Buparlisib (BKM120) is an oral pan-phosphatidylinositol 3-kinase inhibitor, targeting all four isoforms of class I PI3K (α, β, γ and δ). This open-label Phase I dose-escalation study was conducted to determine the maximum tolerated dose of continuous daily buparlisib in Japanese patients with advanced solid tumors. Secondary objectives included safety and tolerability, pharmacokinetics, antitumor activity and pharmacodynamic marker changes. Fifteen patients were treated at 25 mg/day (n = 3), 50 mg/day (n = 3) and 100 mg/day (n = 9) dose levels. One dose-limiting toxicity of Grade 4 abnormal liver function occurred at 100 mg/day. Considering the safety profile and the maximum tolerated dose in the first-in-man study of buparlisib in non-Japanese patients, further dose escalation was stopped and 100 mg/day was declared the recommended dose. The most common treatment-related adverse events were rash, abnormal hepatic function (including increased transaminase levels), increased blood insulin levels and increased eosinophil count. Hyperglycemia was experienced by two patients, one Grade 1 and one Grade 4, and mood alterations were experienced by three patients, two Grade 1 and one Grade 2. Pharmacokinetic results showed that buparlisib was rapidly absorbed in a dose-proportional manner. Best overall response was stable disease for six patients, including one unconfirmed partial response. In these Japanese patients with advanced solid tumors, buparlisib had a manageable safety profile, with similar pharmacokinetics to non-Japanese patients. The recommended dose of 100 mg/day will be used in future studies of buparlisib in Japanese patients.
Background: The fibroblast growth factor 19 (FGF19)-fibroblast growth factor receptor 4 (FGFR4)-Klotho β (KLB) signaling pathway regulates bile acid synthesis and is also a key driver in certain subtypes of hepatocellular carcinoma (HCC). FGF401 is a highly selective FGFR4 inhibitor with antitumor activity in several HCC models. This first-in-human study was designed to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of FGF401 in patients (pts) with advanced cancers and FGFR4/KLB expression. Methods: An ongoing Phase (Ph) I/II, open-label study (NCT02325739) is evaluating FGF401 in pts with HCC or solid tumors with positive FGFR4 and KLB expression (RT-qPCR prescreening). Based on the known effect of FGF19 signaling on bile acid synthesis, the safety of FGF401 was explored under fasted and fed states, and dose escalation was guided by a Bayesian hierarchical model which estimates dose-toxicity relationships at each state. The primary objective was to determine the maximum tolerated doses (MTDs) and recommended Phase II doses (RP2Ds). Pre- and on-treatment specimens (blood, tumor) were collected for PK monitoring and evaluation of PD markers, including 7-alpha-hydroxy-4-cholesten-3-1, total bile acids, total cholesterol, and FGF19. The Ph II part will explore safety and preliminary efficacy of FGF401 in 3 pt groups. Results: Data are presented from the Ph I dose escalation part of the study (n=67; data cut-off Nov 30, 2016). Median age was 61 years (range, 23-80), 81% of pts were male, and the primary tumor type was HCC in 79% of pts. Dose levels were 50 mg once daily (QD), 80 mg QD, 120 mg QD, and 150 mg QD under fasted conditions, and 80 mg QD and 120 mg QD under fed conditions. Dose-limiting toxicities were observed in 6 pts (1 × 50 mg dose, 2 × 120 mg, 3 × 150 mg): ALT increased (↑) in 2 pts, AST↑ in 4 pts, and blood bilirubin↑ in 1 pt. The most common (>15%) adverse events (AE) suspected to be related to FGF401 were diarrhea (70%; Grade 1/2, 67%), AST↑ (46%), and ALT↑ (40%). Grade 3/4 AEs (>5%) were AST↑ (16%) and ALT↑ (12%). The RP2D was declared for the fasting cohort as 120 mg QD based on all data, including safety, PK, PD, and efficacy evaluations; updated PK and PD data will be presented. The RP2D for the fed cohort is under evaluation; MTDs have not been determined for either cohort. At the data cut-off of Nov 14, 2016, the overall response rate across doses in Ph I pts with HCC (N=53) was 8% and stable disease was seen in 53% of pts. Median time to progression was 4.1 months with one-sided 90% CI: (2.8, NE). Objective responses were seen in both FGF19-positive and -negative pts. Conclusions: Preliminary data suggest FGF401 has a manageable safety profile that is consistent with FGFR4 pathway inhibition. Promising clinical activity was observed in pts with advanced HCC in this dose escalation part of the study. Studies to further evaluate FGF401 as a single agent and in combination are ongoing. Citation Format: Stephen L. Chan, Chia-Jui Yen, Martin Schuler, Chia-Chi Lin, Su Pin Choo, Karl-Heinz Weiss, Andreas Geier, Takuji Okusaka, Ho Yeong Lim, Teresa Macarulla, Andrew X. Zhu, Tomoyuki Kakizume, Yi (Gary) Gu, Diana Graus Porta, Andrea P. Myers, Jean-Pierre Delord. Ph I/II study of FGF401 in adult pts with HCC or solid tumors characterized by FGFR4/KLB expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT106. doi:10.1158/1538-7445.AM2017-CT106
Background Deregulation of FGF19-FGFR4 signaling is found in several cancers, including hepatocellular carcinoma (HCC), nominating it for therapeutic targeting. FGF401 is a potent, selective FGFR4 inhibitor with antitumor activity in preclinical models. This study was designed to determine the recommended phase 2 dose (RP2D), characterize PK/PD, and evaluate the safety and efficacy of FGF401 alone and combined with the anti-PD-1 antibody, spartalizumab. Methods Patients with HCC or other FGFR4/KLB expressing tumors were enrolled. Dose-escalation was guided by a Bayesian model. Phase 2 dose-expansion enrolled patients with HCC from Asian countries (group1), non-Asian countries (group2), and patients with other solid tumors expressing FGFR4 and KLB (group3). FGF401 and spartalizumab combination was evaluated in patients with HCC. Results Seventy-four patients were treated in the phase I with single-agent FGF401 at 50 to 150 mg. FGF401 displayed favorable PK characteristics and no food effect when dosed with low-fat meals. The RP2D was established as 120 mg qd. Six of 70 patients experienced grade 3 dose-limiting toxicities: increase in transaminases (n = 4) or blood bilirubin (n = 2). In phase 2, 30 patients in group 1, 36 in group 2, and 20 in group 3 received FGF401. In total, 8 patients experienced objective responses (1 CR, 7 PR; 4 each in phase I and phase II, respectively). Frequent adverse events (AEs) were diarrhea (73.8%), increased AST (47.5%), and ALT (43.8%). Increase in levels of C4, total bile acid, and circulating FGF19, confirmed effective FGFR4 inhibition. Twelve patients received FGF401 plus spartalizumab. RP2D was established as FGF401 120 mg qd and spartalizumab 300 mg Q3W; 2 patients reported PR. Conclusions At biologically active doses, FGF401 alone or combined with spartalizumab was safe in patients with FGFR4/KLB-positive tumors including HCC. Preliminary clinical efficacy was observed. Further clinical evaluation of FGF401 using a refined biomarker strategy is warranted. Trial registration NCT02325739.
Capmatinib is a highly specific, potent and selective MET inhibitor. This was an open‐label, multicenter, dose‐escalation, phase I study conducted in Japanese patients with advanced solid tumors (not selected based on their MET status). The primary objective was to determine the maximum tolerated dose ( MTD ) and/or highest studied dose being safe. Secondary objectives included safety, pharmacokinetics and preliminary antitumor activity. Dose escalation was guided by a Bayesian Logistic Regression Model dependent on dose‐limiting toxicities ( DLT ) in cycle 1. Of 44 adult Japanese patients with confirmed advanced solid tumors enrolled, 29 received capmatinib capsules (doses ranging from 100 mg once daily [q.d.] to 600 mg twice daily [b.i.d.]) and 15 received tablets (200 mg b.i.d. and 400 mg b.i.d.). DLT occurred in two patients: grade 2 suicidal ideation (600 mg b.i.d. capsule) and grade 3 depression (400 mg b.i.d. tablet). MTD was not reached. The highest studied dose determined to be safe as tablet was 400 mg b.i.d., whereas it is not yet determined for capsules. Most common adverse events suspected to be drug‐related were increased blood creatinine, nausea, decreased appetite, vomiting and diarrhea. Following repeated daily dosing up to day 15 by q.d. or b.i.d. regimen using capsules, median time to reach maximum plasma drug concentration ( T max ) was 1.0‐4.0 hours; absorption was more rapid after dosing using tablets, with median T max of 1.0 hour on both days 1 and 15. Eight patients had a best overall response of stable disease. These data support further clinical development of capmatinib.
The cyclin D‐CDK4/6‐INK4‐Rb pathway is frequently dysregulated in cancers. Ribociclib, an orally available, selective CDK4/6 inhibitor, showed preliminary clinical activity in a phase I study in the USA and Europe for patients with solid tumors and lymphomas. The present study aimed to determine the single‐agent maximum tolerated dose (MTD) and recommended dose for expansion (RDE) in Japanese patients with advanced solid tumors. Ribociclib safety, tolerability, pharmacokinetic profile, and preliminary antitumor activity were also assessed. Japanese patients with solid tumors that had progressed on prior therapies received escalating doses of single‐agent ribociclib on a 3‐weeks‐on/1‐week‐off schedule. Treatment continued until the development of toxicity or disease progression. A dose escalation was planned for patients with esophageal cancer. In the dose‐escalation phase, 4 patients received 400 mg ribociclib and 13 patients received 600 mg ribociclib. Four patients experienced dose‐limiting toxicities, 3 of whom were in the 600 mg group. The RDE was declared to be 600 mg, and the MTD was not determined. The most frequent adverse events were hematologic and gastrointestinal. Four patients achieved stable disease at the 600 mg dose; no patients achieved complete or partial response. All patients discontinued the study, the majority due to disease progression. No patients discontinued due to adverse events. Dose escalation was not pursued due to lack of observed efficacy in esophageal cancer. At the RDE of 600 mg/d on a 3‐weeks‐on/1‐week‐off schedule, ribociclib showed acceptable safety and tolerability profiles in Japanese patients with advanced solid tumors.
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