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Phase 1 Study of JNJ-64619178, a Protein Arginine Methyltransferase 5 Inhibitor, in Advanced Solid Tumors
Maria Vieito1, Victor Moreno2, Anna Spreafico3
1Vall de Hebron Institute of Oncology, Barcelona, Spain.
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.
Insights
This Phase 1 study of JNJ-64619178, a PRMT5 inhibitor, in advanced cancers showed manageable toxicity and antitumor activity, particularly in adenoid cystic carcinoma. Recommended Phase 2 doses were identified for further investigation.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Protein arginine methyltransferase 5 (PRMT5) is implicated in various cancers.
- Targeting PRMT5 offers a potential therapeutic strategy for advanced malignancies.
Purpose of the Study:
- Evaluate the safety and tolerability of JNJ-64619178, a novel PRMT5 inhibitor.
- Determine the recommended Phase 2 dose (RP2D) for JNJ-64619178.
- Assess the preliminary clinical activity of JNJ-64619178 in patients with advanced solid tumors or non-Hodgkin lymphomas (NHL).
Main Methods:
- Phase 1, open-label, multicenter study.
- Adult patients with treatment-refractory advanced solid tumors or NHL received escalating doses of JNJ-64619178 on two schedules.
- Safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity were assessed.
Main Results:
- Ninety patients were treated; thrombocytopenia was the primary dose-limiting toxicity.
- JNJ-64619178 exhibited dose-proportional PK and target engagement.
- An overall objective response rate (ORR) of 5.6% was observed, with a higher ORR of 11.5% in adenoid cystic carcinoma (ACC) patients.
Conclusions:
- JNJ-64619178 demonstrated manageable toxicity and preliminary antitumor activity, especially in ACC.
- Two provisional RP2Ds were established: 1.5 mg intermittently and 1.0 mg daily.
- Further development requires biomarkers to identify patients likely to respond to PRMT5 inhibition.
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