Phase i study of zotiraciclib in combination with temozolomide for patients with recurrent high-grade astrocytomas

Jing Wu; Ying Yuan; Debra A.Long Priel; Danielle Fink; Cody J. Peer; Tristan M. Sissung; Yu Ting Su; Ying Pang; Guangyang Yu; Madison K. Butler; Tito R. Mendoza; Elizabeth Vera; Salman Ahmad; Christine Bryla; Matthew Lindsley; Ewa Grajkowska; Kelly Mentges; Lisa Boris; Ramya Antony; Nancy Garren; Christine Siegel; Nicole Lollo; Christine Cordova; Orwa Aboud; Brett J. Theeler; Eric M. Burton; Marta Penas-Prado; Heather Leeper; Javier Gonzales; Terri S. Armstrong; Katherine R. Calvo; William D. Figg; Douglas B. Kuhns; John I. Gallin; Mark R. Gilbert

doi:10.1158/1078-0432.CCR-20-4730

Phase i study of zotiraciclib in combination with temozolomide for patients with recurrent high-grade astrocytomas

Jing Wu, Ying Yuan, Debra A.Long Priel, Danielle Fink, Cody J. Peer, Tristan M. Sissung, Yu Ting Su, Ying Pang, Guangyang Yu, Madison K. Butler, Tito R. Mendoza, Elizabeth Vera, Salman Ahmad, Christine Bryla, Matthew Lindsley, Ewa Grajkowska, Kelly Mentges, Lisa Boris, Ramya Antony, Nancy GarrenChristine Siegel, Nicole Lollo, Christine Cordova, Orwa Aboud, Brett J. Theeler, Eric M. Burton, Marta Penas-Prado, Heather Leeper, Javier Gonzales, Terri S. Armstrong, Katherine R. Calvo, William D. Figg, Douglas B. Kuhns, John I. Gallin, Mark R. Gilbert

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

Abstract

Purpose: To investigate the toxicity profile and establish an optimal dosing schedule of zotiraciclib with temozolomide in patients with recurrent high-grade astrocytoma. Patients and Methods: This two-stage phase I trial determined theMTDof zotiraciclib combined with either dose-dense (Arm1) or metronomic (Arm2) temozolomide using a Bayesian Optimal Interval design; then a randomized cohort expansion compared the progression-free survival rate at 4 months (PFS4) of the two arms for an efficient determination of a temozolomide schedule to combine with zotiraciclib at MTD. Pharmacokinetic and pharmacogenomic profiling were included. Patient-reported outcome was evaluated by longitudinal symptom burden. Results: Fifty-three patients were enrolled. Dose-limiting toxicities were neutropenia, diarrhea, elevated liver enzymes, and fatigue. MTD of zotiraciclib was 250 mg in both arms and thus selected for the cohort expansion. Dose-dense temozolomide plus zotiraciclib (PSF4 40%) compared favorably with metronomic temozolomide (PFS4 25%). Symptom burden worsened at cycle 2 but stabilized by cycle 4 in both arms. A significant decrease in absolute neutrophil count and neutrophil reactive oxygen species production occurred 12-24 hours after an oral dose of zotiraciclib but both recovered by 72 hours. Pharmacokinetic/pharmacogenomic analyses revealed that the CYP1A2_5347T>C (rs2470890) polymorphism was associated with higher AUCinf value. Conclusions: Zotiraciclib combined with temozolomide is safe in patients with recurrent high-grade astrocytomas. Zotiraciclibinduced neutropenia can be profound but mostly transient, warranting close monitoring rather than treatment discontinuation. Once validated, polymorphisms predicting drug metabolism may allow personalized dosing of zotiraciclib.

Original language	American English
Pages (from-to)	3298-3306
Number of pages	9
Journal	Clinical Cancer Research
Volume	27
Issue number	12
DOIs	https://doi.org/10.1158/1078-0432.CCR-20-4730
State	Published - Jan 2021

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10.1158/1078-0432.CCR-20-4730

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Wu, J., Yuan, Y., Priel, D. A. L., Fink, D., Peer, C. J., Sissung, T. M., Su, Y. T., Pang, Y., Yu, G., Butler, M. K., Mendoza, T. R., Vera, E., Ahmad, S., Bryla, C., Lindsley, M., Grajkowska, E., Mentges, K., Boris, L., Antony, R., ... Gilbert, M. R. (2021). Phase i study of zotiraciclib in combination with temozolomide for patients with recurrent high-grade astrocytomas. Clinical Cancer Research, 27(12), 3298-3306. https://doi.org/10.1158/1078-0432.CCR-20-4730

@article{dbd6996117434308be341890939ce442,

title = "Phase i study of zotiraciclib in combination with temozolomide for patients with recurrent high-grade astrocytomas",

abstract = "Purpose: To investigate the toxicity profile and establish an optimal dosing schedule of zotiraciclib with temozolomide in patients with recurrent high-grade astrocytoma. Patients and Methods: This two-stage phase I trial determined theMTDof zotiraciclib combined with either dose-dense (Arm1) or metronomic (Arm2) temozolomide using a Bayesian Optimal Interval design; then a randomized cohort expansion compared the progression-free survival rate at 4 months (PFS4) of the two arms for an efficient determination of a temozolomide schedule to combine with zotiraciclib at MTD. Pharmacokinetic and pharmacogenomic profiling were included. Patient-reported outcome was evaluated by longitudinal symptom burden. Results: Fifty-three patients were enrolled. Dose-limiting toxicities were neutropenia, diarrhea, elevated liver enzymes, and fatigue. MTD of zotiraciclib was 250 mg in both arms and thus selected for the cohort expansion. Dose-dense temozolomide plus zotiraciclib (PSF4 40%) compared favorably with metronomic temozolomide (PFS4 25%). Symptom burden worsened at cycle 2 but stabilized by cycle 4 in both arms. A significant decrease in absolute neutrophil count and neutrophil reactive oxygen species production occurred 12-24 hours after an oral dose of zotiraciclib but both recovered by 72 hours. Pharmacokinetic/pharmacogenomic analyses revealed that the CYP1A2_5347T>C (rs2470890) polymorphism was associated with higher AUCinf value. Conclusions: Zotiraciclib combined with temozolomide is safe in patients with recurrent high-grade astrocytomas. Zotiraciclibinduced neutropenia can be profound but mostly transient, warranting close monitoring rather than treatment discontinuation. Once validated, polymorphisms predicting drug metabolism may allow personalized dosing of zotiraciclib.",

author = "Jing Wu and Ying Yuan and Priel, {Debra A.Long} and Danielle Fink and Peer, {Cody J.} and Sissung, {Tristan M.} and Su, {Yu Ting} and Ying Pang and Guangyang Yu and Butler, {Madison K.} and Mendoza, {Tito R.} and Elizabeth Vera and Salman Ahmad and Christine Bryla and Matthew Lindsley and Ewa Grajkowska and Kelly Mentges and Lisa Boris and Ramya Antony and Nancy Garren and Christine Siegel and Nicole Lollo and Christine Cordova and Orwa Aboud and Theeler, {Brett J.} and Burton, {Eric M.} and Marta Penas-Prado and Heather Leeper and Javier Gonzales and Armstrong, {Terri S.} and Calvo, {Katherine R.} and Figg, {William D.} and Kuhns, {Douglas B.} and Gallin, {John I.} and Gilbert, {Mark R.}",

year = "2021",

month = jan,

doi = "10.1158/1078-0432.CCR-20-4730",

language = "American English",

volume = "27",

pages = "3298--3306",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "12",

}

Wu, J, Yuan, Y, Priel, DAL, Fink, D, Peer, CJ, Sissung, TM, Su, YT, Pang, Y, Yu, G, Butler, MK, Mendoza, TR, Vera, E, Ahmad, S, Bryla, C, Lindsley, M, Grajkowska, E, Mentges, K, Boris, L, Antony, R, Garren, N, Siegel, C, Lollo, N, Cordova, C, Aboud, O, Theeler, BJ, Burton, EM, Penas-Prado, M, Leeper, H, Gonzales, J, Armstrong, TS, Calvo, KR, Figg, WD, Kuhns, DB, Gallin, JI & Gilbert, MR 2021, 'Phase i study of zotiraciclib in combination with temozolomide for patients with recurrent high-grade astrocytomas', Clinical Cancer Research, vol. 27, no. 12, pp. 3298-3306. https://doi.org/10.1158/1078-0432.CCR-20-4730

TY - JOUR

T1 - Phase i study of zotiraciclib in combination with temozolomide for patients with recurrent high-grade astrocytomas

AU - Wu, Jing

AU - Yuan, Ying

AU - Priel, Debra A.Long

AU - Fink, Danielle

AU - Peer, Cody J.

AU - Sissung, Tristan M.

AU - Su, Yu Ting

AU - Pang, Ying

AU - Yu, Guangyang

AU - Butler, Madison K.

AU - Mendoza, Tito R.

AU - Vera, Elizabeth

AU - Ahmad, Salman

AU - Bryla, Christine

AU - Lindsley, Matthew

AU - Grajkowska, Ewa

AU - Mentges, Kelly

AU - Boris, Lisa

AU - Antony, Ramya

AU - Garren, Nancy

AU - Siegel, Christine

AU - Lollo, Nicole

AU - Cordova, Christine

AU - Aboud, Orwa

AU - Theeler, Brett J.

AU - Burton, Eric M.

AU - Penas-Prado, Marta

AU - Leeper, Heather

AU - Gonzales, Javier

AU - Armstrong, Terri S.

AU - Calvo, Katherine R.

AU - Figg, William D.

AU - Kuhns, Douglas B.

AU - Gallin, John I.

AU - Gilbert, Mark R.

PY - 2021/1

Y1 - 2021/1

N2 - Purpose: To investigate the toxicity profile and establish an optimal dosing schedule of zotiraciclib with temozolomide in patients with recurrent high-grade astrocytoma. Patients and Methods: This two-stage phase I trial determined theMTDof zotiraciclib combined with either dose-dense (Arm1) or metronomic (Arm2) temozolomide using a Bayesian Optimal Interval design; then a randomized cohort expansion compared the progression-free survival rate at 4 months (PFS4) of the two arms for an efficient determination of a temozolomide schedule to combine with zotiraciclib at MTD. Pharmacokinetic and pharmacogenomic profiling were included. Patient-reported outcome was evaluated by longitudinal symptom burden. Results: Fifty-three patients were enrolled. Dose-limiting toxicities were neutropenia, diarrhea, elevated liver enzymes, and fatigue. MTD of zotiraciclib was 250 mg in both arms and thus selected for the cohort expansion. Dose-dense temozolomide plus zotiraciclib (PSF4 40%) compared favorably with metronomic temozolomide (PFS4 25%). Symptom burden worsened at cycle 2 but stabilized by cycle 4 in both arms. A significant decrease in absolute neutrophil count and neutrophil reactive oxygen species production occurred 12-24 hours after an oral dose of zotiraciclib but both recovered by 72 hours. Pharmacokinetic/pharmacogenomic analyses revealed that the CYP1A2_5347T>C (rs2470890) polymorphism was associated with higher AUCinf value. Conclusions: Zotiraciclib combined with temozolomide is safe in patients with recurrent high-grade astrocytomas. Zotiraciclibinduced neutropenia can be profound but mostly transient, warranting close monitoring rather than treatment discontinuation. Once validated, polymorphisms predicting drug metabolism may allow personalized dosing of zotiraciclib.

AB - Purpose: To investigate the toxicity profile and establish an optimal dosing schedule of zotiraciclib with temozolomide in patients with recurrent high-grade astrocytoma. Patients and Methods: This two-stage phase I trial determined theMTDof zotiraciclib combined with either dose-dense (Arm1) or metronomic (Arm2) temozolomide using a Bayesian Optimal Interval design; then a randomized cohort expansion compared the progression-free survival rate at 4 months (PFS4) of the two arms for an efficient determination of a temozolomide schedule to combine with zotiraciclib at MTD. Pharmacokinetic and pharmacogenomic profiling were included. Patient-reported outcome was evaluated by longitudinal symptom burden. Results: Fifty-three patients were enrolled. Dose-limiting toxicities were neutropenia, diarrhea, elevated liver enzymes, and fatigue. MTD of zotiraciclib was 250 mg in both arms and thus selected for the cohort expansion. Dose-dense temozolomide plus zotiraciclib (PSF4 40%) compared favorably with metronomic temozolomide (PFS4 25%). Symptom burden worsened at cycle 2 but stabilized by cycle 4 in both arms. A significant decrease in absolute neutrophil count and neutrophil reactive oxygen species production occurred 12-24 hours after an oral dose of zotiraciclib but both recovered by 72 hours. Pharmacokinetic/pharmacogenomic analyses revealed that the CYP1A2_5347T>C (rs2470890) polymorphism was associated with higher AUCinf value. Conclusions: Zotiraciclib combined with temozolomide is safe in patients with recurrent high-grade astrocytomas. Zotiraciclibinduced neutropenia can be profound but mostly transient, warranting close monitoring rather than treatment discontinuation. Once validated, polymorphisms predicting drug metabolism may allow personalized dosing of zotiraciclib.

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U2 - 10.1158/1078-0432.CCR-20-4730

DO - 10.1158/1078-0432.CCR-20-4730

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