Phase I Study of Continuous Infusion Schedule of FMdC in Hematologic Malignancies

Study Overview
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Brief Summary
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The goal of this clinical research study is to find the highest dose of Tezacitabine (FMdC) which can be safely given as a continuous infusion by vein to patients with hematologic malignancies. The general safety and effectiveness of this drug will also be studied.

Detailed Description
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Patients with leukemias that have relapsed from previous therapies have a low cure rate. Hence the need to discover new antileukemic agents. Tezacitabine is a nucleoside analogue with equivalent or even superior activity when compared with ara-C in leukemic cell lines. It has shown significant antitumor activity in vitro and in vivo tumor models. Several phase I studies with various dosing schedules have been conducted in solid tumors where the dose-limiting toxicity (DLT) is mainly myelosuppression, usually a favorable feature for development of leukemia. In a phase I study in hematological malignancies, we used Tezacitabine as a bolus infusion daily x 5. The DLT consisted of grade 3 CNS toxicities and mucositis in 3/6 patients. The study is ongoing and we are currently evaluating a dose level of 7.5 mg/m2 as possible Maximum Tolerated Dose (MTD). However, in view of the fact that tezacitabine is a cell cycle specific agent with a short terminal plasma half-life of 2 to 6 hours, a continuous infusion dosing schedule may enhance the activity and reduce the incidence of adverse effects of tezacitabine.

Official Title
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Phase I Study of Continuous Infusion Schedule of (E)-2'-Deoxy-2'-(Fluoromethylene) Cytidine (Tezacitabine, FMdC) in Hematologic Malignancies

Conditions
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Hematologic Malignancies

Intervention / Treatment
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* Drug: Tezacitabine (FMdC)


Participation Criteria
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Eligibility Criteria
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Patient with relapsed/refractory acute leukemias (AML, ALL, high-grade myelodysplastic syndromes, CMML in transformation with >/= 10% peripheral blood/bone marrow blasts, CML in blast crisis), or patients with relapsed/refractory CLL and an absolute neutrophil count of >/= 1,000/ml and platelet count of >/= 75,000/ml. Signed informed consent indicating that patients are aware of the investigational nature of this study, and in keeping with the policies of this hospital. The only acceptable consent form is attached at the end of this protocol. Age >/= 15 years. ECOG performance status </= 2. No severe, concurrent disease, infection, or co-morbidity that, in the judgment of the Investigator, would make the patient inappropriate for study entry. Pregnant and/or lactating females are not eligible. Normal organ function (serum bilirubin £ 2 mg/dL, serum creatinine £ 2 mg/dL). Patients with renal or liver dysfunction due to organ leukemic involvement may be eligible after discussion with the principle investigator. Patients must be off of all previous chemotherapy, immunotherapy, or radiotherapy for at least 2 weeks prior to entering this study, and must have recovered from all toxic effects, unless life-threatening increases in tumor burden occur.

Ages Eligible for Study
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Minimum Age: 15 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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tezacitabine<br>Tezacitabine as a bolus infusion daily x 5 | Drug: Tezacitabine (FMdC)<br>* 7.5 mg/m2 bolus infusion daily x 5<br>* Other names: (E)-2'-Deoxy-2'-(Fluoromethylene) Cytidine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) | MTD determination made from dose level without a dose-limiting toxicity (DLT) |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Investigational, Chemotherapy, Hematologic Malignancies, Nucleoside analogue