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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 : Not yet recruiting
First Posted : July 31, 2020
Last Update Posted : November 10, 2020
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

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.

Condition or disease Intervention/treatment Phase
Endometrial Serous Adenocarcinoma Procedure: Resection Drug: Triapine Early Phase 1

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 6-8 hours after completion of triapine infusion.

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 0 Window-of-Opportunity Pharmacodynamic Trial of Triapine (NSC# 663249) in Uterine Corpus Serous Adenocarcinoma
Estimated Study Start Date : November 27, 2020
Estimated Primary Completion Date : March 1, 2022
Estimated Study Completion Date : March 1, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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 6-8 hours after completion of triapine infusion.
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-191




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.


Other Outcome Measures:
  1. 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.

  2. 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.



Information from the National Library of Medicine

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

Inclusion Criteria:

  • Patients must have histologically confirmed uterine corpus serous adenocarcinoma
  • Patients must be planned for surgical hysterectomy and operative staging
  • 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%)
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/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) who have a legally-authorized representative (LAR) and/or family member available will also be eligible

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 are ineligible. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04494113


Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Rebecca L Stone JHU Sidney Kimmel Comprehensive Cancer Center LAO
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04494113    
Other Study ID Numbers: NCI-2020-05457
NCI-2020-05457 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
10401 ( Other Identifier: JHU Sidney Kimmel Comprehensive Cancer Center LAO )
10401 ( Other Identifier: CTEP )
UM1CA186691 ( U.S. NIH Grant/Contract )
First Posted: July 31, 2020    Key Record Dates
Last Update Posted: November 10, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
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

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Adenocarcinoma
Cystadenocarcinoma, Serous
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Cystadenocarcinoma
Neoplasms, Cystic, Mucinous, and Serous