537MO - First-in-human study of JNJ-64619178, a protein arginine methyltransferase 5 (PRMT5) inhibitor, in patients with advanced cancers

Background

PRMT5 regulates proteins important for tumorigenesis via symmetric arginine dimethylation (SDMA). JNJ64619178 is an oral, potent and selective PRMT5 inhibitor that demonstrates efficacy in multiple tumor models. Here, we present a phase I study of JNJ64619178 in adults with advanced solid tumors and non-Hodgkin lymphoma (Part 1).

Methods

Dose escalation was supported by a modified continual reassessment method. Patients (pts) received JNJ64619178 either intermittently (14 days on/7 days off) or once daily (QD) on a 21-day cycle. Safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy were evaluated to identify the recommended phase II doses (RP2D).

Results

Fifty-four pts were enrolled as of 17 Mar 2020. The most common tumor types were adenoid cystic carcinoma (ACC; 20%), prostate cancer (15%), and uveal melanoma (13%). Median age was 59 (range 28-82), and median number of prior systemic therapies was 3 (range 0-11). Dosing ranged from 0.5 mg to 4 mg intermittently, and from 1 mg to 2 mg QD. Median treatment duration was 1.5 mo (range 0.4-22.4). The only dose-limiting toxicity observed was thrombocytopenia, at 3 and 4 mg intermittently and 2 mg QD. Fifty-one pts (91%) experienced treatment-related adverse events (TRAE), the most common being thrombocytopenia (52%), anemia (41%), nausea (39%), fatigue (32%), dysgeusia (30%), asthenia (24%), and diarrhea (20%). Grade 3/4 TRAEs in >1 pt were thrombocytopenia (20%), anemia (17%), and neutropenia (6%). Thirty pts (56%) had dose interruptions or reductions due to AE. JNJ64619178 plasma C_max and AUC were linearly dose-proportional. Robust target engagement, as measured by plasma SDMA, was achieved even with intermittent dosing. A confirmed partial response (RECIST) was observed in ACC, and 7 pts (13%) with ACC, prostate cancer, salivary gland carcinomas, and other tumor types had stable disease >6 mo. Two provisional RP2Ds were selected: 1.5 mg intermittently and 1 mg QD.

Conclusions

JNJ64619178 demonstrated manageable toxicity and preliminary evidence of antitumor activity at selected dose levels. Intermittent dosing maintains target inhibition. Assessment of two provisional RP2Ds is ongoing.

Clinical trial identification

NCT03573310.

Editorial acknowledgement

Editorial assistance was provided by Ramji Narayanan of SIRO Clinpharm Pvt Ltd, funded by Janssen Global Services, LLC.

Legal entity responsible for the study

Janssen Research & Development, LLC.

Funding

Janssen Research & Development, LLC.

Disclosure

M. Vieito Villar: Advisory/Consultancy, Unpaid consultant: Debiopharma; Advisory/Consultancy, Unpaid consultant: Roche. A. Spreafico: Advisory/Consultancy: Merck; Advisory/Consultancy, Research grant/Funding (self): Bristol-Myers Squibb; Advisory/Consultancy, Research grant/Funding (self): Novartis ; Advisory/Consultancy: Oncorus; Research grant/Funding (self): Symphogen AstraZeneca/Medimmune; Research grant/Funding (self): Bayer; Research grant/Funding (self): Surface Oncology; Research grant/Funding (self): Northern Biologics; Research grant/Funding (self): Janssen; Research grant/Funding (self): Roche; Research grant/Funding (self): Array Biopharma. I. Braña: Advisory/Consultancy: MSD; Speaker Bureau/Expert testimony, Research grant/Funding (self): AstraZeneca; Speaker Bureau/Expert testimony, Research grant/Funding (self): Bristol-Myers Squibb; Research grant/Funding (self): Gliknik; Research grant/Funding (self): GlaxoSmithKline; Research grant/Funding (self): MSD; Research grant/Funding (self): Novartis; Research grant/Funding (self): Pfizer; Research grant/Funding (self): Shattuck Labs; Research grant/Funding (self): Roche; Speaker Bureau/Expert testimony: Merck Serono. J.S. Wang: Honoraria (self), Speaker Bureau/Expert testimony: AstraZeneca. N. Haddish-Berhane: Full/Part-time employment: Janssen. J. Mehta: Full/Part-time employment: Janssen. A. Johnson: Full/Part-time employment: Janssen. A. Maes: Full/Part-time employment: Janssen. J. Haslam: Full/Part-time employment: Janssen. P. Mistry: Full/Part-time employment: Janssen. A. Kalota: Full/Part-time employment: Janssen. L. Lenox: Full/Part-time employment: Janssen. J.R. Infante: Full/Part-time employment: Janssen. M.V. Lorenzi: Full/Part-time employment: Janssen. H. Xie: Full/Part-time employment: Janssen. J. Lauring: Full/Part-time employment: Janssen. M.R. Patel: Honoraria (self): Gilead; Honoraria (self): Exelixis; Honoraria (self): BMS; Honoraria (self): Genentech; Honoraria (self): Medivation. All other authors have declared no conflicts of interest.