First-in-Human Clinical Trial of Oral ONC201 in Patients with Refractory Solid Tumors.
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 aCmaxof 1.5 to 7.5 μg/mL (∼3.9-19.4 μmol/L), mean half-life of 11.3 hours, and mean AUC of 37.7 h·μg/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.Clin Cancer Res; 23(15); 4163-9. ©2017 AACR.
Clinical Investigations and Precision Therapeutics Research Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey. steinmn@cinj.rutgers.edu.
Mark N
MN
Stein
Clinical Investigations and Precision Therapeutics Research Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
Joseph R
JR
Bertino
Clinical Investigations and Precision Therapeutics Research Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
Howard L
HL
Kaufman
Clinical Investigations and Precision Therapeutics Research Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
Tina
T
Mayer
Formerly at Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
Rebecca
R
Moss
Clinical Investigations and Precision Therapeutics Research Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
Ann
A
Silk
Clinical Investigations and Precision Therapeutics Research Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
Nancy
N
Chan
Clinical Investigations and Precision Therapeutics Research Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
Jyoti
J
Malhotra
Clinical Investigations and Precision Therapeutics Research Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
Lorna
L
Rodriguez
Clinical Investigations and Precision Therapeutics Research Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
Joseph
J
Aisner
Clinical Investigations and Precision Therapeutics Research Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
Robert D
RD
Aiken
Clinical Investigations and Precision Therapeutics Research Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.|Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
Bruce G
BG
Haffty
Formerly at Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
Robert S
RS
DiPaola
Clinical Investigations and Precision Therapeutics Research Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
Tracie
T
Saunders
Clinical Investigations and Precision Therapeutics Research Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
Andrew
A
Zloza
Clinical Investigations and Precision Therapeutics Research Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
Sherri
S
Damare
Clinical Investigations and Precision Therapeutics Research Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
Yasmeen
Y
Beckett
Clinical Investigations and Precision Therapeutics Research Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
Bangning
B
Yu
Clinical Investigations and Precision Therapeutics Research Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
Saltanat
S
Najmi
Clinical Investigations and Precision Therapeutics Research Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
Christian
C
Gabel
Clinical Investigations and Precision Therapeutics Research Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
Siobhan
S
Dickerson
Clinical Investigations and Precision Therapeutics Research Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
Ling
L
Zheng
Fox Chase Cancer Center, Philadelphia, Pennsylvania.
Wafik S
WS
El-Deiry
Oncoceutics, Philadelphia, Pennsylvania.
Joshua E
JE
Allen
Oncoceutics, Philadelphia, Pennsylvania.
Martin
M
Stogniew
Oncoceutics, Philadelphia, Pennsylvania.
Wolfgang
W
Oster
Clinical Investigations and Precision Therapeutics Research Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
Janice M
JM
Mehnert
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D006801:Humans; D007093:Imidazoles; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011725:Pyridines; D011743:Pyrimidines; D017448:Receptors, Dopamine D2 / Q000235:genetics*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; C581293:DRD2 protein, human; D006576:Heterocyclic Compounds, 4 or More Rings; D007093:Imidazoles; D011725:Pyridines; D011743:Pyrimidines; D017448:Receptors, Dopamine D2; C585684:TIC10 compound