A Phase I Study of GTI2040 (NSC 722929; IND 67368) in Combination With High-dose Cytarabine in Refractory or Relapsed Acute Myeloid Leukemia (AML)
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.
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.
Inclusion Criteria:
Histologically confirmed acute myeloid leukemia according to the WHO classification
Relapsed or refractory disease, meeting 1 of the following criteria:
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)
No concurrent combination antiretroviral therapy for HIV-positive patients