This phase I/II trial studies the side effects and best dose of 8-chloroadenosine and to see how well it works in treating patients with acute myeloid leukemia that has returned after a period of improvement (relapsed) or does not respond to treatment (refractory). Drugs used in chemotherapy, such as 8-chloroadenosine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (recommended phase II dose, RP2D) of 8-chloro-adenosine, when given as a single agent, in patients with relapsed or refractory acute myeloid leukemia. (Phase I) II. To assess tolerability and safety of 8-chloro-adenosine at each dose level by evaluation of toxicities including: type, frequency, severity, attribution, time course and duration. (Phase I) III. To estimate the response rate and to evaluate the antitumor activity of 8-chloro-adenosine, when given as a single agent, as assessed by complete remission rate (complete remission \[CR\] + complete remission with incomplete blood count recovery \[CRi\]). (Phase II) SECONDARY OBJECTIVES: I. To evaluate for disease response to 8-chloro-adenosine in refractory/relapsed acute myeloid leukemia (AML) on each dose level tested. (Phase I) II. To obtain estimates of remission duration and survival probabilities (overall and event-free). (Phase II) III. To obtain an estimate of the overall response rate (CR + CRi + partial response \[PR\]). (Phase II) IV. To summarize and evaluate toxicities by type, frequency, severity, attribution, time course and duration. (Phase II) CLINICAL PHARMACOLOGY OBJECTIVES: I. To describe the plasma, urinary and cellular pharmacokinetics of 8-chloro-adenosine and metabolites. II. To determine the impact of 8-chloro-adenosine on cellular adenosine triphosphate (ATP) pool in AML blasts. III. To assess the impact of 8-chloro-adenosine therapy on select short-lived messenger (m) ribonucleic acids (RNAs) and corresponding proteins in circulating AML blasts. IV. To correlate clinical responses and toxicity with plasma/urine 8-chloro-adenosine level (pharmacokinetic \[PK\]), cellular 8-chloro-ATP (PK) and cellular ATP pool. EXPLORATORY EX-VIVO MOLECULAR OBJECTIVES: I. To determine the cytotoxicity of 8-chloro-adenosine toward leukemic progenitor cells in vitro. II. To generate a preliminary pre-treatment RNA/micro RNA (miRNA) signature in leukemic progenitor cells, and explore its possible association with in vitro cytotoxicity to 8-chloro-adenosine. III. To explore the possible association between the preliminary RNA/miRNA signature and clinical response to 8-chloro-adenosine. OUTLINE: This is a phase I, dose-escalation study followed by a phase II study. Patients receive 8-chloro-adenosine intravenously (IV) over 4 hours on days 1-5. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then every 3 months for up to 2 years.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
20
Given IV
Correlative studies
Correlative studies
City of Hope Medical Center
Duarte, California, United States
Recommended Phase II Dose (RP2D) of 8-Chloro-adenosine (8-Cl-Ado)
According to the standard 3+3 rules, where the highest DL that produced ≤ 1/6 DLTs in cycle 1 would be defined as the maximum tolerated dose (MTD). The RP2D of 8-Cl-Ado would generally be the MTD, but it could be less than the initially calculated MTD as determined from a review of the available data and cumulative toxicities from phase 1.
Time frame: Up to 28 days following first study agent administration.
Dose Limiting Toxicity (DLT)
Toxicity was graded according to the NCI-Common Terminology Criteria for Adverse Events version 4.03. A DLT was defined as any of the following toxicities (please see the details in section of 13.2 of the protocol) that occur during cycle 1, per CTCAE version 4.03, and were considered related to the study drug.
Time frame: Up to 28 days following first study agent administration.
Complete Remission Rate (CR + CRi)
Complete remission rate (CR + CRi) based on the Döhner 2010 criteria and calculated as the percent of evaluable patients that have confirmed CR or CRi is to evaluate the antitumor activity of 8-chloro-adenosine.
Time frame: Up to 2 years following first study agent administration.
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