Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 19 of 1198 for:    adenosine

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02509546
Recruitment Status : Recruiting
First Posted : July 28, 2015
Last Update Posted : May 23, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
City of Hope Medical Center

Tracking Information
First Submitted Date  ICMJE June 10, 2015
First Posted Date  ICMJE July 28, 2015
Last Update Posted Date May 23, 2019
Study Start Date  ICMJE September 2, 2015
Estimated Primary Completion Date December 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 16, 2015)
  • Complete remission rate (CR + CRi), calculated as the percent of evaluable patients that have confirmed CR or CRi (Phase II) [ Time Frame: 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).
  • Incidence of toxicity, graded according to the NCI CTCAE version 4.03 [ Time Frame: 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.
  • Maximum tolerated dose of 8-chloro-adenosine, defined as the highest dose at which =< 1/6 patients in a cohort experience a dose limiting toxicity (DLT) (Phase I) [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: July 24, 2015)
  • Complete remission rate (CR + CRi), calculated as the percent of evaluable patients that have confirmed CR or CRi (Phase II) [ Time Frame: 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).
  • Incidence of toxicity, graded according to the NCI CTCAE version 4.03 [ Time Frame: 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.
  • Maximum tolerated dose of tocladesine, defined as the highest dose at which 1/6 patients in a cohort experience a dose limiting toxicity (DLT) (Phase I) [ Time Frame: 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.
Change History Complete list of historical versions of study NCT02509546 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 24, 2015)
  • Duration of response [ Time Frame: 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.
  • Event-free survival [ Time Frame: 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.
  • Overall response rate (CR/CRi/PR), calculated as the percent of evaluable patients that have confirmed CR or CRi or PR [ Time Frame: Up to 2 years ]
    Response rates will be evaluated based on number and type of prior therapy(ies).
  • Overall survival [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: October 16, 2015)
  • Cellular PK parameters of concentrations of 8-chloro-adenosine and 8-chloro-ATP in circulating leukemia cells in peripheral blood [ Time Frame: 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/PD parameters for the population will be derived from the parameters obtained from the individual patients.
  • Plasma PK parameters of 8-chloro-adenosine its deaminated metabolite, 8-chloro-inosine, and its base 8-chloro-adenine [ Time Frame: 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/PD parameters for the population will be derived from the parameters obtained from the individual patients.
  • Level of protein expression and protein modifications [ Time Frame: 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.
  • Urine PK parameters of 8-chloro-adenosine, its deaminated metabolite, 8-chloro-Inosine, and its base 8-chloro-adenine [ Time Frame: 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.
Original Other Pre-specified Outcome Measures
 (submitted: July 24, 2015)
  • Cellular PK parameters of concentrations of 8-chloro-adenosine and 8-chloro-ATP in circulating leukemia cells in peripheral blood [ Time Frame: Course 1: pre-treatment, 1, 2, 4, 6-10, and 12-18 hours after administration (day 1); 24, 25, 48, 49, 72, 73, 96, and 97 hours after administration (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.
  • Plasma PK parameters of 8-chloro-adenosine its deaminated metabolite, 8-chloro-inosine, and its base 8-chloro-adenine [ Time Frame: Course 1: pre-treatment, 1, 2, 4, 6-10, and 12-18 hours after administration (day 1); 24, 25, 48, 49, 72, 73, 96, and 97 hours after administration (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.
  • Level of protein expression and protein modifications [ Time Frame: 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.
  • Urine PK parameters of 8-chloro-adenosine, its deaminated metabolite, 8-chloro-Inosine, and its base 8-chloro-adenine [ Time Frame: 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.
 
Descriptive Information
Brief Title  ICMJE 8-Chloro-Adenosine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia
Official Title  ICMJE A Phase I/II Trial of 8-Chloro-Adenosine in Relapsed or Refractory Acute Myeloid Leukemia
Brief Summary This phase I/II trial studies the side effects and best dose of 8-chloro-adenosine and how well it works in treating patients with acute myeloid leukemia that has returned after a period of improvement (relapsed) or has not responded to previous treatment (refractory). Drugs used in chemotherapy, such as 8-chloro-adenosine, 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

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)

TERTIARY 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 ribonucleic acids (mRNAs) 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.

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

VI. To generate a preliminary pre-treatment RNA/micro ribonucleic acid (miRNA) signature in leukemic progenitor cells, and explore its possible association with in vitro cytotoxicity to 8-chloro-adenosine.

VII. 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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Recurrent Adult Acute Myeloid Leukemia
  • Relapsed Adult Acute Myeloid Leukemia
  • Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
  • Acute Myeloid Leukemia Arising From Previous Myeloproliferative Disorder
Intervention  ICMJE
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Other: Pharmacological Study
    Correlative studies
  • Drug: 8-chloro-adenosine
    Given IV
Study Arms  ICMJE 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.
Interventions:
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
  • Drug: 8-chloro-adenosine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 24, 2015)
43
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2019
Estimated Primary Completion Date December 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
  • 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; 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 of 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; 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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02509546
Other Study ID Numbers  ICMJE 14269
NCI-2015-00871 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
14269 ( Other Identifier: City of Hope Medical Center )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party City of Hope Medical Center
Study Sponsor  ICMJE City of Hope Medical Center
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Vinod Pullarkat City of Hope Medical Center
PRS Account City of Hope Medical Center
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP