3-AP and High-Dose Cytarabine in Treating Patients With Advanced Hematologic Malignancies

Study Overview
=================
Brief Summary
-----------------
Drugs used in chemotherapy, such as cytarabine, work in different ways to stop cancer cells from dividing so they stop growing or die. 3-AP may help cytarabine kill more cancer cells by making them more sensitive to the drug. This phase I trial is studying the side effects and best dose of 3-AP when given with high-dose cytarabine in treating patients with advanced hematologic malignancies

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose of 3-AP (Triapine) administered with high-dose cytarabine in patients with advanced hematologic malignancies. SECONDARY OBJECTIVES: I. Determine the clinical activity of this regimen in these patients. II. Determine the effect of treatment with 3-AP (Triapine) on intracellular levels of cytarabine in these patients. OUTLINE: This is a dose-escalation study of 3-AP (Triapine). Patients receive high-dose cytarabine IV over 2 hours on days 1-5 and 3-AP (Triapine) IV over 2 hours on days 2-5. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients in each stratum receive escalating doses of 3-AP (Triapine) until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Patients are followed for up to 2 years. PROJECTED ACCRUAL: A total of 6-48 patients (3-24 per stratum) will be accrued for this study within 15-24 months.

Official Title
-----------------
A Phase I Study of Triapine in Combination With High Dose Ara-C (Hi-DAC) in Patients With Advanced Hematologic Malignancies

Conditions
-----------------
Accelerated Phase Chronic Myelogenous Leukemia, Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, 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), Blastic Phase Chronic Myelogenous Leukemia, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Relapsing Chronic Myelogenous Leukemia, Secondary Acute Myeloid Leukemia

Intervention / Treatment
-----------------
* Drug: cytarabine
* Drug: triapine
* Other: laboratory biomarker analysis


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed diagnosis of 1 of the following hematologic malignancies: Relapsed or refractory acute myeloid leukemia (AML) Relapsed or refractory acute lymphoblastic leukemia Secondary AML, including AML arising from antecedent hematologic diseases, such as myelodysplastic syndromes or myeloproliferative disorders OR therapy-related AML Chronic myeloid leukemia in accelerated or blast phase Refractory to standard therapy or no standard therapy exists No known brain metastases Performance status - CALGB 0-2 Performance status - Karnofsky 60-100% No G6PD deficiency Bilirubin < 2.0 mg/dL (unless due to Gilbert's syndrome) AST and ALT < 2.5 times upper limit of normal (ULN) Creatinine < 1.5 times ULN No symptomatic congestive heart failure No unstable angina pectoris No cardiac arrhythmia No pulmonary disease requiring oxygen Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No prior allergic reactions attributed to compounds of similar chemical or biological composition to study drugs No neuropathy No ongoing or active infection No psychiatric illness or social situation that would preclude study compliance No other concurrent uncontrolled illness No concurrent biologic agents At least 72 hours since prior hydroxyurea At least 2 weeks since other prior chemotherapy (6 weeks for mitomycin or nitrosoureas) No other concurrent chemotherapy At least 2 weeks since prior radiotherapy No concurrent radiotherapy Recovered from all prior therapy At least 4 weeks since prior investigational agents No other concurrent investigational therapy No other concurrent anticancer therapy No concurrent combination antiretroviral therapy for HIV-positive patients

Ages Eligible for Study
-----------------
Minimum Age: 18 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 (cytarabine and triapine)<br>Patients receive high-dose cytarabine IV over 2 hours on days 1-5 and triapine IV over 2 hours on days 2-5. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. | Drug: cytarabine<br>* Given IV<br>* Other names: cytosine arabinoside;Drug: triapine<br>* Given IV<br>* Other names: OCX-191;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD defined as the dose preceding that at which greater than or equal to 2 patients experience dose-limiting toxicity assessed using NCI CTCAE version 3.0 |  | 28 days |