8-Chloroadenosine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase I/II Trial of 8-Chloro-Adenosine in Relapsed or Refractory Acute Myeloid Leukemia

Conditions
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Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome, Recurrent Acute Myeloid Leukemia, Refractory Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: 8-Chloroadenosine
* Other: Laboratory Biomarker Analysis
* Other: Pharmacological Study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All subjects must have the ability to understand and the willingness to sign a written informed consent Patients must have a life expectancy of > 3 months Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 Patients must have a diagnosis of AML as per World Health Organization (WHO) Classification of Hematologic Neoplasms Patients must meet one of the three treatment history criteria: Relapsed AML who have failed at least 1 line of salvage therapy De novo AML who have not achieved CR after 2 lines of therapy AML evolving from myelodysplastic syndrome (MDS) or myeloproliferative disorder who have failed hypomethylating agent or induction chemotherapy Patients who have relapsed after allogeneic hematopoietic cell transplant (HCT) are eligible if they are at least 3 months after HCT, do not have active graft vs. host disease (GVHD) and are off immunosuppression except for maintenance dose of steroids (prednisone 10 mg/day or less) At least 2 weeks from prior chemotherapy or radiation therapy to time of start of treatment, except for hydroxyurea or corticosteroid therapy which may be continued through cycle 1 Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN) Total bilirubin =< 1.5 X ULN Corrected QT (QTc) =< 480 ms Calculated creatinine clearance (CrCl) >= 50 mL/min per 24 hour urine collection or the Cockcroft-Gault formula Negative serum or urine beta-human chorionic gonadotropin (beta-HCG) test (female of childbearing potential only), to be performed locally within the screening period Agreement by females of childbearing potential and sexually active males to use an effective method of contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for three months following duration of study participation; the effects of study treatment on a developing fetus have the potential for teratogenic or abortifacient effects; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately Exclusion Criteria: Current or planned use of other investigational agents, or concurrent biological chemotherapy, or radiation therapy during the study treatment period Expected to undergo HCT within 120 days of enrollment Current or planned use of agents that prolong or suspected to prolong QTc Diagnosis of acute promyelocytic leukemia Active central nervous system leukemia Active fungal infection or bacterial sepsis Active peptic ulcer disease History of heart failure or cardiac arrhythmia Other active malignancy except for localized skin cancer, bladder, prostate, breast or cervical carcinoma in situ Pregnant women and women who are lactating; 8-chloro-adenosine is an agent with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with 8-chloro-adenosine, breastfeeding should be discontinued if the mother is treated with 8-chloro-adenosine Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I - 100mg/m^2 1-hour infusion<br>100mg/m^2 8-chloro-adenosine administered a one-hour intravenous infusion daily for first 5 days of each 28-day cycle, up to four cycles. | Drug: 8-Chloroadenosine<br>* Given IV<br>* Other names: 8-Cl-Ado;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>|
| Experimental: Phase I - 200mg/m^2 1-hour infusion<br>200mg/m^2 8-chloro-adenosine administered a one-hour intravenous infusion daily for first 5 days of each 28-day cycle, up to four cycles. | Drug: 8-Chloroadenosine<br>* Given IV<br>* Other names: 8-Cl-Ado;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>|
| Experimental: Phase I - 400mg/m^2 1-hour infusion<br>400mg/m^2 8-chloro-adenosine administered a one-hour intravenous infusion daily for first 5 days of each 28-day cycle, up to four cycles. | Drug: 8-Chloroadenosine<br>* Given IV<br>* Other names: 8-Cl-Ado;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>|
| Experimental: Phase I - 800mg/m^2 1-hour infusion<br>800mg/m^2 8-chloro-adenosine administered a one-hour intravenous infusion daily for first 5 days of each 28-day cycle, up to four cycles. | Drug: 8-Chloroadenosine<br>* Given IV<br>* Other names: 8-Cl-Ado;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>|
| Experimental: Phase I - 400mg/m^2 4-hour infusion<br>400mg/m^2 8-chloro-adenosine administered a four-hour intravenous infusion daily for first 5 days of each 28-day cycle, up to four cycles. | Drug: 8-Chloroadenosine<br>* Given IV<br>* Other names: 8-Cl-Ado;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>|
| Experimental: Phase I - 600mg/m^2 4-hour infusion<br>600mg/m^2 8-chloro-adenosine administered a four-hour intravenous infusion daily for first 5 days of each 28-day cycle, up to four cycles. | Drug: 8-Chloroadenosine<br>* Given IV<br>* Other names: 8-Cl-Ado;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | Up to 28 days following first study agent administration. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 2 years following first study agent administration. |