Purpose Ribociclib (an oral, highly-specific cyclin-dependent kinase 4/6 inhibitor) inhibits tumor growth in preclinical models with intact retinoblastoma protein (Rb+). This first-in-human study investigated the maximum tolerated dose (MTD), recommended dose for expansion (RDE), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of ribociclib in patients with Rb+ advanced solid tumors or lymphomas. Experimental Design Patients received escalating doses of ribociclib (3-weeks-on/1-week-off or continuous). Dose escalation was guided by a Bayesian Logistic Regression Model with overdose control principle. Results Among 132 patients, 125 received ribociclib 3-weeks-on/1-week-off and 7 were dosed continuously. Nine dose-limiting toxicities were observed among 70 MTD/RDE evaluable patients during Cycle 1, most commonly neutropenia (n = 3) and thrombocytopenia (n = 2). The MTD and RDE were established as 900 and 600 mg/day 3-weeks-on/1-week-off, respectively. Common treatment-related adverse events were (all-grade; grade 3/4) neutropenia (46%; 27%), leukopenia (43%; 17%), fatigue (45%; 2%), and nausea (42%; 2%). Asymptomatic Fridericia’s corrected QT prolongation was specific to doses ≥600 mg/day (9% of patients at 600 mg/day; 33% at doses >600 mg/day). Plasma exposure increases were slightly higher than dose proportional; mean half-life at the RDE was 32.6 hours. Reduced Ki67 was observed in paired skin and tumor biopsies, consistent with ribociclib-mediated antiproliferative activity. There were 3 partial responses and 43 patients achieved a best response of stable disease; 8 patients were progression-free for >6 months. Conclusion Ribociclib demonstrated an acceptable safety profile, dose-dependent plasma exposure, and preliminary signs of clinical activity. Phase I–III studies of ribociclib are underway in various indications.

Background Bromodomain and extra-terminal domain proteins are promising epigenetic anticancer drug targets. This first-in-human study evaluated the safety, recommended phase II dose, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the bromodomain and extra-terminal domain inhibitor molibresib (GSK525762) in patients with nuclear protein in testis (NUT) carcinoma (NC) and other solid tumors. Methods This was a phase I and II, open-label, dose-escalation study. Molibresib was administered orally once daily. Single-patient dose escalation (from 2 mg/d) was conducted until the first instance of grade 2 or higher drug-related toxicity, followed by a 3 + 3 design. Pharmacokinetic parameters were obtained during weeks 1 and 3. Circulating monocyte chemoattractant protein-1 levels were measured as a pharmacodynamic biomarker. Results Sixty-five patients received molibresib. During dose escalation, 11% experienced dose-limiting toxicities, including six instances of grade 4 thrombocytopenia, all with molibresib 60–100 mg. The most frequent treatment-related adverse events of any grade were thrombocytopenia (51%) and gastrointestinal events, including nausea, vomiting, diarrhea, decreased appetite, and dysgeusia (22%–42%), anemia (22%), and fatigue (20%). Molibresib demonstrated an acceptable safety profile up to 100 mg; 80 mg once daily was selected as the recommended phase II dose. Following single and repeat dosing, molibresib showed rapid absorption and elimination (maximum plasma concentration: 2 hours; t1/2: 3–7 hours). Dose-dependent reductions in circulating monocyte chemoattractant protein-1 levels were observed. Among 19 patients with NC, four achieved either confirmed or unconfirmed partial response, eight had stable disease as best response, and four were progression-free for more than 6 months. Conclusions Once-daily molibresib was tolerated at doses demonstrating target engagement. Preliminary data indicate proof-of-concept in NC.

Tenosynovial giant cell tumors (TGCT), are rare colony stimulating factor-1(CSF-1)-driven proliferative disorders affecting joints. Diffuse-type TGCT often causes significant morbidity due to local recurrences necessitating multiple surgeries. Imatinib mesylate (IM) blocks the CSF-1 receptor. This study investigated the long term effects of IM in TGCT. We conducted an international multi-institutional retrospective study to assess the activity of IM: data was collected anonymously from individual patients with locally advanced, recurrent or metastatic TGCT. Sixty-two patients from 12 institutions across Europe, Australia and the United States were identified. Four patients with metastatic TGCT progressed rapidly on IM and were excluded for further analyses. Seventeen of 58 evaluable patients achieved complete response (CR) or partial response (PR). One- and five-year progression-free survival rates were 71% and 48%, respectively. Thirty-eight (66%) patients discontinued IM after a median of 7 (range 1–80) months. Reported adverse events in 45 (78%) patients were among other edema (48%) and fatigue (50%), mostly grade 1–2 (89%). Five patients experienced grade 3–4 toxicities. This study confirms, with additional follow-up, the efficacy of IM in TGCT. In responding cases we confirmed prolonged IM activity on TGCT symptoms even after discontinuation, but with high rates of treatment interruption and additional treatments.

Background: Fibroblast growth factor receptors (FGFRs) play a role in cell proliferation and survival. Genetic alterations of FGFRs can lead to deregulated activation in various cancers, including squamous cell carcinoma (SCC) of the lung and urothelial bladder cancer. Here, we report on a phase I study of BGJ398 a potent, selective pan-FGFR inhibitor. Methods: Eligible patients (pts; ≥ 18 years of age) had tumors with any FGFR genetic alteration identified by central or local prescreening. Pts received BGJ398 once or twice daily (qd or bid) in 28-day cycles in escalating cohorts. Dose-limiting toxicities (DLTs) were predefined and included both severe events and those resulting in significant dosing delays. Upon determination of maximum tolerated dose (MTD), 3 expansion arms were treated: arm 1 included FGFR1-amplified SCC of the lung (continuous qd dosing); arms 2 and 3 included FGFR-altered solid tumors given qd continuous doses (arm 2) or qd doses on a 3-weeks-on/1-week-off schedule (arm 3). Results: As of September 24, 2013, 94 pts were enrolled (median age 57.5 years). Pts were treated in qd dose cohorts (5-150 mg; n = 90) or a bid dose cohort (50 mg; n = 4). Arms 1 and 3 are ongoing. Of the 82 pts who discontinued, the most common reasons were disease progression (n = 56), consent withdrawal (n = 12), and adverse events (AEs; n = 10). DLTs during dose escalation were grade 3 aminotransferase increases (1 each at 100 and 125 mg), hyperphosphatemia (125 mg), and grade 1 corneal toxicity (150 mg). The 125-mg qd dose was identified as the MTD. Common treatment-emergent AEs (any grade, suspected to be related) at 125 mg qd (n = 41) include hyperphosphatemia (78%), stomatitis (37%), alopecia (32%), decreased appetite (32%), and fatigue (22%) and were generally mild, with stomatitis (7%) the only grade 3/4 AE occurring ≥ 5%. Elevated serum phosphate levels, a pharmacodynamic marker of FGFR pathway inhibition, could be managed through diet, phosphate lowering therapy, and drug interruptions. Preliminary analysis of efficacy data indicates tumor regressions in pts with various FGFR genetic alterations, including 4 of 5 pts with urothelial cell carcinomas (4 of which originated in the bladder) with FGFR3-activating mutations (with tumor reductions ranging from 27% to 48%). Additionally, 1 pt with FGFR1-amplified SCC lung cancer achieved confirmed partial response (PR) while another pt achieved a PR confirmed after 27 days. Tumor reductions were also observed in cholangiocarcinoma with an FGFR2 gene fusion, and FGFR1-amplified breast cancer. Conclusions: BGJ398 had a tolerable safety profile and demonstrated single-agent activity in pts with FGFR-genetically altered solid tumors. The 3-weeks-on/1-week-off schedule has been chosen for future studies based on its improved safety profile. Clinical activity was observed in multiple tumor types, and pts with FGFR3-mutated bladder cancer may be especially sensitive to BGJ398. Citation Format: Lecia V. Sequist, Phillippe Cassier, Andrea Varga, Josep Tabernero, Jan HM Schellens, Jean-Pierre Delord, Patricia LoRusso, D. Ross Camidge, Manuel Hidalgo Medina, Martin Schuler, Mario Campone, G. Gary Tian, Steven Wong, Jesus Corral, Randi Isaacs, Suman K. Sen, Diana Graus Porta, Swarupa G. Kulkarni, Caroline Lefebvre, Jürgen Wolf. Phase I study of BGJ398, a selective pan-FGFR inhibitor in genetically preselected advanced solid tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT326. doi:10.1158/1538-7445.AM2014-CT326

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