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

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

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.

Study Overview

• Status: Completed
• Conditions: Recurrent Adult Acute Myeloid Leukemia; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; 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); Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Myelodysplastic Syndromes; Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Acute Undifferentiated Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; de Novo Myelodysplastic Syndromes; Blastic Phase Chronic Myelogenous Leukemia
• Intervention / Treatment: Procedure: laboratory biomarker analysis; Procedure: pharmacological study; Drug: GTI-2040

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.

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 Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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

Outcome Measure	Time Frame
Overall survival	Up to 3 years
Duration of response	Up to 3 years
Objective tumor response	Up to 3 years
Time to failure	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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)

Study record dates

Study Major Dates

• Study Start: March 1, 2007
• Primary Completion (Actual): December 1, 2010

Study Registration Dates

• First Submitted: April 9, 2007
• First Submitted That Met QC Criteria: April 9, 2007
• First Posted (Estimate): April 11, 2007

Study Record Updates

• Last Update Posted (Estimate): December 4, 2015
• Last Update Submitted That Met QC Criteria: December 3, 2015
• Last Verified: April 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Disease; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Neoplastic Processes; Precancerous Conditions; Cell Transformation, Neoplastic; Carcinogenesis; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Neoplasm Metastasis; Recurrence; Preleukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Blast Crisis
• Other Study ID Numbers: NCI-2009-00206; U01CA062505 (U.S. NIH Grant/Contract); PHI-57; CDR0000539257