Phase I and Pharmacodynamic Study of GTI-2040 (NSC 722929, IND 67368) in Acute Leukemias
Trial Snapshot
- Phase
- Phase 1
- Status
- Completed
- Enrollment
- 24
- Locations
- 1
- Primary Endpoint
- Change in dCTP levels in PBMC and bone marrow by Real-Time PCR
Study Overview
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.
Detailed Description
OBJECTIVES:
I. 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.
II. 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.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
Exclusion Criteria
- Not provided
Arms & Interventions
Arm I
Patients receive GTI-2040 IV continuously on days 1-4 and 15-18.
Intervention: GTI-2040 (Drug)
Arm I
Patients receive GTI-2040 IV continuously on days 1-4 and 15-18.
Intervention: pharmacological study (Procedure)
Arm I
Patients receive GTI-2040 IV continuously on days 1-4 and 15-18.
Intervention: laboratory biomarker analysis (Procedure)
Outcomes
Primary Outcomes
Change in dCTP levels in PBMC and bone marrow by Real-Time PCR
Time Frame: Days 1, 4, 15, and 19 of course 1
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)
Time Frame: 28 days
Secondary Outcomes
- 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)