GTI-2040 in Treating Patients With Relapsed, Refractory, or High-Risk Acute Leukemia, High-Grade Myelodysplastic Syndromes, or Refractory or Blastic Phase Chronic Myelogenous Leukemia

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Completed

CT.gov ID

NCT00459212

Collaborator

(none)

Enrollment

Location

Arm

Study Details

Study Description

Brief Summary

This phase I trial is studying the side effects and best dose of GTI-2040 in treating patients with relapsed, refractory, or high-risk acute leukemia, high-grade myelodysplastic syndromes, or refractory or blastic phase chronic myelogenous leukemia. Drugs used in chemotherapy, such as GTI-2040, work in different ways to stop the growth of cancer or abnormal cells, either by killing the cells or by stopping them from dividing.

Condition or Disease	Intervention/Treatment	Phase
Acute Undifferentiated 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 de Novo Myelodysplastic Syndromes Previously Treated Myelodysplastic Syndromes Recurrent Adult Acute Lymphoblastic Leukemia Recurrent Adult Acute Myeloid Leukemia Relapsing Chronic Myelogenous Leukemia Secondary Acute Myeloid Leukemia Secondary Myelodysplastic Syndromes Untreated Adult Acute Lymphoblastic Leukemia Untreated Adult Acute Myeloid Leukemia	Drug: GTI-2040 Procedure: pharmacological study Procedure: laboratory biomarker analysis	Phase 1

Detailed Description

OBJECTIVES:

Determine the maximum tolerated dose of GTI-2040 in patients with relapsed, refractory, or high-risk acute leukemia, high-grade myelodysplastic syndromes, or refractory or blastic phase chronic myelogenous leukemia.
Assess the toxicity and efficacy of this drug in these patients. III. Assess plasma and intracellular pharmacokinetics of this drug in these patients.

OUTLINE: This is a multicenter, dose-escalation study.

Patients receive GTI-2040 IV continuously on days 1-4 and 15-18. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of GTI-2040 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.

Blood samples are collected on days 1, 4, 15, and 19 of course 1 for pharmacokinetic studies. Samples are analyzed by proteomic assay, dCTP pool measurement, and real-time polymerase chain reaction for mRNA of RRM2, RRM1, and p53R2.

Study Design

Study Type:

Interventional

Actual Enrollment :

24 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase I and Pharmacodynamic Study of GTI-2040 (NSC 722929, IND 67368) in Acute Leukemias

Study Start Date :

Mar 1, 2007

Actual Primary Completion Date :

Dec 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I Patients receive GTI-2040 IV continuously on days 1-4 and 15-18.	Drug: GTI-2040 Given IV Procedure: pharmacological study Correlative study Other Names: pharmacological studies Procedure: laboratory biomarker analysis Correlative study

Arm

Intervention/Treatment

Experimental: Arm I

Patients receive GTI-2040 IV continuously on days 1-4 and 15-18.

Drug: GTI-2040

Given IV

Procedure: pharmacological study

Correlative study

Other Names:

pharmacological studies

Procedure: laboratory biomarker analysis

Correlative study

Outcome Measures

Primary Outcome Measures

Maximum tolerated dose (MTD) determined according to dose-limiting toxicities (DLTs) graded using Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0) [28 days]
Change in dCTP levels in PBMC and bone marrow by Real-Time PCR [Days 1, 4, 15, and 19 of course 1]

Secondary Outcome Measures

Objective tumor response [Up to 3 years]
Overall survival [Up to 3 years]
Time to failure [Up to 3 years]
Duration of response [Up to 3 years]
Change in expression levels of R1, R2, and p53R2 mRNA in PBMC by Real-Time PCR [Day 1, 4, 15, and 19 of course 1]
Change in intracellular levels of GTI-2040 by ELISA [Day 1, 4, 15, and 19 of course 1]
Incidence of grade 3 or higher toxicity assessed by CTCAE v3.0 [Up to 3 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Diagnosis of 1 of the following:
Acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) refractory to primary standard induction therapy
Relapsed or refractory acute leukemia
Chronic myelogenous leukemia (CML) in blast crisis at diagnosis OR that failed prior aggressive induction chemotherapy
Diagnosis of 1 of the following:
Acute leukemia secondary to preexisting hematologic condition or prior chemotherapy at diagnosis OR that failed prior aggressive induction chemotherapy
Advanced myelodysplastic syndromes (intermediate-1 or greater)
De novo acute leukemia (myeloid or nonmyeloid)
Not a candidate for aggressive standard induction chemotherapy
De novo AML or ALL (patients > 60 years of age)
No suspected or proven active CNS leukemia
ECOG performance status (PS) 0-2 OR Karnofsky PS 50-100%
Life expectancy >= 8 weeks
Bilirubin =< 1.5 mg/dL
AST and ALT < 3 times upper limit of normal (ULN)
Creatinine =< 1.5 times ULN
No HIV positivity
Fertile patients must use effective contraception
No history of allergic reactions attributed to other phosphorothiolated oligonucleotides
No uncontrolled intercurrent illness including, but not limited to, any of the following:
Ongoing, active, or poorly controlled infection
Symptomatic congestive heart failure
Unstable angina pectoris
No uncontrolled intercurrent illness including, but not limited to, any of the following:
Cardiac arrhythmia
Poorly controlled pulmonary disease
Psychiatric illness or social situation that would preclude study compliance
Recovered from all prior therapies
Prior autologous or allogeneic stem cell transplantation allowed (No active graft-vs-host disease > grade 2)
At least 2 weeks since prior and no concurrent cytotoxic chemotherapy
At least 2 weeks since prior and no concurrent biologic therapy
At least 2 weeks since any other prior investigational agent
No other concurrent anticancer therapy, including radiotherapy or hormonal therapy
Concurrent imatinib mesylate for CML allowed
Not pregnant or nursing
Negative pregancy test