GTI-2040 and High-Dose Cytarabine in Treating Patients With Refractory or Relapsed Acute Myeloid Leukemia

A Phase I Study of GTI2040 (NSC 722929; IND 67368) in Combination With High-dose Cytarabine in Refractory or Relapsed Acute Myeloid Leukemia (AML)

This phase I trial is studying the side effects and best dose of GTI-2040 and high-dose cytarabine in treating patients with refractory or relapsed acute myeloid leukemia. GTI-2040 may stop the growth of cancer cells by blocking the enzymes necessary for cancer cell growth. Drugs used in chemotherapy, such as cytarabine, use different ways to stop cancer cells from dividing so they stop growing or die. Giving GTI-2040 together with cytarabine may kill more cancer cells.

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); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
• Intervention / Treatment: Drug: cytarabine; Other: laboratory biomarker analysis; Other: pharmacological study; Biological: GTI-2040

Detailed Description

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose and recommended phase II dose of GTI-2040 and high-dose cytarabine in patients with relapsed or refractory acute myeloid leukemia.

SECONDARY OBJECTIVES:

I. Determine the therapeutic response in patients treated with this regimen. II. Determine the pharmacokinetics of this regimen in these patients.

OUTLINE: This is a dose-escalation study. Patients are stratified according to age (under age 60 vs age 60 and over). Patients are assigned to 1 of 2 strata.

Stratum I (under age 60): Patients receive GTI-2040 IV continuously on days 1-6 and high-dose cytarabine IV over 2 hours twice daily on days 2, 4, and 6.

Stratum II (age 60 and over): Patients receive GTI-2040 IV continuously on days 1-6 and high-dose cytarabine IV over 4 hours once daily on days 2-6.

In both strata, treatment continues in the absence of unacceptable toxicity.

Cohorts of 3-6 patients per stratum receive escalating doses of GTI-2040 and high-dose cytarabine 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.

PROJECTED ACCRUAL: A total of 6-51patients will be accrued for this study within 2-16 months.

• Study Type: Interventional
• Enrollment (Actual): 51
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University 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:

• Histologically confirmed acute myeloid leukemia according to the WHO classification

• Relapsed or refractory disease, meeting 1 of the following criteria:

  • Unresponsive to initial treatment
  • Recurrent disease after treatment with prior conventional or high-dose chemotherapy with or without stem cell support
• CNS involvement allowed provided there are no residual leukemic cells detected in the cerebrospinal fluid after intrathecal or radiation chemotherapy
• Performance status - ECOG 0-2
• At least 4 weeks
• Bilirubin no greater than 2 times upper limit of normal* (ULN) (unless due to Gilbert's syndrome)
• AST and ALT no greater than 3 times ULN*
• Creatinine no greater than 1.5 mg/dL*
• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia
• Resting ejection fraction at least 50%*
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No prior allergy to study medications
• No ongoing or active infection requiring IV antibiotics
• No other concurrent uncontrolled illness
• No serious medical or psychiatric illness that would preclude giving informed consent
• More than 4 weeks since prior chemotherapy (except hydroxyurea) (6 weeks for nitrosoureas or mitomycin)
• No other concurrent chemotherapy
• No concurrent hormonal therapy except steroids for adrenal failure and hormones for non-disease-related conditions (e.g., insulin for diabetes)
• More than 4 weeks since prior radiotherapy
• No concurrent palliative radiotherapy
• Prior therapy with antisense oligonucleotides allowed provided no toxic effects were experienced that were directly attributable to the antisense agents
• No other concurrent investigational agents
• No other concurrent anticancer therapy

• No concurrent chronic systemic anticoagulant therapy for medical conditions (e.g., prior deep vein thrombosis or atrial fibrillation)

  • Concurrent heparin to maintain central line patency (i.e., catheter flush) is allowed
• No concurrent combination antiretroviral therapy for HIV-positive patients

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Stratum I (GTI-2040, cytarabine); Patients receive GTI-2040 IV continuously on days 1-6 and high-dose cytarabine IV over 2 hours twice daily on days 2, 4, and 6.	Drug: cytarabine; Given IV; Other Names: Cytosar-U; cytosine arabinoside; ARA-C; arabinofuranosylcytosine; arabinosylcytosine; Other: laboratory biomarker analysis; Optional correlative studies; Other: pharmacological study; Optional correlative studies; Other Names: pharmacological studies; Biological: GTI-2040; Given IV
Experimental: Stratum II (GTI-2040, cytarabine); Patients receive GTI-2040 IV continuously on days 1-6 and high-dose cytarabine IV over 4 hours once daily on days 2-6. In both strata, treatment continues in the absence of unacceptable toxicity.	Drug: cytarabine; Given IV; Other Names: Cytosar-U; cytosine arabinoside; ARA-C; arabinofuranosylcytosine; arabinosylcytosine; Other: laboratory biomarker analysis; Optional correlative studies; Other: pharmacological study; Optional correlative studies; Other Names: pharmacological studies; Biological: GTI-2040; Given IV

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum-tolerated dose (MTD) as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0	Up to day 42

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Therapeutic response	Standard paired statistical tests, parametric and nonparametric, will be used to baseline with treatment values. With data collected serially over time, repeated measures analysis of variance will be used to analyze data.	Up to 6 years
Change in R2 expression in circulating and marrow leukemia cells	Standard paired statistical tests, parametric and nonparametric, will be used to baseline with treatment values. With data collected serially over time, repeated measures analysis of variance will be used to analyze data.	From baseline to up to 6 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Guido Marcucci, Ohio State University

Study record dates

Study Major Dates

• Study Start: September 1, 2003
• Primary Completion (Actual): February 1, 2009

Study Registration Dates

• First Submitted: October 3, 2003
• First Submitted That Met QC Criteria: October 6, 2003
• First Posted (Estimate): October 7, 2003

Study Record Updates

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

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Cytarabine
• Other Study ID Numbers: NCI-2012-01443; U01CA076576 (U.S. NIH Grant/Contract); 0304; CDR0000334898; OSU-20030030; NCI-6108; OSU-0304