Clinical Trials /

Testing the Response to the Anti-cancer Drug, Triapine, in Uterine Cancers Using Markers From the Tissue at the Time of Hysterectomy

NCT04494113

Description:

This early phase I trial investigates the response of the anti-cancer drug, triapine, in uterine cancers by using markers from tissue samples at the time of removal of the uterus, ovaries, and fallopian tubes (hysterectomy and bilateral salpingo-oophorectomy). Triapine may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Adding triapine to the usual approach of surgery followed by chemotherapy alone or in combination with radiation therapy may help to slow the growth of uterine cancer.

Related Conditions:
  • Endometrial Serous Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Testing the Response to the Anti-cancer Drug, Triapine, in Uterine Cancers Using Markers From the Tissue at the Time of Hysterectomy
  • Official Title: A Phase 0 Window-of-Opportunity Pharmacodynamic Trial of Triapine (NSC# 663249) in Uterine Corpus Serous Adenocarcinoma

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-05457
  • SECONDARY ID: NCI-2020-05457
  • SECONDARY ID: 10401
  • SECONDARY ID: 10401
  • SECONDARY ID: 10401
  • SECONDARY ID: UM1CA186691
  • NCT ID: NCT04494113

Conditions

  • Endometrial Serous Adenocarcinoma

Interventions

DrugSynonymsArms
Triapine3-aminopyridine-2-carboxaldehyde thiosemicarbazone, 3-AP, 3-Apct, OCX-0191, OCX-191, OCX191, PAN-811Treatment (triapine, surgical resection)

Purpose

This early phase I trial investigates the response of the anti-cancer drug, triapine, in uterine cancers by using markers from tissue samples at the time of removal of the uterus, ovaries, and fallopian tubes (hysterectomy and bilateral salpingo-oophorectomy). Triapine may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Adding triapine to the usual approach of surgery followed by chemotherapy alone or in combination with radiation therapy may help to slow the growth of uterine cancer.

Detailed Description

      PRIMARY OBJECTIVE:

      I. Determine whether intravenous (IV) triapine 25 mg/m^2 will induce cell cycle arrest as
      measured by phospho-histone H3 (pHH3) in uterine serous adenocarcinoma cells removed at the
      time of hysterectomy.

      SECONDARY OBJECTIVES:

      I. Determine whether a preoperative dose of intravenous triapine 25 mg/m^2 can be safely
      given prior to hysterectomy and staging for uterine serous adenocarcinoma.

      II. Determine whether changes in cyclin D/E and Ki-67 protein expression are detectable using
      immunohistochemistry pre- and post-triapine treatment in uterine serous adenocarcinomas.

      III. Evaluate plasma and tissue triapine concentrations.

      EXPLORATORY OBJECTIVES:

      I. Determine the feasibility of using single-cell transcriptome analysis to quantify changes
      in gene expression following triapine treatment and to evaluate their concordance with
      immunohistochemistry (IHC) endpoints of cell cycle arrest.

      II. Identify genomic variants of uterine serous adenocarcinoma (including but not limited to
      p53) with treatment response to ribonucleotide reductase inhibitors such as triapine using
      whole exome sequencing (WES).

      OUTLINE:

      Patients receive triapine IV over 2 hours on day 1 in the absence of unacceptable toxicity.
      Patients then undergo surgical resection and tissue collection 6-8 hours after the initiation
      of the triapine infusion.

      After completion of study treatment, patients are followed up for 42 days.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (triapine, surgical resection)ExperimentalPatients receive triapine IV over 2 hours on day 1 in the absence of unacceptable toxicity. Patients then undergo surgical resection and tissue collection 6-8 hours after the initiation of the triapine infusion.
  • Triapine

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically confirmed uterine corpus serous adenocarcinoma

          -  Patients must be planned for surgical hysterectomy and operative staging

          -  Patients must have adequate archival tissue less than 6 weeks old or have sufficient
             tumor tissue and be willing to undergo an endometrial pipelle biopsy prior to
             beginning study treatment

          -  Patients must have adequate primary tumor volume, as determined by imaging (e.g.,
             computed tomography [CT], ultrasound, magnetic resonance imaging [MRI]) at eligibility
             screening, to accommodate research specimen collections in addition to clinical
             pathology evaluation

          -  Patients must not have received any prior anticancer treatment for endometrial cancer

          -  Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status =<
             2 (Karnofsky >= 60%)

          -  Absolute neutrophil count >= 1,000/mcL

          -  Platelets >= 100,000/mcL

          -  Hemoglobin >= 9.0 g/dL

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 3 x institutional ULN

          -  International normalized ratio (INR) =< 2

          -  Creatinine =< 1.5 x institutional ULN OR glomerular filtration rate (GFR) >= 60
             mL/min/1.73 m^2 unless data exists supporting safe use at lower kidney function
             values, no lower than 30 mL/min/1.73 m^2

          -  Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
             therapy with undetectable viral load within 6 months are eligible for this trial

          -  For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
             load must be undetectable on suppressive therapy, if indicated

          -  Patients with a history of hepatitis C virus (HCV) infection must have been treated
             and cured. For patients with HCV infection who are currently on treatment, they are
             eligible if they have an undetectable HCV viral load

          -  Patients with a prior or concurrent malignancy whose natural history or treatment does
             not have the potential to interfere with the safety or efficacy assessment of the
             investigational regimen are eligible for this trial

          -  Patients with known history or current symptoms of cardiac disease, or history of
             treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
             function using the New York Heart Association Functional Classification. To be
             eligible for this trial, patients should be class 2B or better

          -  Patients of childbearing potential must have a negative pregnancy test result prior to
             beginning study treatment

          -  Ability to understand and the willingness to sign a written informed consent document.
             Participants with impaired decision-making capacity (IDMC) are not eligible as there
             is limited likelihood of direct benefit for participants in this study

        Exclusion Criteria:

          -  Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
             nitrosoureas or mitomycin C) prior to entering the study

          -  Patients who have not recovered from adverse events due to prior anti-cancer therapy
             (i.e., have residual toxicities > grade 1) with the exception of alopecia

          -  Patients who are receiving any other investigational agents

          -  Patients who have known brain metastases, as they are not candidates for surgery

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to triapine

          -  Patients receiving any medications or substances that are inhibitors or inducers of
             triapine, as well as medications known to be associated with methemoglobinemia, are
             ineligible. Triapine drug interactions have not yet been identified. As part of the
             enrollment/informed consent procedures, the patient will be counseled on the risk of
             interactions with other agents, and what to do if new medications need to be
             prescribed or if the patient is considering a new over-the-counter medicine or herbal
             product

          -  Patients with uncontrolled intercurrent illness

          -  Patients with psychiatric illness/social situations that would limit compliance with
             study requirements

          -  Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency are not eligible.
             Patients at risk for G6PD deficiency must be screened prior to enrollment
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Pharmacodynamic response
Time Frame:Up to 6-8 hours post-triapine infusion
Safety Issue:
Description:Pharmacodynamic response rate will be estimated as the proportion of evaluable patients who achieve pharmacodynamic response defined as a decrease in phospho-histone H3 (pHH3) immunoscore of >= 1 from baseline to post-exposure of intravenous triapine for each patient. The corresponding 95% confidence interval will be provided.

Secondary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to day 42
Safety Issue:
Description:Dose-limiting toxicities (DLTs), as listed by Common Terminology Criteria for Adverse Events (CTCAE), version 5, are defined as any pre-surgical grade 3 or higher non-hematologic toxicity or grade 4 neutropenia, neutropenic fever, or thrombocytopenia within 24 hours of triapine administration. Toxicity will be tabulated by type and grade.
Measure:Pharmacokinetic (PK) analysis
Time Frame:Baseline, 5 minutes before end of triapine infusion, 6-8 hours post-infusion (at time of surgical tissue resection), and 24 hours post-infusion
Safety Issue:
Description:End of infusion plasma concentrations represent maximum concentration (Cmax) and will be compared with historical data. Post-triapine plasma and tissue concentrations will generate plasma to tissue ratios, which represent the tissue partitioning coefficient, a useful PK parameter.

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

May 18, 2021