First-in-human clinical trial of oral ONC201 in patients with refractory solid tumors

Mark Stein, Joseph Bertino, Howard L. Kaufman, Tina Mayer, Rebecca Moss, Ann Silk, Nancy Chan, Jyoti Malhotra, Lorna Rodriguez-Rust, Joseph Aisner, Robert Aiken, Bruce Haffty, Robert S. DiPaola, Tracie Saunders, Sherri Damare, Yasmeen Beckett, Bangning Yu, Saltanat Najmi, Christian Gabel, Siobhan DickersonLing Zheng, Wafik S. El-Deiry, Joshua E. Allen, Martin Stogniew, Wolfgang Oster, Janice Mehnert

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Abstract

Purpose: ONC201 is a small-molecule selective antagonist of the G protein–coupled receptor DRD2 that is the founding member of the imipridone class of compounds. A first-in-human phase I study of ONC201 was conducted to determine its recommended phase II dose (RP2D). Experimental Design: This open-label study treated 10 patients during dose escalation with histologically confirmed advanced solid tumors. Patients received ONC201 orally once every 3 weeks, defined as one cycle, at doses from 125 to 625 mg using an accelerated titration design. An additional 18 patients were treated at the RP2D in an expansion phase to collect additional safety, pharmacokinetic, and pharmacodynamic information. Results: No grade >1 drug-related adverse events occurred, and the RP2D was defined as 625 mg. Pharmacokinetic analysis revealed a Cmax of 1.5 to 7.5 mg/mL (3.9–19.4 mmol/L), mean half-life of 11.3 hours, and mean AUC of 37.7 hmg/L. Pharmacodynamic assays demonstrated induction of caspase-cleaved keratin 18 and prolactin as serum biomarkers of apoptosis and DRD2 antagonism, respectively. No objective responses by RECIST were achieved; however, radiographic regression of several individual metastatic lesions was observed along with prolonged stable disease (>9 cycles) in prostate and endometrial cancer patients. Conclusions: ONC201 is a selective DRD2 antagonist that is well tolerated, achieves micromolar plasma concentrations, and is biologically active in advanced cancer patients when orally administered at 625 mg every 3 weeks.

Original languageEnglish (US)
Pages (from-to)4163-4169
Number of pages7
JournalClinical Cancer Research
Volume23
Issue number15
DOIs
StatePublished - Aug 1 2017

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Clinical Trials
Neoplasms
Pharmacokinetics
Keratin-18
Endometrial Neoplasms
Caspases
Drug-Related Side Effects and Adverse Reactions
Prolactin
Area Under Curve
Half-Life
Prostatic Neoplasms
Research Design
Biomarkers
TIC10 compound
Apoptosis
Safety
Serum

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Stein, Mark ; Bertino, Joseph ; Kaufman, Howard L. ; Mayer, Tina ; Moss, Rebecca ; Silk, Ann ; Chan, Nancy ; Malhotra, Jyoti ; Rodriguez-Rust, Lorna ; Aisner, Joseph ; Aiken, Robert ; Haffty, Bruce ; DiPaola, Robert S. ; Saunders, Tracie ; Damare, Sherri ; Beckett, Yasmeen ; Yu, Bangning ; Najmi, Saltanat ; Gabel, Christian ; Dickerson, Siobhan ; Zheng, Ling ; El-Deiry, Wafik S. ; Allen, Joshua E. ; Stogniew, Martin ; Oster, Wolfgang ; Mehnert, Janice. / First-in-human clinical trial of oral ONC201 in patients with refractory solid tumors. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 15. pp. 4163-4169.
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title = "First-in-human clinical trial of oral ONC201 in patients with refractory solid tumors",
abstract = "Purpose: ONC201 is a small-molecule selective antagonist of the G protein–coupled receptor DRD2 that is the founding member of the imipridone class of compounds. A first-in-human phase I study of ONC201 was conducted to determine its recommended phase II dose (RP2D). Experimental Design: This open-label study treated 10 patients during dose escalation with histologically confirmed advanced solid tumors. Patients received ONC201 orally once every 3 weeks, defined as one cycle, at doses from 125 to 625 mg using an accelerated titration design. An additional 18 patients were treated at the RP2D in an expansion phase to collect additional safety, pharmacokinetic, and pharmacodynamic information. Results: No grade >1 drug-related adverse events occurred, and the RP2D was defined as 625 mg. Pharmacokinetic analysis revealed a Cmax of 1.5 to 7.5 mg/mL (3.9–19.4 mmol/L), mean half-life of 11.3 hours, and mean AUC of 37.7 hmg/L. Pharmacodynamic assays demonstrated induction of caspase-cleaved keratin 18 and prolactin as serum biomarkers of apoptosis and DRD2 antagonism, respectively. No objective responses by RECIST were achieved; however, radiographic regression of several individual metastatic lesions was observed along with prolonged stable disease (>9 cycles) in prostate and endometrial cancer patients. Conclusions: ONC201 is a selective DRD2 antagonist that is well tolerated, achieves micromolar plasma concentrations, and is biologically active in advanced cancer patients when orally administered at 625 mg every 3 weeks.",
author = "Mark Stein and Joseph Bertino and Kaufman, {Howard L.} and Tina Mayer and Rebecca Moss and Ann Silk and Nancy Chan and Jyoti Malhotra and Lorna Rodriguez-Rust and Joseph Aisner and Robert Aiken and Bruce Haffty and DiPaola, {Robert S.} and Tracie Saunders and Sherri Damare and Yasmeen Beckett and Bangning Yu and Saltanat Najmi and Christian Gabel and Siobhan Dickerson and Ling Zheng and El-Deiry, {Wafik S.} and Allen, {Joshua E.} and Martin Stogniew and Wolfgang Oster and Janice Mehnert",
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Stein, M, Bertino, J, Kaufman, HL, Mayer, T, Moss, R, Silk, A, Chan, N, Malhotra, J, Rodriguez-Rust, L, Aisner, J, Aiken, R, Haffty, B, DiPaola, RS, Saunders, T, Damare, S, Beckett, Y, Yu, B, Najmi, S, Gabel, C, Dickerson, S, Zheng, L, El-Deiry, WS, Allen, JE, Stogniew, M, Oster, W & Mehnert, J 2017, 'First-in-human clinical trial of oral ONC201 in patients with refractory solid tumors', Clinical Cancer Research, vol. 23, no. 15, pp. 4163-4169. https://doi.org/10.1158/1078-0432.CCR-16-2658

First-in-human clinical trial of oral ONC201 in patients with refractory solid tumors. / Stein, Mark; Bertino, Joseph; Kaufman, Howard L.; Mayer, Tina; Moss, Rebecca; Silk, Ann; Chan, Nancy; Malhotra, Jyoti; Rodriguez-Rust, Lorna; Aisner, Joseph; Aiken, Robert; Haffty, Bruce; DiPaola, Robert S.; Saunders, Tracie; Damare, Sherri; Beckett, Yasmeen; Yu, Bangning; Najmi, Saltanat; Gabel, Christian; Dickerson, Siobhan; Zheng, Ling; El-Deiry, Wafik S.; Allen, Joshua E.; Stogniew, Martin; Oster, Wolfgang; Mehnert, Janice.

In: Clinical Cancer Research, Vol. 23, No. 15, 01.08.2017, p. 4163-4169.

Research output: Contribution to journalArticle

TY - JOUR

T1 - First-in-human clinical trial of oral ONC201 in patients with refractory solid tumors

AU - Stein, Mark

AU - Bertino, Joseph

AU - Kaufman, Howard L.

AU - Mayer, Tina

AU - Moss, Rebecca

AU - Silk, Ann

AU - Chan, Nancy

AU - Malhotra, Jyoti

AU - Rodriguez-Rust, Lorna

AU - Aisner, Joseph

AU - Aiken, Robert

AU - Haffty, Bruce

AU - DiPaola, Robert S.

AU - Saunders, Tracie

AU - Damare, Sherri

AU - Beckett, Yasmeen

AU - Yu, Bangning

AU - Najmi, Saltanat

AU - Gabel, Christian

AU - Dickerson, Siobhan

AU - Zheng, Ling

AU - El-Deiry, Wafik S.

AU - Allen, Joshua E.

AU - Stogniew, Martin

AU - Oster, Wolfgang

AU - Mehnert, Janice

PY - 2017/8/1

Y1 - 2017/8/1

N2 - Purpose: ONC201 is a small-molecule selective antagonist of the G protein–coupled receptor DRD2 that is the founding member of the imipridone class of compounds. A first-in-human phase I study of ONC201 was conducted to determine its recommended phase II dose (RP2D). Experimental Design: This open-label study treated 10 patients during dose escalation with histologically confirmed advanced solid tumors. Patients received ONC201 orally once every 3 weeks, defined as one cycle, at doses from 125 to 625 mg using an accelerated titration design. An additional 18 patients were treated at the RP2D in an expansion phase to collect additional safety, pharmacokinetic, and pharmacodynamic information. Results: No grade >1 drug-related adverse events occurred, and the RP2D was defined as 625 mg. Pharmacokinetic analysis revealed a Cmax of 1.5 to 7.5 mg/mL (3.9–19.4 mmol/L), mean half-life of 11.3 hours, and mean AUC of 37.7 hmg/L. Pharmacodynamic assays demonstrated induction of caspase-cleaved keratin 18 and prolactin as serum biomarkers of apoptosis and DRD2 antagonism, respectively. No objective responses by RECIST were achieved; however, radiographic regression of several individual metastatic lesions was observed along with prolonged stable disease (>9 cycles) in prostate and endometrial cancer patients. Conclusions: ONC201 is a selective DRD2 antagonist that is well tolerated, achieves micromolar plasma concentrations, and is biologically active in advanced cancer patients when orally administered at 625 mg every 3 weeks.

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