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

Abstract

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.

PRMT5: An Emerging Target for Pancreatic Adenocarcinoma

“…Regardless, this targeted treatment will still be the only treatment that encapsulates a substantial subgroup within the PDAC cohort [24]. Furthermore, early phase trials have already demonstrated the safety of this class of drugs [110,111]. Thus, PRMT5 is poised for rapid translation into PDAC treatment once the underlying mechanism is better elucidated.…”

“…This has led to phase I trials of PRMT5 inhibitors (GSK3326595 and JNJ64619178) in haematological malignancies and solid cancers. Their respective activities in head and neck squamous cell carcinoma, breast and adenoid cystadenocarcinoma have recently been reported with proven safety [110,111]. Similar trials with PF-06939999 (NCT03854227), PRT811 (NCT04089449) and PRT543 (NCT03886831) are currently ongoing.…”

“…The challenge will be developing methods to comprehensively measure the change in the repertoire of mRNA and protein interactions due to PRMT5 inhibition and determine how this affects the translational capacity and efficiency, with and without splicing factor mutations [133,160]. Unfortunately, the inability to identify specific subgroups of patients that may benefit from treatment with a PRMT5 inhibitor has contributed to its limited utility and efficacy seen in the current early phase trials [110,111].…”

Chemogenomics for drug discovery: clinical molecules from open access chemical probes

“…These results led Janssen to advance JNJ64619178 to phase I trials in 2018 for the treatment of relapsed/refractory B cell non-Hodgkin lymphoma or advanced solid tumours (NCT03573310). 268 Thus far, any observed adverse events have been manageable and there has been evidence of clinical activity. Full results are expected to be reported in July 2022.…”

Epigenetic Genes Alterations in Metastatic Solid Tumors: Results from the Prospective Precision Medicine MOSCATO and MATCH-R Trials

“…By contrast, the e cacy of rst-and second-generation epigenetic drugs in solid tumors has been disappointing. However, recent results obtained with histone methyltransferase Enhancer of Zeste Homolog 2 (EZH2) inhibitors in SMARCB1-defective tumors [12], isocitrate dehydrogenase (IDH1) inhibitors in IDH-mutant cholangiocarcinoma [13] and PRMT5 inhibitors in adenoid cystic carcinoma [14][15][16] have challenged this paradigm, and suggested that, like targeted therapies, epigenetic-modifying drugs should be used in a "precision medicine" approach based on a molecular selection.…”