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

• ClinicalTrials.gov Identifier: NCT02509546
• Recruitment Status: Recruiting
• First Posted: July 28, 2015
• Last Update Posted: May 23, 2019
• Sponsor: City of Hope Medical Center
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): City of Hope Medical Center

Study Description

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.

Condition or disease	Intervention/treatment	Phase
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	Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: 8-chloro-adenosine	Phase 1; Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 43 participants
• 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
• Study Start Date: September 2, 2015
• Estimated Primary Completion Date: December 2019
• Estimated Study Completion Date: December 2019

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.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Drug: 8-chloro-adenosine; Given IV

Outcome Measures

Primary Outcome Measures :

1. 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).
2. 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.
3. 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.

Secondary Outcome Measures :

1. 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.
2. 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.
3. 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).
4. 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.

Other Outcome Measures:

1. 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.
2. 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.
3. 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.
4. 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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)

Contacts and Locations

Locations

United States, California

City of Hope Medical Center; Recruiting

Duarte, California, United States, 91010

Contact: Vinod Pullarkat 626-256-4673 vpullarkat@coh.org

Principal Investigator: Vinod Pullarkat

Sponsors and Collaborators

City of Hope Medical Center

National Cancer Institute (NCI)

Investigators

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

More Information

• Responsible Party: City of Hope Medical Center
• ClinicalTrials.gov Identifier: NCT02509546 History of Changes
• Other Study ID Numbers: 14269; NCI-2015-00871 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 14269 ( Other Identifier: City of Hope Medical Center )
• First Posted: July 28, 2015
• Last Update Posted: May 23, 2019
• Last Verified: May 2019

Additional relevant MeSH terms:

Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Myeloproliferative Disorders; Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Adenosine; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Arrhythmia Agents; Vasodilator Agents; Purinergic P1 Receptor Agonists; Purinergic Agonists; Purinergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action