Safety and enhanced immunostimulatory activity of the DRD2 antagonist ONC201 in advanced solid tumor patients with weekly oral administration

Mark N. Stein, Jyoti Malhotra, Rohinton S. Tarapore, Usha Malhotra, Ann W. Silk, Nancy Chan, Lorna Rodriguez-Rust, Joseph Aisner, Robert D. Aiken, Tina Mayer, Bruce G. Haffty, Jenna H. Newman, Salvatore M. Aspromonte, Praveen K. Bommareddy, Ricardo Estupinian, Charles B. Chesson, Evita T. Sadimin, Shengguo Li, Daniel J. Medina, Tracie Saunders & 14 others Melissa Frankel, Aparna Kareddula, Sherrie Damare, Elayne Wesolowsky, Christian Gabel, Wafik S. El-Deiry, Varun V. Prabhu, Joshua E. Allen, Martin Stogniew, Wolfgang Oster, Joseph R. Bertino, Steven K. Libutti, Janice M. Mehnert, Andrew Zloza

Research output: Contribution to journalArticle

Abstract

Background: ONC201 is a small molecule antagonist of DRD2, a G protein-coupled receptor overexpressed in several malignancies, that has prolonged antitumor efficacy and immunomodulatory properties in preclinical models. The first-in-human trial of ONC201 previously established a recommended phase II dose (RP2D) of 625 mg once every three weeks. Here, we report the results of a phase I study that evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of weekly ONC201. Methods: Patients ≥ 18 years old with an advanced solid tumor refractory to standard treatment were enrolled. Dose escalation proceeded with a 3 + 3 design from 375 mg to 625 mg of ONC201. One cycle, also the dose-limiting toxicity (DLT) window, was 21 days. The primary endpoint was to determine the RP2D of weekly ONC201, which was confirmed in an 11-patient dose expansion cohort. Results: Twenty patients were enrolled: three at 375 mg and 17 at 625 mg of ONC201. The RP2D was defined as 625 mg with no DLT, treatment discontinuation, or dose modifications due to drug-related toxicity. PK profiles were consistent with every-three-week dosing and similar between the first and fourth dose. Serum prolactin and caspase-cleaved cytokeratin-18 induction were detected, along with intratumoral integrated stress response activation and infiltration of granzyme B+ Natural Killer cells. Induction of immune cytokines and effectors was higher in patients who received ONC201 once weekly versus once every three weeks. Stable disease of > 6 months was observed in several prostate and endometrial cancer patients. Conclusions: Weekly, oral ONC201 is well-tolerated and results in enhanced immunostimulatory activity that warrants further investigation. Trial registration: NCT02250781 (Oral ONC201 in Treating Patients With Advanced Solid Tumors), NCT02324621 (Continuation of Oral ONC201 in Treating Patients With Advanced Solid Tumors).

Original languageEnglish (US)
Article number136
JournalJournal for ImmunoTherapy of Cancer
Volume7
Issue number1
DOIs
StatePublished - May 22 2019

Fingerprint

Oral Administration
Safety
Neoplasms
Pharmacokinetics
TIC10 compound
Keratin-18
Granzymes
Endometrial Neoplasms
Caspases
G-Protein-Coupled Receptors
Drug-Related Side Effects and Adverse Reactions
Natural Killer Cells
Prolactin
Prostatic Neoplasms
Cytokines
Therapeutics
Serum

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Oncology
  • Cancer Research
  • Immunology and Allergy
  • Pharmacology
  • Immunology

Keywords

  • Cancer
  • Dopamine
  • Immuno-oncology
  • Immunotherapy
  • ONC201
  • Solid tumors

Cite this

Stein, Mark N. ; Malhotra, Jyoti ; Tarapore, Rohinton S. ; Malhotra, Usha ; Silk, Ann W. ; Chan, Nancy ; Rodriguez-Rust, Lorna ; Aisner, Joseph ; Aiken, Robert D. ; Mayer, Tina ; Haffty, Bruce G. ; Newman, Jenna H. ; Aspromonte, Salvatore M. ; Bommareddy, Praveen K. ; Estupinian, Ricardo ; Chesson, Charles B. ; Sadimin, Evita T. ; Li, Shengguo ; Medina, Daniel J. ; Saunders, Tracie ; Frankel, Melissa ; Kareddula, Aparna ; Damare, Sherrie ; Wesolowsky, Elayne ; Gabel, Christian ; El-Deiry, Wafik S. ; Prabhu, Varun V. ; Allen, Joshua E. ; Stogniew, Martin ; Oster, Wolfgang ; Bertino, Joseph R. ; Libutti, Steven K. ; Mehnert, Janice M. ; Zloza, Andrew. / Safety and enhanced immunostimulatory activity of the DRD2 antagonist ONC201 in advanced solid tumor patients with weekly oral administration. In: Journal for ImmunoTherapy of Cancer. 2019 ; Vol. 7, No. 1.
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abstract = "Background: ONC201 is a small molecule antagonist of DRD2, a G protein-coupled receptor overexpressed in several malignancies, that has prolonged antitumor efficacy and immunomodulatory properties in preclinical models. The first-in-human trial of ONC201 previously established a recommended phase II dose (RP2D) of 625 mg once every three weeks. Here, we report the results of a phase I study that evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of weekly ONC201. Methods: Patients ≥ 18 years old with an advanced solid tumor refractory to standard treatment were enrolled. Dose escalation proceeded with a 3 + 3 design from 375 mg to 625 mg of ONC201. One cycle, also the dose-limiting toxicity (DLT) window, was 21 days. The primary endpoint was to determine the RP2D of weekly ONC201, which was confirmed in an 11-patient dose expansion cohort. Results: Twenty patients were enrolled: three at 375 mg and 17 at 625 mg of ONC201. The RP2D was defined as 625 mg with no DLT, treatment discontinuation, or dose modifications due to drug-related toxicity. PK profiles were consistent with every-three-week dosing and similar between the first and fourth dose. Serum prolactin and caspase-cleaved cytokeratin-18 induction were detected, along with intratumoral integrated stress response activation and infiltration of granzyme B+ Natural Killer cells. Induction of immune cytokines and effectors was higher in patients who received ONC201 once weekly versus once every three weeks. Stable disease of > 6 months was observed in several prostate and endometrial cancer patients. Conclusions: Weekly, oral ONC201 is well-tolerated and results in enhanced immunostimulatory activity that warrants further investigation. Trial registration: NCT02250781 (Oral ONC201 in Treating Patients With Advanced Solid Tumors), NCT02324621 (Continuation of Oral ONC201 in Treating Patients With Advanced Solid Tumors).",
keywords = "Cancer, Dopamine, Immuno-oncology, Immunotherapy, ONC201, Solid tumors",
author = "Stein, {Mark N.} and Jyoti Malhotra and Tarapore, {Rohinton S.} and Usha Malhotra and Silk, {Ann W.} and Nancy Chan and Lorna Rodriguez-Rust and Joseph Aisner and Aiken, {Robert D.} and Tina Mayer and Haffty, {Bruce G.} and Newman, {Jenna H.} and Aspromonte, {Salvatore M.} and Bommareddy, {Praveen K.} and Ricardo Estupinian and Chesson, {Charles B.} and Sadimin, {Evita T.} and Shengguo Li and Medina, {Daniel J.} and Tracie Saunders and Melissa Frankel and Aparna Kareddula and Sherrie Damare and Elayne Wesolowsky and Christian Gabel and El-Deiry, {Wafik S.} and Prabhu, {Varun V.} and Allen, {Joshua E.} and Martin Stogniew and Wolfgang Oster and Bertino, {Joseph R.} and Libutti, {Steven K.} and Mehnert, {Janice M.} and Andrew Zloza",
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Stein, MN, Malhotra, J, Tarapore, RS, Malhotra, U, Silk, AW, Chan, N, Rodriguez-Rust, L, Aisner, J, Aiken, RD, Mayer, T, Haffty, BG, Newman, JH, Aspromonte, SM, Bommareddy, PK, Estupinian, R, Chesson, CB, Sadimin, ET, Li, S, Medina, DJ, Saunders, T, Frankel, M, Kareddula, A, Damare, S, Wesolowsky, E, Gabel, C, El-Deiry, WS, Prabhu, VV, Allen, JE, Stogniew, M, Oster, W, Bertino, JR, Libutti, SK, Mehnert, JM & Zloza, A 2019, 'Safety and enhanced immunostimulatory activity of the DRD2 antagonist ONC201 in advanced solid tumor patients with weekly oral administration', Journal for ImmunoTherapy of Cancer, vol. 7, no. 1, 136. https://doi.org/10.1186/s40425-019-0599-8

Safety and enhanced immunostimulatory activity of the DRD2 antagonist ONC201 in advanced solid tumor patients with weekly oral administration. / Stein, Mark N.; Malhotra, Jyoti; Tarapore, Rohinton S.; Malhotra, Usha; Silk, Ann W.; Chan, Nancy; Rodriguez-Rust, Lorna; Aisner, Joseph; Aiken, Robert D.; Mayer, Tina; Haffty, Bruce G.; Newman, Jenna H.; Aspromonte, Salvatore M.; Bommareddy, Praveen K.; Estupinian, Ricardo; Chesson, Charles B.; Sadimin, Evita T.; Li, Shengguo; Medina, Daniel J.; Saunders, Tracie; Frankel, Melissa; Kareddula, Aparna; Damare, Sherrie; Wesolowsky, Elayne; Gabel, Christian; El-Deiry, Wafik S.; Prabhu, Varun V.; Allen, Joshua E.; Stogniew, Martin; Oster, Wolfgang; Bertino, Joseph R.; Libutti, Steven K.; Mehnert, Janice M.; Zloza, Andrew.

In: Journal for ImmunoTherapy of Cancer, Vol. 7, No. 1, 136, 22.05.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Safety and enhanced immunostimulatory activity of the DRD2 antagonist ONC201 in advanced solid tumor patients with weekly oral administration

AU - Stein, Mark N.

AU - Malhotra, Jyoti

AU - Tarapore, Rohinton S.

AU - Malhotra, Usha

AU - Silk, Ann W.

AU - Chan, Nancy

AU - Rodriguez-Rust, Lorna

AU - Aisner, Joseph

AU - Aiken, Robert D.

AU - Mayer, Tina

AU - Haffty, Bruce G.

AU - Newman, Jenna H.

AU - Aspromonte, Salvatore M.

AU - Bommareddy, Praveen K.

AU - Estupinian, Ricardo

AU - Chesson, Charles B.

AU - Sadimin, Evita T.

AU - Li, Shengguo

AU - Medina, Daniel J.

AU - Saunders, Tracie

AU - Frankel, Melissa

AU - Kareddula, Aparna

AU - Damare, Sherrie

AU - Wesolowsky, Elayne

AU - Gabel, Christian

AU - El-Deiry, Wafik S.

AU - Prabhu, Varun V.

AU - Allen, Joshua E.

AU - Stogniew, Martin

AU - Oster, Wolfgang

AU - Bertino, Joseph R.

AU - Libutti, Steven K.

AU - Mehnert, Janice M.

AU - Zloza, Andrew

PY - 2019/5/22

Y1 - 2019/5/22

N2 - Background: ONC201 is a small molecule antagonist of DRD2, a G protein-coupled receptor overexpressed in several malignancies, that has prolonged antitumor efficacy and immunomodulatory properties in preclinical models. The first-in-human trial of ONC201 previously established a recommended phase II dose (RP2D) of 625 mg once every three weeks. Here, we report the results of a phase I study that evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of weekly ONC201. Methods: Patients ≥ 18 years old with an advanced solid tumor refractory to standard treatment were enrolled. Dose escalation proceeded with a 3 + 3 design from 375 mg to 625 mg of ONC201. One cycle, also the dose-limiting toxicity (DLT) window, was 21 days. The primary endpoint was to determine the RP2D of weekly ONC201, which was confirmed in an 11-patient dose expansion cohort. Results: Twenty patients were enrolled: three at 375 mg and 17 at 625 mg of ONC201. The RP2D was defined as 625 mg with no DLT, treatment discontinuation, or dose modifications due to drug-related toxicity. PK profiles were consistent with every-three-week dosing and similar between the first and fourth dose. Serum prolactin and caspase-cleaved cytokeratin-18 induction were detected, along with intratumoral integrated stress response activation and infiltration of granzyme B+ Natural Killer cells. Induction of immune cytokines and effectors was higher in patients who received ONC201 once weekly versus once every three weeks. Stable disease of > 6 months was observed in several prostate and endometrial cancer patients. Conclusions: Weekly, oral ONC201 is well-tolerated and results in enhanced immunostimulatory activity that warrants further investigation. Trial registration: NCT02250781 (Oral ONC201 in Treating Patients With Advanced Solid Tumors), NCT02324621 (Continuation of Oral ONC201 in Treating Patients With Advanced Solid Tumors).

AB - Background: ONC201 is a small molecule antagonist of DRD2, a G protein-coupled receptor overexpressed in several malignancies, that has prolonged antitumor efficacy and immunomodulatory properties in preclinical models. The first-in-human trial of ONC201 previously established a recommended phase II dose (RP2D) of 625 mg once every three weeks. Here, we report the results of a phase I study that evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of weekly ONC201. Methods: Patients ≥ 18 years old with an advanced solid tumor refractory to standard treatment were enrolled. Dose escalation proceeded with a 3 + 3 design from 375 mg to 625 mg of ONC201. One cycle, also the dose-limiting toxicity (DLT) window, was 21 days. The primary endpoint was to determine the RP2D of weekly ONC201, which was confirmed in an 11-patient dose expansion cohort. Results: Twenty patients were enrolled: three at 375 mg and 17 at 625 mg of ONC201. The RP2D was defined as 625 mg with no DLT, treatment discontinuation, or dose modifications due to drug-related toxicity. PK profiles were consistent with every-three-week dosing and similar between the first and fourth dose. Serum prolactin and caspase-cleaved cytokeratin-18 induction were detected, along with intratumoral integrated stress response activation and infiltration of granzyme B+ Natural Killer cells. Induction of immune cytokines and effectors was higher in patients who received ONC201 once weekly versus once every three weeks. Stable disease of > 6 months was observed in several prostate and endometrial cancer patients. Conclusions: Weekly, oral ONC201 is well-tolerated and results in enhanced immunostimulatory activity that warrants further investigation. Trial registration: NCT02250781 (Oral ONC201 in Treating Patients With Advanced Solid Tumors), NCT02324621 (Continuation of Oral ONC201 in Treating Patients With Advanced Solid Tumors).

KW - Cancer

KW - Dopamine

KW - Immuno-oncology

KW - Immunotherapy

KW - ONC201

KW - Solid tumors

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DO - https://doi.org/10.1186/s40425-019-0599-8

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JO - Journal for ImmunoTherapy of Cancer

JF - Journal for ImmunoTherapy of Cancer

SN - 2051-1426

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