an effective contraceptive method during the study and for a minimum of 6 months after study treatment Exclusion Criteria: Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol Patients with acute promyelocytic leukemia (APL) Use of investigational agents within 30 days or any anticancer therapy within 2 weeks before study entry with the exception of hydroxyurea; the patient must have recovered from all acute toxicities from any previous therapy 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 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) Pregnant or lactating patients Any significant concurrent disease, illness, 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 or definitive radiotherapy has been performed Have currently active gastrointestinal disease, or prior surgery that may affect the ability of the patient to absorb oral clofarabine

Ages Eligible for Study
-----------------
Minimum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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)<br>Patients receive clofarabine PO QD on days 1-5 and low-dose cytarabine SC BID on days 1-10 or SC QD on days 1-14. Treatment repeats every 21-28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. | Drug: clofarabine<br>* Given PO<br>* Other names: Clolar;Drug: cytarabine<br>* Given SC<br>* Other names: cytosine arabinoside;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Dose Limiting Toxicity | Dose limiting toxicity (DLT) consists of grade 3-4 non-hematologic toxicity at least possibly related to study drug. Exceptions include neutropenic fever; drug-related fever; alopecia; anorexia; inadequately treated nausea, vomiting and/or diarrhea; and grade 3/4 increase in ALT, AST, or bilirubin recovering to < grade 2 by 7 days. Prolonged grade 2 myelosuppression lasting longer than 49 days in patients who don't proceed to additional cytotoxic therapy is considered a DLT. The MTD or recommended phase II dose is the highest dose level at which no more than 1 patient out of 6 experiences DLT. | Outcomes by day 30 | 
| Maximum Tolerated Dose | We identified 20 mg/d for 5 d as the maximum tolerated dose (MTD) of oral clofarabine. | up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Response | CR = no evidence of leukemia with complete blood count recovery (ANC >1,000 and PLTS >100k) CRi = no evidence of leukemia but with incomplete blood count recovery | Up to 5 years | 
| Disease Free Survival | Median disease-free survival | Up to 5 years | 
| Overall Survival | Median overall survival | Up to 5 years |