Phase 1 Study of JNJ-64619178, a Protein Arginine Methyltransferase 5 Inhibitor, in Advanced Solid Tumors

Author:

Vieito Maria1ORCID,Moreno Victor2ORCID,Spreafico Anna3ORCID,Brana Irene1ORCID,Wang Judy S.4ORCID,Preis Meir5ORCID,Hernández Tatiana2ORCID,Genta Sofia3ORCID,Hansen Aaron R.3ORCID,Doger Bernard2ORCID,Galvao Vladimir1ORCID,Lenox Laurie6ORCID,Brown Regina J.6ORCID,Kalota Anna6ORCID,Mehta Jaydeep6ORCID,Pastore Friederike7ORCID,Patel Bharvin6ORCID,Mistry Pankaj8ORCID,Gu Junchen6ORCID,Lauring Josh6ORCID,Patel Manish R.4ORCID

Affiliation:

1. 1Vall de Hebron Institute of Oncology, Barcelona, Spain.

2. 2START MADRID-FJD, Hospital Fundacion Jimenez Diaz, Madrid Spain.

3. 3Princess Margaret Cancer Center, University of Toronto, Toronto, Ontario, Canada.

4. 4Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, Florida.

5. 5Carmel Medical Center, Haifa, Israel.

6. 6Janssen Research & Development, Spring House, Pennsylvania.

7. 7Janssen Research & Development, Zug, Switzerland.

8. 8Janssen Research & Development, High Wycombe, United Kingdom.

Abstract

Abstract Purpose: In this first-in-human, Phase 1, open-label, multicenter study, we evaluated JNJ-64619178, a selective and potent PRMT5 inhibitor, in patients with advanced malignant solid tumors or non-Hodgkin lymphomas (NHL). The primary objective was to evaluate the safety and to identify a recommended Phase 2 dose (RP2D) of JNJ-64619178. Patients and Methods: Adult patients with treatment-refractory advanced solid tumors or NHL and measurable disease received escalating doses of JNJ-64619178 following two schedules (Schedule A: 14 days on/7 days off; Schedule B: every day on a 21-day cycle). Safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity were evaluated. Results: Ninety patients received JNJ-64619178. Thrombocytopenia was identified as the only dose-limiting toxicity. JNJ-64619178 showed dose-proportional PK and robust target engagement, as measured by plasma symmetric dimethylarginine, across all dose levels. The objective response rate was 5.6% (5 of 90). Patients with adenoid cystic carcinoma (ACC) had an ORR of 11.5% (3 of 26) and a median progression-free survival of 19.1 months. Conclusions: JNJ-64619178 demonstrated manageable dose-dependent toxicity and preliminary evidence of antitumor activity in ACC and other tumor types. Plasma exposure was dose dependent, and target inhibition was maintained with intermittent and continuous dosing. On the basis of safety, clinical activity, PK, and PD findings, two provisional RP2Ds were selected: 1.5 mg intermittently and 1.0 mg once daily. Aside from ACC, clinical benefit was limited, and biomarkers to enrich for responsiveness to PRMT5 inhibition will be needed for further development.

Funder

n/a

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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