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

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ClinicalTrials.gov Identifier: NCT04494113
Recruitment Status : Recruiting
First Posted : July 31, 2020
Last Update Posted : October 14, 2021
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE July 30, 2020
First Posted Date  ICMJE July 31, 2020
Last Update Posted Date October 14, 2021
Actual Study Start Date  ICMJE November 11, 2020
Estimated Primary Completion Date November 10, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 30, 2020)
Pharmacodynamic response [ Time Frame: Up to 6-8 hours post-triapine infusion ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 30, 2020)
  • Incidence of adverse events [ Time Frame: Up to day 42 ]
    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.
  • 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 ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: July 30, 2020)
  • Single-cell transcriptome analysis [ Time Frame: Baseline, post-triapine infusion, surgical resection ]
    Single-cell transcriptome analysis will be conducted to quantify changes in gene expression following triapine treatment. Changes of gene expression will be correlated with immunohistochemistry (IHC) endpoints of cell cycle arrest.
  • Whole exome sequencing (WES) analysis [ Time Frame: Baseline ]
    WES will be used to identify genomic variants of uterine serous adenocarcinoma (including but not limited to p53) that can predict the treatment response to triapine.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Testing the Response to the Anti-cancer Drug, Triapine, in Uterine Cancers Using Markers From the Tissue at the Time of Hysterectomy
Official Title  ICMJE A Phase 0 Window-of-Opportunity Pharmacodynamic Trial of Triapine (NSC# 663249) in Uterine Corpus Serous Adenocarcinoma
Brief Summary 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Early Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Endometrial Serous Adenocarcinoma
Intervention  ICMJE
  • Procedure: Biospecimen Collection
    Undergo tissue collection
    Other Names:
    • Biological Sample Collection
    • Biospecimen Collected
  • Procedure: Resection
    Undergo surgical resection
    Other Name: Surgical Resection
  • Drug: Triapine
    Given IV
    Other Names:
    • 3-aminopyridine-2-carboxaldehyde thiosemicarbazone
    • 3-AP
    • 3-Apct
    • OCX-0191
    • OCX-191
    • OCX191
    • PAN-811
Study Arms  ICMJE Experimental: Treatment (triapine, surgical resection)
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.
Interventions:
  • Procedure: Biospecimen Collection
  • Procedure: Resection
  • Drug: Triapine
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 30, 2020)
12
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 10, 2021
Estimated Primary Completion Date November 10, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
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 NCT04494113
Other Study ID Numbers  ICMJE NCI-2020-05457
NCI-2020-05457 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
10401
10401 ( Other Identifier: JHU Sidney Kimmel Comprehensive Cancer Center LAO )
10401 ( Other Identifier: CTEP )
UM1CA186691 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
URL: https://grants.nih.gov/policy/sharing.htm
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Rebecca L Stone JHU Sidney Kimmel Comprehensive Cancer Center LAO
PRS Account National Cancer Institute (NCI)
Verification Date July 2021

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