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; Sarah Behr; Kristine L. Cooper; Haider Mahdi; Denise Fabian; Holly Gallion; Frederick Ueland; John Vargo; Brian Orr; Eugenia Girda; Madeleine Courtney-Brooks; Alexander B. Olawaiye; Leslie M. Randall; Debra L. Richardson; Stephanie A. Sullivan; Marilyn Huang; Susan M. Christner; Sushil Beriwal; Yan Lin; Aman Chauhan; Edward Chu; Elise C. Kohn; Charles Kunos; S. Percy Ivy; Jan H. Beumer

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, Sarah Behr, Kristine L. Cooper, Haider Mahdi, Denise Fabian, Holly Gallion, Frederick Ueland, John Vargo, Brian Orr, Eugenia Girda, Madeleine Courtney-Brooks, Alexander B. Olawaiye, Leslie M. Randall, Debra L. Richardson, Stephanie A. Sullivan, Marilyn Huang, Susan M. Christner, Sushil Beriwal, Yan Lin, Aman ChauhanEdward Chu, Elise C. Kohn, Charles Kunos, S. Percy Ivy, Jan H. Beumer

Cancer Institute of New Jersey (CINJ), Gynecology Oncology

Rutgers, The State University

Research output: Contribution to journal › Article › peer-review

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.

Original language	American English
Article number	4
Journal	Cancer chemotherapy and pharmacology
Volume	95
Issue number	1
DOIs	https://doi.org/10.1007/s00280-024-04720-1
State	Published - Dec 2025

ASJC Scopus subject areas

Oncology
Toxicology
Pharmacology
Cancer Research
Pharmacology (medical)

Keywords

Bioavailability
Dose finding
Pharmacodynamics
Pharmacokinetics
Triapine

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10.1007/s00280-024-04720-1

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Taylor, S. E., Behr, S., Cooper, K. L., Mahdi, H., Fabian, D., Gallion, H., Ueland, F., Vargo, J., Orr, B., Girda, E., Courtney-Brooks, M., Olawaiye, A. B., Randall, L. M., Richardson, D. L., Sullivan, S. A., Huang, M., Christner, S. M., Beriwal, S., Lin, Y., ... Beumer, J. H. (2025). Dose finding, bioavailability, and PK-PD of oral triapine with concurrent chemoradiation for locally advanced cervical cancer and vaginal cancer (ETCTN 9892). Cancer chemotherapy and pharmacology, 95(1), Article 4. https://doi.org/10.1007/s00280-024-04720-1

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

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",

author = "Taylor, {Sarah E.} and Sarah Behr and Cooper, {Kristine L.} and Haider Mahdi and Denise Fabian and Holly Gallion and Frederick Ueland and John Vargo and Brian Orr and Eugenia Girda and Madeleine Courtney-Brooks and Olawaiye, {Alexander B.} and Randall, {Leslie M.} and Richardson, {Debra L.} and Sullivan, {Stephanie A.} and Marilyn Huang and Christner, {Susan M.} and Sushil Beriwal and Yan Lin and Aman Chauhan and Edward Chu and Kohn, {Elise C.} and Charles Kunos and Ivy, {S. Percy} and Beumer, {Jan H.}",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2024.",

year = "2025",

month = dec,

doi = "10.1007/s00280-024-04720-1",

language = "American English",

volume = "95",

journal = "Cancer chemotherapy and pharmacology",

issn = "0344-5704",

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Taylor, SE, Behr, S, Cooper, KL, Mahdi, H, Fabian, D, Gallion, H, Ueland, F, Vargo, J, Orr, B, Girda, E, Courtney-Brooks, M, Olawaiye, AB, Randall, LM, Richardson, DL, Sullivan, SA, Huang, M, Christner, SM, Beriwal, S, Lin, Y, Chauhan, A, Chu, E, Kohn, EC, Kunos, C, Ivy, SP & Beumer, JH 2025, 'Dose finding, bioavailability, and PK-PD of oral triapine with concurrent chemoradiation for locally advanced cervical cancer and vaginal cancer (ETCTN 9892)', Cancer chemotherapy and pharmacology, vol. 95, no. 1, 4. https://doi.org/10.1007/s00280-024-04720-1

TY - JOUR

T1 - Dose finding, bioavailability, and PK-PD of oral triapine with concurrent chemoradiation for locally advanced cervical cancer and vaginal cancer (ETCTN 9892)

AU - Taylor, Sarah E.

AU - Behr, Sarah

AU - Cooper, Kristine L.

AU - Mahdi, Haider

AU - Fabian, Denise

AU - Gallion, Holly

AU - Ueland, Frederick

AU - Vargo, John

AU - Orr, Brian

AU - Girda, Eugenia

AU - Courtney-Brooks, Madeleine

AU - Olawaiye, Alexander B.

AU - Randall, Leslie M.

AU - Richardson, Debra L.

AU - Sullivan, Stephanie A.

AU - Huang, Marilyn

AU - Christner, Susan M.

AU - Beriwal, Sushil

AU - Lin, Yan

AU - Chauhan, Aman

AU - Chu, Edward

AU - Kohn, Elise C.

AU - Kunos, Charles

AU - Ivy, S. Percy

AU - Beumer, Jan H.

N1 - Publisher Copyright: © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2024.

PY - 2025/12

Y1 - 2025/12

N2 - 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.

AB - 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.

KW - Bioavailability

KW - Dose finding

KW - Pharmacodynamics

KW - Pharmacokinetics

KW - Triapine

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UR - http://www.scopus.com/inward/citedby.url?scp=85211898238&partnerID=8YFLogxK

U2 - 10.1007/s00280-024-04720-1

DO - 10.1007/s00280-024-04720-1

M3 - Article

C2 - 39673591

SN - 0344-5704

VL - 95

JO - Cancer chemotherapy and pharmacology

JF - Cancer chemotherapy and pharmacology

IS - 1

M1 - 4

ER -

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

Abstract

ASJC Scopus subject areas

Keywords

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