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Clinical Trial
. 2024 Dec 14;95(1):4.
doi: 10.1007/s00280-024-04720-1.

Dose finding, bioavailability, and PK-PD of oral triapine with concurrent chemoradiation for locally advanced cervical cancer and vaginal cancer (ETCTN 9892)

Sarah E Taylor  1   2 , Sarah Behr  3 , Kristine L Cooper  4 , Haider Mahdi  5   6 , Denise Fabian  7 , Holly Gallion  7 , Frederick Ueland  7 , John Vargo  8 , Brian Orr  5 , Eugenia Girda  9 , Madeleine Courtney-Brooks  5 , Alexander B Olawaiye  5 , Leslie M Randall  10 , Debra L Richardson  11 , Stephanie A Sullivan  10 , Marilyn Huang  12 , Susan M Christner  3 , Sushil Beriwal  8 , Yan Lin  3   4 , Aman Chauhan  13 , Edward Chu  14 , Elise C Kohn  15 , Charles Kunos  13 , S Percy Ivy  15 , Jan H Beumer  16   17   18
Affiliations
Clinical Trial

Dose finding, bioavailability, and PK-PD of oral triapine with concurrent chemoradiation for locally advanced cervical cancer and vaginal cancer (ETCTN 9892)

Sarah E Taylor et al. Cancer Chemother Pharmacol. .

Abstract

Background: The addition of IV triapine to chemoradiation appeared active in phase I and II studies but drug delivery is cumbersome. We examined PO triapine with cisplatin chemoradiation.

Methods: We implemented a 3 + 3 design for PO triapine dose escalation with expansion, starting at 100 mg, five days a week for five weeks while receiving radiation with weekly IV cisplatin for locally advanced cervical or vaginal cancer. Maximum tolerated dose (MTD), dose limiting toxicity (DLT), adverse events, pharmacokinetics (PK), pharmacodynamics (PD), and metabolic complete response (mCR) were assessed.

Results: 19/21 patients were DLT evaluable. DLTs included grade 4 neutropenia (n = 2), leukopenia (n = 2), lymphopenia (n = 2), and hypokalemia (n = 1). Grade 3 toxicities at least possibly related were as expected for cisplatin chemoradiation: lymphopenia (n = 12), anemia (n = 10), neutropenia (n = 4), leukopenia (n = 8), decreased platelets (n = 2), hypertension (n = 1), and hyponatremia (n = 1). MTD and RP2D were established at 100 mg. 8/13 evaluable patients had a mCR. Triapine had a bioavailability of 59%. Methemoglobin levels correlated with triapine exposure. Smoking almost doubled CYP1A2 mediated triapine clearance.

Conclusions: Oral triapine is safe when given with cisplatin chemoradiation, convenient, bioavailable. Exposure is negatively impacted by smoking, and methemoglobin is a biomarker of exposure.

Clinical trial registration: NCT02595879.

Keywords: Bioavailability; Dose finding; Pharmacodynamics; Pharmacokinetics; Triapine.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: This was an NCI, CTEP sponsored, multicenter trial performed at five NCI-designated cancer centers, approved by the respective institutional review boards and ethics committees, under the NCI CIRB as the IRB of record. All participants signed informed consent, priort to research procedures, with adherence to the ethical principles outlined in the Declaration of Helsinki. Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This trial was registered under ClinicalTrials.gov Identifier: NCT02595879. Informed consent: Informed consent was obtained from all individual participants included in the study. Consent for publication: Not applicable. Conflict of interest: The authors declare no potential conflicts of interest. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Pharmacokinetic profiles of triapine after 50 mg IV over 2 h (A, D; N = 20), 100 mg PO (B, E; N = 17), or 150 mg PO (C, F; N = 4), with 0–8 h close-up (D, E, F)
Fig. 2
Fig. 2
Impact of smoking status on triapine oral clearance (left panel, bars indicate geometric means; p = 0.014, ANOVA on log-normal transformed values), and exposure-response relationship of PO triapine (right panel; not significant)
Fig. 3
Fig. 3
Hysteresis of methemoglobin levels as a function of changes in triapine concentrations (top panel), and exposure-methemoglobin biomarker response relationship of triapine Cmax (middle panel; Pearson correlation coefficient 0.882; p < 0.001) or AUC (bottom panel; Pearson correlation coefficient 0.903; p < 0.001) after IV (○) or PO (Δ) dosing, with red markers indicating PO values for patients who experienced DLT
See this image and copyright information in PMC

References

    1. Siegel RL, Miller KD, Jemal A (2020) Cancer statistics, 2020. CA: a cancer journal for clinicians 70. 17–30. 10.3322/caac.21590 - DOI - PubMed
    1. Wang N, Guan QL, Wang K, Zhou X, Gao C, Yang HT, Ni TG (2011) Radiochemotherapy versus radiotherapy in locally advanced cervical cancer: a meta-analysis. Arch Gynecol Obstet 283(1):103–108. 10.1007/s00404-010-1385-5 - DOI - PubMed
    1. Wright JD, Matsuo K, Huang Y, Tergas AI, Hou JY, Khoury-Collado F, St Clair CM, Ananth CV, Neugut AI, Hershman DL (2019) Prognostic performance of the 2018 International Federation of Gynecology and Obstetrics Cervical Cancer Staging guidelines. Obstet Gynecol 134(1):49–57. 10.1097/AOG.0000000000003311 - DOI - PMC - PubMed
    1. Kunos CA, Radivoyevitch T, Kresak A, Dawson D, Jacobberger J, Yang B, Abdul-Karim FW (2012) Elevated ribonucleotide reductase levels associate with suppressed radiochemotherapy response in human cervical cancers. Int J Gynecol cancer: Official J Int Gynecol Cancer Soc 22(9):1463–1469. 10.1097/IGC.0b013e318270577f - DOI - PMC - PubMed
    1. Kunos CA (2012) Therapeutic mechanisms of treatment in cervical and vaginal Cancer. Oncol Hematol Rev 8(1):55–60 - PMC - PubMed

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