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

Sponsor
City of Hope Medical Center (Other)
Overall Status
Active, not recruiting
CT.gov ID
NCT02509546
Collaborator
National Cancer Institute (NCI) (NIH)
20
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87.5
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Study Details

Study Description

Brief Summary

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.

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:
  1. 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:
  1. 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
    1. To summarize and evaluate toxicities by type, frequency, severity, attribution, time course and duration. (Phase II)
CLINICAL PHARMACOLOGY OBJECTIVES:
  1. To describe the plasma, urinary and cellular pharmacokinetics of 8-chloro-adenosine and metabolites.

  2. To determine the impact of 8-chloro-adenosine on cellular adenosine triphosphate (ATP) pool in AML blasts.

  3. 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.

  4. 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:
  1. To determine the cytotoxicity of 8-chloro-adenosine toward leukemic progenitor cells in vitro.

  2. 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.

  3. 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 Design

Study Type:
Interventional
Actual Enrollment :
20 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase I/II Trial of 8-Chloro-Adenosine in Relapsed or Refractory Acute Myeloid Leukemia
Actual Study Start Date :
Sep 2, 2015
Anticipated Primary Completion Date :
Dec 15, 2022
Anticipated Study Completion Date :
Dec 17, 2022

Arms and Interventions

Arm Intervention/Treatment
Experimental: Treatment (8-chloro-adenosine)

Patients receive 8-chloro-adenosine 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.

Drug: 8-Chloroadenosine
Given IV
Other Names:
  • 8-Chloro-adenosine
  • 8-Cl-adenosine
  • 8-Cl-Ado
  • Other: Laboratory Biomarker Analysis
    Correlative studies

    Other: Pharmacological Study
    Correlative studies

    Outcome Measures

    Primary Outcome Measures

    1. Maximum tolerated dose defined as the highest dose at which =< 1/6 patients in a cohort experience a dose limiting toxicity (Phase I) [28 days]

      Graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study of treatment and reversibility or outcome.

    2. Incidence of toxicity, graded according to the NCI CTCAE version 4.03 [Up to 30 days after completion of study treatment]

      Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study of treatment and reversibility or outcome.

    3. Complete remission rate (CR + CRi), calculated as the percent of evaluable patients that have confirmed CR or CRi (Phase II) [Up to 2 years]

      The complete remission (CR + CRi) rate will be calculated as the percent of evaluable patients; exact 95% confidence intervals will be calculated for these estimates. Response rates will also be evaluated based on number and type of prior therapy(ies).

    Secondary Outcome Measures

    1. Duration of response [Date of first documented response (CR + CRi) to documented disease relapse or death whichever occurs first, assessed up to 2 years]

      Duration of response will be estimated using the product-limit method of Kaplan and Meier.

    2. Overall survival [Date of first dose of study drug to date of death from any cause, assessed up to 2 years]

      Overall survival will estimated using the product-limiting method of Kaplan and Meier.

    3. Event-free survival [Date of first dose of study drug to first documented disease progression or death from any cause, whichever occurs first, assessed up to 2 years]

      Event-free survival will be estimated using the product-limit method of Kaplan and Meier.

    4. Overall response rate (CR/CRi/PR), calculated as the percent of evaluable patients that have confirmed CR or CRi or PR [Up to 2 years]

      Response rates will be evaluated based on number and type of prior therapy(ies).

    Other Outcome Measures

    1. Plasma pharmacokinetic (PK) parameters of 8-chloro-adenosine its deaminated metabolite, 8-chloro-inosine, and its base 8-chloro-adenine [Course 1: pre-infusion, start of infusion, within last 15 minutes of infusion, end of infusion (EOI), 1, 3, 6-8, and 12-18 hours after infusion (day 1); pre-infusion, start of infusion, within last 15 minutes, and EOI (days 2-5)]

      Will be quantitated as continual measurement variables. Descriptive statistics and graphical displays will be used to summarize levels of 8-chloro-adenosine and its metabolites at each time point to evaluate changes pre- and post-treatment measurement. A pair t-test will be used to determine if there is a statistically significant change. Summary statistics of the PK/pharmacodynamic (PD) parameters for the population will be derived from the parameters obtained from the individual patients.

    2. Cellular PK parameters of concentrations of 8-chloro-adenosine and 8-chloro-ATP in circulating leukemia cells in peripheral blood [Course 1: pre-infusion, start of infusion, within last 15 minutes of infusion, EOI, 1, 3, 6-8, and 12-18 hours after infusion (day 1); pre-infusion, start of infusion, within last 15 minutes, and EOI (days 2-5)]

      Will be quantitated as continual measurement variables. Descriptive statistics and graphical displays will be used to summarize levels of 8-chloro-adenosine and its metabolites at each time point to evaluate changes pre- and post-treatment measurement. A pair t-test will be used to determine if there is a statistically significant change. Summary statistics of the PK/PD parameters for the population will be derived from the parameters obtained from the individual patients.

    3. Urine PK parameters of 8-chloro-adenosine, its deaminated metabolite, 8-chloro-Inosine, and its base 8-chloro-adenine [0-8 hours, 8-16 hours, and 16-24 hours during the first 24 hours after administration on day 1]

      Will be quantitated as continual measurement variables. Descriptive statistics and graphical displays will be used to summarize levels of 8-chloro-adenosine and its metabolites at each time point to evaluate changes pre- and post-treatment measurement. A pair t-test will be used to determine if there is a statistically significant change. Summary statistics of the PK/PD parameters for the population will be derived from the parameters obtained from the individual patients.

    4. Level of protein expression and protein modifications [Up to day 22]

      Protein level (e.g., phosphorylation, cleavage, and fatty acid modification) will be summarized descriptively using means, medians, standard deviations and ranges. Summary statistics of the PK/PD parameters for the population will be derived from the parameters obtained from the individual patients.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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)

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 City of Hope Medical Center Duarte California United States 91010

    Sponsors and Collaborators

    • City of Hope Medical Center
    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Vinod Pullarkat, City of Hope Medical Center

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    City of Hope Medical Center
    ClinicalTrials.gov Identifier:
    NCT02509546
    Other Study ID Numbers:
    • 14269
    • NCI-2015-00871
    • 123456
    • 122489
    • 14269
    First Posted:
    Jul 28, 2015
    Last Update Posted:
    Mar 3, 2022
    Last Verified:
    Feb 1, 2022

    Study Results

    No Results Posted as of Mar 3, 2022