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

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.

BET inhibitor trotabresib in heavily pretreated patients with solid tumors and diffuse large B-cell lymphomas.

Bromodomain and extraterminal proteins (BET) play key roles in regulation of gene expression, and may play a role in cancer-cell proliferation, survival, and oncogenic progression. CC-90010-ST-001 (NCT03220347) is an open-label phase I study of trotabresib, an oral BET inhibitor, in heavily pretreated patients with advanced solid tumors and relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Primary endpoints were the safety, tolerability, maximum tolerated dose, and RP2D of trotabresib. Secondary endpoints were clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD] of ≥4 months' duration), objective response rate (CR + PR), duration of response or SD, progression-free survival, overall survival, and the pharmacokinetics (PK) of trotabresib. In addition, part C assessed the effects of food on the PK of trotabresib as a secondary endpoint. The dose escalation (part A) showed that trotabresib was well tolerated, had single-agent activity, and determined the recommended phase 2 dose (RP2D) and schedule for the expansion study. Here, we report long-term follow-up results from part A (N = 69) and data from patients treated with the RP2D of 45 mg/day 4 days on/24 days off or an alternate RP2D of 30 mg/day 3 days on/11 days off in the dose-expansion cohorts (parts B [N = 25] and C [N = 41]). Treatment-related adverse events (TRAEs) are reported in almost all patients. The most common severe TRAEs are hematological. Toxicities are generally manageable, allowing some patients to remain on treatment for ≥2 years, with two patients receiving ≥3 years of treatment. Trotabresib monotherapy shows antitumor activity, with an ORR of 13.0% (95% CI, 2.8-33.6) in patients with R/R DLBCL (part B) and an ORR of 0.0% (95% CI, 0.0-8.6) and a CBR of 31.7% (95% CI, 18.1-48.1) in patients with advanced solid tumors (part C). These results support further investigation of trotabresib in combination with other anticancer agents.

Phase I prognostic online (PIPO): A web tool to improve patient selection for oncology early phase clinical trials.

PURPOSE: Patient selection in phase 1 clinical trials (Ph1t) continues to be a challenge. The aim of this study was to develop a user-friendly prognostic calculator for predicting overall survival (OS) outcomes in patients to be included in Ph1t with immune checkpoint inhibitors (ICIs) or targeted agents (TAs) based on clinical parameters assessed at baseline. METHODS: Using a training cohort with consecutive patients from the VHIO phase 1 unit, we constructed a prognostic model to predict median OS (mOS) as a primary endpoint and 3-month (3m) OS rate as a secondary endpoint. The model was validated in an internal cohort after temporal data splitting and represented as a web application. RESULTS: We recruited 799 patients (training and validation sets, 558 and 241, respectively). Median follow-up was 21.2 months (m), mOS was 10.2 m (95% CI, 9.3-12.7) for ICIs cohort and 7.7 m (95% CI, 6.6-8.6) for TAs cohort. In the multivariable analysis, six prognostic variables were independently associated with OS - ECOG, number of metastatic sites, presence of liver metastases, derived neutrophils/(leukocytes minus neutrophils) ratio [dNLR], albumin and lactate dehydrogenase (LDH) levels. The phase 1 prognostic online (PIPO) calculator showed adequate discrimination and calibration performance for OS, with C-statistics of 0.71 (95% CI 0.64-0.78) in the validation set. The overall accuracy of the model for 3m OS prediction was 87.2% (95% CI 85%-90%). CONCLUSIONS: PIPO is a user-friendly objective and interactive tool to calculate specific survival probabilities for each patient before enrolment in a Ph1t. The tool is available at https://pipo.vhio.net/.