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What Is This Summary About?: This summary describes the results from a phase 2 study called FOENIXCCA2. The study evaluated treatment with futibatinib in people with a rare form of advanced bile duct cancer called intrahepatic cholangiocarcinoma (or iCCA), where the tumors have changes in the structure of a gene called FGFR2. These changes include FGFR2 gene fusions. Bile duct cancer often returns after surgery or cannot be treated by surgery because the tumor has spread, so it requires treatment with chemotherapy. People live for a median of 1 year after their first chemotherapy treatment and 6 months after their second treatment. This study included people whose cancer had grown/spread after one or more chemotherapy treatments. The aims of the study were to see if futibatinib could shrink the size of tumors and stop the cancer from growing/spreading and to see how long people lived when treated with futibatinib. Clinicians also looked at side effects from taking futibatinib and at how it affected people's quality of life., What Were the Results?: Futibatinib treatment shrank tumors in over 80% of people who received treatment. Tumors shrank by at least 30% in 42% of people. Futibatinib stopped tumors from growing/spreading for a median of 9.7 months. People who took the medicine lived for a median of 21.7 months, and 72% of people were still alive after 1 year. Side effects from taking futibatinib were like those reported for similar medicines, and clinicians considered the side effects to be manageable by adjusting the dose of futibatinib or treating the side effects. Most people reported that their quality of life stayed the same or improved during the first 9 months of taking futibatinib., What Do the Results Mean?: The results support the use of futibatinib for treating people with advanced bile duct cancer. Based on the results of this study, futibatinib is now approved in the US, Europe, and Japan. Futibatinib is approved for treating adults with advanced bile duct cancer who have received previous treatment for their cancer, and whose tumors have a gene fusion or other change in the FGFR2 gene. Clinical Trial Registration: NCT02052778 (FOENIX-CCA2).

Futibatinib, a selective, irreversible fibroblast growth factor receptor 1-4 inhibitor, is being investigated for tumors harboring FGFR aberrations and was recently approved for the treatment of FGFR2 fusion/rearrangement-positive intrahepatic cholangiocarcinoma. In vitro studies identified cytochrome P450 (CYP) 3A as the major CYP isoform in futibatinib metabolism and indicated that futibatinib is likely a P-glycoprotein (P-gp) substrate and inhibitor. Futibatinib also showed time-dependent inhibition of CYP3A in vitro. Phase I studies investigated the drug-drug interactions of futibatinib with itraconazole (a dual P-gp and strong CYP3A inhibitor), rifampin (a dual P-gp and strong CYP3A inducer), or midazolam (a sensitive CYP3A substrate) in healthy adult participants. Compared with futibatinib alone, coadministration of futibatinib with itraconazole increased futibatinib mean peak plasma concentration and area under the plasma concentration-time curve by 51% and 41%, respectively, and coadministration of futibatinib with rifampin lowered futibatinib mean peak plasma concentration and area under the plasma concentration-time curve by 53% and 64%, respectively. Coadministration of midazolam with futibatinib had no effect on midazolam pharmacokinetics compared with midazolam administered alone. These findings suggest that concomitant use of dual P-gp and strong CYP3A inhibitors/inducers with futibatinib should be avoided, but futibatinib can be concomitantly administered with other drugs metabolized by CYP3A. Drug-drug interaction studies with P-gp-specific substrates and inhibitors are planned., (© 2023 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Futibatinib, a selective, irreversible fibroblast growth factor receptor 1-4 inhibitor, was recently approved for FGFR2 rearrangement-positive cholangiocarcinoma. This Phase I study evaluated the mass balance and metabolic profile of 14 C-futibatinib single oral 20-mg dose in healthy participants (n = 6). Futibatinib was rapidly absorbed; median time to peak drug concentration was 1.0 hours. The mean elimination half-life in plasma was 2.3 hours for futibatinib, and 11.9 hours for total radioactivity. Mean recovery of total radioactivity was 70% of the dose, with 64% recovered in feces and 6% in urine. The major excretion route was fecal; negligible levels were excreted as parent futibatinib. Futibatinib was the most abundant plasma component, comprising 59% of circulating radioactivity (CRA). The most abundant metabolites were cysteinylglycine-conjugated futibatinib in plasma (13% CRA) and reduction of desmethyl futibatinib in feces (17% of dose). In human hepatocytes, 14 C-futibatinib metabolites included glucuronide and sulfate of desmethyl futibatinib, whose formation was inhibited by 1-aminobenzotriazole (a pan-cytochrome P450 inhibitor), and glutathione- and cysteine-conjugated futibatinib. These data indicate the primary metabolic pathways of futibatinib are O-desmethylation and glutathione conjugation, with cytochrome P450 enzyme-mediated desmethylation as the main oxidation pathway. 14 C-futibatinib was well tolerated in this Phase 1 study., (© 2023 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Background: In the phase III TAGS trial, trifluridine/tipiracil showed survival benefit versus placebo in patients with metastatic gastric/gastroesophageal junction cancer and ≥ 2 prior chemotherapies. This post hoc exploratory analysis assessed the impact of prior therapy type on outcomes., Methods: Based on prior treatment, patients in TAGS (N = 507) were categorized into overlapping subgroups: ramucirumab ± other agents (n = 169), no ramucirumab (n = 338), paclitaxel but no ramucirumab (n = 136), ramucirumab + paclitaxel sequentially or in combination (n = 154), neither paclitaxel nor ramucirumab (n = 202), irinotecan (n = 281), and no irinotecan (n = 226). Overall and progression-free survival, time to Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 2, and safety were assessed., Results: Baseline characteristics and prior therapy patterns were generally well balanced between trifluridine/tipiracil and placebo arms across subgroups. Trifluridine/tipiracil was associated with survival benefits versus placebo regardless of prior treatment: across subgroups, median overall survival was 4.6-6.1 versus 3.0-3.8 months (hazard ratios, 0.47-0.88), median progression-free survival was 1.9-2.3 versus 1.7-1.8 months (hazard ratios, 0.49-0.67), and median time to ECOG PS ≥ 2 was 4.0-4.7 versus 1.9-2.5 months (hazard ratios, 0.56-0.88). Among trifluridine/tipiracil-randomized patients, median overall and progression-free survival trended longer in those who had not received ramucirumab, paclitaxel and ramucirumab, or irinotecan (6.0-6.1 and 2.1-2.3 months, respectively) than in those who previously received these agents (4.6-5.7 and 1.9 months). The trifluridine/tipiracil safety profile was consistent across subgroups, with similar overall incidences of grade ≥ 3 adverse events. Minor variations in hematologic toxicities were noted., Conclusions: In TAGS, third- or later-line trifluridine/tipiracil treatment demonstrated overall and progression-free survival and functioning benefits versus placebo and a consistent safety profile in patients with metastatic gastric/gastroesophageal junction cancer, regardless of prior treatment type., Clinical Trials Registration: clinicaltrials.gov NCT02500043., (© 2023. The Author(s).)

Background: In this phase Ib/II open-label study, tumor immune suppression was targeted in patients with advanced refractory solid tumors and patients with recurrent/refractory non-small cell lung cancer (NSCLC) using galunisertib with nivolumab., Methods: Eligible patients were ≥ 18 years old, had an Eastern Cooperative Oncology Group performance status ≤ 1, and were treatment-naive for anti-programmed cell death-1, its ligand, or transforming growth factor β receptor 1 kinase inhibitors. Phase Ib was an open-label, dose-escalation assessment of the safety and tolerability of galunisertib with nivolumab in patients with advanced refractory solid tumors. Phase II evaluated the safety of galunisertib with nivolumab in NSCLC patients who had received prior platinum-based treatment but were immuno-oncology agent-naive., Results: This trial was conducted between October 2015 and August 2020. No dose-limiting toxicities were observed in phase I. In the phase II NSCLC cohort (n = 25), patients received 150 mg twice daily galunisertib (14 days on/14 days off dosing schedule for all phases) plus nivolumab at 3 mg/kg (intravenously every 2 weeks). In this phase, the most frequent treatment-related adverse events (AEs) were pruritus (n = 9, 36%), fatigue (n = 8, 32%), and decreased appetite (n = 7, 28%). No grade 4 or 5 treatment-related AEs were observed. Six (24%) patients had confirmed partial response (PR) and 4 (16%) had stable disease; 1 additional patient had confirmed PR after initial pseudo-progression. The median duration of response was 7.43 months (95% confidence interval [CI]: 3.75, NR). Among the 7 responders, including the delayed responder, 1 had high PD-L1 expression (≥ 50%). The median progression-free survival was 5.26 months (95% CI: 1.77, 9.20) and the median overall survival was 11.99 months (95% CI: 8.15, NR). Interferon gamma response genes were induced post-treatment and cell adhesion genes were repressed, although the association of these observations with tumor response and clinical outcomes was not statistically powered due to limited samples available., Conclusions: The study met its primary endpoint as galunisertib combined with nivolumab was well tolerated. Preliminary efficacy was observed in a subset of patients in the Phase 2 NSCLC cohort., Trial Registration: Trial registered with ClinicalTrials.gov (NCT02423343; 22.04.2015)., (© 2023. The Author(s).)

Background: Body weight loss (BWL) is a negative prognostic factor in metastatic gastric or gastroesophageal junction cancer (mGC/GEJC). In the phase III TAGS study, trifluridine/tipiracil improved survival versus placebo in third- or later-line mGC/GEJC. These retrospective analyses examined the association of early BWL with survival outcomes in TAGS., Methods: Efficacy and safety were assessed in patients who experienced < 3% or ≥ 3% BWL from treatment start until day 1 of cycle 2 (early BWL). The effect of early BWL on overall survival (OS) was assessed by univariate and multivariate analyses., Results: Body weight data were available for 451 of 507 (89%) patients in TAGS. In the trifluridine/tipiracil and placebo arms, respectively, 74% (224/304) and 65% (95/147) experienced < 3% BWL, whereas 26% (80/304) and 35% (52/147) experienced ≥ 3% BWL at cycle 1 end. Median OS was longer in < 3% BWL versus ≥ 3% BWL subgroups (6.5 vs 4.9 months for trifluridine/tipiracil; 6.0 vs 2.5 months for placebo). In univariate analyses, an unadjusted HR of 0.58 (95% CI, 0.46-0.73) for the < 3% vs ≥ 3% BWL subgroup indicated a strong prognostic effect of early BWL. Multivariate analyses confirmed early BWL as both prognostic (P < 0.0001) and predictive (interaction P = 0.0003) for OS. Similar results were obtained for progression-free survival. Any-cause grade ≥ 3 adverse events were reported in 77% and 82% of trifluridine/tipiracil-treated and 45% and 67% of placebo-treated patients with < 3% and ≥ 3% BWL, respectively., Conclusions: In TAGS, early BWL was a strong negative prognostic factor for OS in patients with mGC/GEJC receiving third- or later-line treatment., (© 2023. The Author(s).)

Background: In a previous phase 3 trial, treatment with trifluridine-tipiracil (FTD-TPI) prolonged overall survival among patients with metastatic colorectal cancer. Preliminary data from single-group and randomized phase 2 trials suggest that treatment with FTD-TPI in addition to bevacizumab has the potential to extend survival., Methods: We randomly assigned, in a 1:1 ratio, adult patients who had received no more than two previous chemotherapy regimens for the treatment of advanced colorectal cancer to receive FTD-TPI plus bevacizumab (combination group) or FTD-TPI alone (FTD-TPI group). The primary end point was overall survival. Secondary end points were progression-free survival and safety, including the time to worsening of the Eastern Cooperative Oncology Group (ECOG) performance-status score from 0 or 1 to 2 or more (on a scale from 0 to 5, with higher scores indicating greater disability)., Results: A total of 246 patients were assigned to each group. The median overall survival was 10.8 months in the combination group and 7.5 months in the FTD-TPI group (hazard ratio for death, 0.61; 95% confidence interval [CI], 0.49 to 0.77; P<0.001). The median progression-free survival was 5.6 months in the combination group and 2.4 months in the FTD-TPI group (hazard ratio for disease progression or death, 0.44; 95% CI, 0.36 to 0.54; P<0.001). The most common adverse events in both groups were neutropenia, nausea, and anemia. No treatment-related deaths were reported. The median time to worsening of the ECOG performance-status score from 0 or 1 to 2 or more was 9.3 months in the combination group and 6.3 months in the FTD-TPI group (hazard ratio, 0.54; 95% CI, 0.43 to 0.67)., Conclusions: Among patients with refractory metastatic colorectal cancer, treatment with FTD-TPI plus bevacizumab resulted in longer overall survival than FTD-TPI alone. (Funded by Servier and Taiho Oncology; SUNLIGHT ClinicalTrials.gov number, NCT04737187; EudraCT number, 2020-001976-14.)., (Copyright © 2023 Massachusetts Medical Society.)

Futibatinib, a fibroblast growth factor receptor (FGFR) 1-4 inhibitor, is being investigated for FGFR-aberrant tumors. A 4-period, crossover, phase 1 thorough QT/QTc study compared effects on Fridericia heart rate-corrected QT (QTcF) interval of single doses of futibatinib 20 and 80 mg (therapeutic and supratherapeutic doses, respectively), placebo, and moxifloxacin (positive control) in healthy subjects. The study objective was to assess the time-matched difference in change from baseline in QTcF (ddQTcF) between futibatinib and placebo. In addition, changes from baseline in QTcF and other electrocardiogram (ECG) parameters, pharmacokinetics, ECG morphology, and safety were assessed. Forty-eight subjects were randomized. ddQTcF upper limits of 2-sided 90%CIs remained <10 milliseconds (clinical threshold) for both futibatinib doses at all time points (range, 2.0-4.5 milliseconds). Assay sensitivity was demonstrated by lower limits of 2-sided 97.5%CIs of the dQTcF difference between moxifloxacin and placebo of >5 milliseconds. Futibatinib exposure increased in a dose-dependent manner, and no significant relationship was detected between plasma futibatinib concentration and ddQTcF. There were no significant effects on heart rate, other ECG parameters, or ECG morphology. No serious adverse events occurred. Futibatinib did not prolong QTcF or affect other cardiac measures at therapeutic or supratherapeutic doses., (© 2022 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Futibatinib, an oral, irreversible fibroblast growth factor receptor (FGFR) 1-4 inhibitor, is being evaluated for FGFR-aberrant tumors. Two open-label phase 1 studies evaluated the effects of high-fat, high-calorie food and concomitant proton pump inhibitors (PPIs; lansoprazole) on single-dose futibatinib (20 mg) pharmacokinetics and safety in healthy adults. In the food effect study (N  =  17), subjects received futibatinib under fed and fasted conditions, separated by a 7-day washout. In the PPI study (N  =  20), subjects received futibatinib alone, underwent a 2-day washout, and then received lansoprazole 60 mg once daily for 5 days, with futibatinib also administered on day 5. Under fed versus fasted conditions, futibatinib bioavailability was 11.2% lower (area under the plasma concentration-time curve from time 0 to infinity geometric mean ratio 88.8%; 90% confidence interval, 79.8%-98.9%), and median time to maximum plasma concentration was significantly delayed (4.0 vs 1.5 hours; P < .0001). There were no significant differences in futibatinib exposure between futibatinib plus lansoprazole and futibatinib alone. No serious adverse events occurred in either study. These findings suggest that food and PPIs are unlikely to have clinically meaningful impacts on futibatinib bioavailability. Thus, futibatinib may be used with or without food and concomitantly with acid-reducing agents., (© 2022 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Background: Alterations in fibroblast growth factor receptor 2 ( FGFR2 ) have emerged as promising drug targets for intrahepatic cholangiocarcinoma, a rare cancer with a poor prognosis. Futibatinib, a next-generation, covalently binding FGFR1-4 inhibitor, has been shown to have both antitumor activity in patients with FGFR -altered tumors and strong preclinical activity against acquired resistance mutations associated with ATP-competitive FGFR inhibitors., Methods: In this multinational, open-label, single-group, phase 2 study, we enrolled patients with unresectable or metastatic FGFR2 fusion-positive or FGFR2 rearrangement-positive intrahepatic cholangiocarcinoma and disease progression after one or more previous lines of systemic therapy (excluding FGFR inhibitors). The patients received oral futibatinib at a dose of 20 mg once daily in a continuous regimen. The primary end point was objective response (partial or complete response), as assessed by independent central review. Secondary end points included the response duration, progression-free and overall survival, safety, and patient-reported outcomes., Results: Between April 16, 2018, and November 29, 2019, a total of 103 patients were enrolled and received futibatinib. A total of 43 of 103 patients (42%; 95% confidence interval, 32 to 52) had a response, and the median duration of response was 9.7 months. Responses were consistent across patient subgroups, including patients with heavily pretreated disease, older adults, and patients who had co-occurring TP53 mutations. At a median follow-up of 17.1 months, the median progression-free survival was 9.0 months and overall survival was 21.7 months. Common treatment-related grade 3 adverse events were hyperphosphatemia (in 30% of the patients), an increased aspartate aminotransferase level (in 7%), stomatitis (in 6%), and fatigue (in 6%). Treatment-related adverse events led to permanent discontinuation of futibatinib in 2% of the patients. No treatment-related deaths occurred. Quality of life was maintained throughout treatment., Conclusions: In previously treated patients with FGFR2 fusion or rearrangement-positive intrahepatic cholangiocarcinoma, the use of futibatinib, a covalent FGFR inhibitor, led to measurable clinical benefit. (Funded by Taiho Oncology and Taiho Pharmaceutical; FOENIX-CCA2 ClinicalTrials.gov number, NCT02052778.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: Trifluridine/tipiracil (FTD/TPI) showed clinical benefit, including improved survival and manageable safety in previously treated patients with metastatic colorectal (mCRC) or gastric/gastroesophageal junction (mGC/GEJC) cancer in the phase III RECOURSE and TAGS trials, respectively. A pooled analysis was conducted to further characterize FTD/TPI safety, including management of haematologic toxicities and use in patients with renal or hepatic impairment., Patients and Methods: Adults with ≥2 prior regimens for advanced mGC/GEJC or mCRC were randomized (2 : 1) to FTD/TPI [35 mg/m 2 twice daily days 1-5 and 8-12 (28-day cycle); same dosage in both trials] or placebo plus best supportive care. Adverse events (AEs) were summarized in the safety population (patients who received ≥1 dose) and analysed by renal/hepatic function., Results: TAGS and RECOURSE included 335 and 533 FTD/TPI-treated and 168 and 265 placebo-treated patients, respectively. Overall safety of FTD/TPI was similar in TAGS and RECOURSE. Haematologic (neutropenia, anaemia) and gastrointestinal (nausea, diarrhoea) AEs were most commonly observed. Laboratory-assessed grade 3-4 neutropenia occurred in 37% (TAGS)/38% (RECOURSE) of FTD/TPI-treated patients (median onset: 29 days/55 days), and 96% (TAGS)/97% (RECOURSE) of cases resolved regardless of renal/hepatic function. Supportive medications for neutropenia were received by 17% (TAGS) and 9% (RECOURSE); febrile neutropenia was reported in 2% and 4%, respectively. Overall grade ≥3 AEs were more frequent in patients with moderate renal impairment [81% (TAGS); 85% (RECOURSE)] versus normal renal function (74%; 67%); anaemia and neutropenia were more common in patients with renal impairment. FTD/TPI safety (including haematologic AEs) was consistent across patients with normal and mildly impaired hepatic function., Conclusions: These results support FTD/TPI as a well-tolerated treatment in patients with mGC/GEJC or mCRC, with a consistent safety profile. Safety was largely similar in patients with normal or mildly impaired renal/hepatic function; however, patients with renal impairment should be monitored for haematologic toxicities., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Notch signaling plays an integral role in development and tissue homeostasis. Inhibition of Notch signaling has been identified as a reasonable target for oncotherapy. Crenigacestat (LY3039478) is a potent Notch inhibitor that decreases Notch signaling and its downstream biologic effects., Methods: I6F-MC-JJCD was a multicenter, nonrandomized, open-label, phase 1b study with 5 separate, parallel dose escalations in patients with advanced or metastatic cancer from a variety of solid tumors followed by a dose-confirmation phase in pre-specified tumor types. This manuscript reports on 2 of 5 groups. The primary objective was to determine the recommended phase 2 dose of crenigacestat combined with other anticancer agents (gemcitabine/cisplatin or gemcitabine/carboplatin). Secondary objectives included evaluation of safety, tolerability, preliminary efficacy, and pharmacokinetics., Results: Patients (N = 31) received treatment between November 2016 and July 2019. Dose-limiting toxicities occurred in 6 patients. The recommended phase 2 dose for crenigacestat was 50 mg TIW in Part 1 (combined with gemcitabine/cisplatin) and not established in Part 2 (combined with gemcitabine/carboplatin) due to poor tolerability. Patients had at least one treatment-emergent adverse event (TEAE), and most had Grade ≥ 3 TEAEs. Over 50% of the patients experienced gastrointestinal disorders (Grade ≥ 3). No patient had complete response; 5 patients had a partial response. Disease control rates were 62.5% (Part 1) and 60.0% (Part 2)., Conclusion: This study demonstrated that the Notch inhibitor, crenigacestat, combined with different anticancer agents (gemcitabine, cisplatin, and carboplatin) was poorly tolerated and resulted in disappointing clinical activity in patients with advanced or metastatic solid tumors., Clinicaltrials: gov Identification Number: NCT02784795., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

PTEN acts as a potent tumor suppressor within the PI3K/AKT/mTOR pathway. Germline mutations in the PTEN gene are a hallmark of PTEN hamartoma tumor syndrome, which includes Cowden syndrome, where they appear to elevate lifetime risk of cancer. Targeted AKT directed therapy has been proposed as an effective approach in cancer patients having germline PTEN mutations. The mechanism of action, safety and dosing regimen for the novel allosteric AKT inhibitor TAS-117 have been explored in a phase I study in Japan in which activity was observed against certain tumor types. Here we describe the study protocol of an international, two-part phase II study evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics and antitumor activity of TAS-117 in patients with advanced solid tumors harboring germline PTEN -inactivating mutations.

Background: Trifluridine and tipiracil (FTD/TPI) demonstrated survival benefit vs placebo and manageable safety in previously treated patients with metastatic gastric/gastroesophageal junction cancer (mGC/GEJC) in the randomized, placebo-controlled, phase 3 TAGS study. This subgroup analysis of TAGS examined efficacy/safety outcomes by age., Methods: In TAGS, patients with mGC/GEJC and ≥ 2 prior therapies were randomized (2:1) to receive FTD/TPI 35 mg/m 2 or placebo, plus best supportive care. A preplanned subgroup analysis was performed to evaluate efficacy and safety outcomes in patients aged < 65, ≥ 65, and ≥ 75 years., Results: Among 507 randomized patients (n = 337 FTD/TPI; n = 170 placebo), 55%, 45%, and 14% were aged < 65, ≥ 65, and ≥ 75 years, respectively. Overall survival hazard ratios for FTD/TPI vs placebo were 0.67 (95% CI 0.51-0.89), 0.73 (95% CI 0.52-1.02), and 0.67 (95% CI 0.33-1.37) in patients aged < 65, ≥ 65, and ≥ 75 years, respectively. Regardless of age, patients receiving FTD/TPI experienced improved progression-free survival and stayed longer on treatment than those receiving placebo. Among FTD/TPI-treated patients, frequencies of any-cause grade ≥ 3 adverse events (AEs) were similar across age subgroups (80% each), although grade ≥ 3 neutropenia was more frequent in older patients [40% (≥ 65 and ≥ 75 years); 29% (< 65 years)]; AE-related discontinuation rates did not increase with age [14% (< 65 years), 12% (≥ 65 years), and 12% (≥ 75 years)]., Conclusions: The results of this subgroup analysis show the efficacy and tolerability of FTD/TPI treatment regardless of age in patients with mGC/GEJC who had received 2 or more prior treatments., (© 2021. The Author(s).)

Futibatinib, a highly selective, irreversible FGFR1-4 inhibitor, was evaluated in a large multihistology phase I dose-expansion trial that enrolled 197 patients with advanced solid tumors. Futibatinib demonstrated an objective response rate (ORR) of 13.7%, with responses in a broad spectrum of tumors (cholangiocarcinoma and gastric, urothelial, central nervous system, head and neck, and breast cancer) bearing both known and previously uncharacterized FGFR1-3 aberrations. The greatest activity was observed in FGFR2 fusion/rearrangement-positive intrahepatic cholangiocarcinoma (ORR, 25.4%). Some patients with acquired resistance to a prior FGFR inhibitor also experienced responses with futibatinib. Futibatinib demonstrated a manageable safety profile. The most common treatment-emergent adverse events were hyperphosphatemia (81.2%), diarrhea (33.5%), and nausea (30.4%). These results formed the basis for ongoing futibatinib phase II/III trials and demonstrate the potential of genomically selected early-phase trials to help identify molecular subsets likely to benefit from targeted therapy. SIGNIFICANCE: This phase I dose-expansion trial demonstrated clinical activity and tolerability of the irreversible FGFR1-4 inhibitor futibatinib across a broad spectrum of FGFR -aberrant tumors. These results formed the rationale for ongoing phase II/III futibatinib trials in cholangiocarcinoma, breast cancer, gastroesophageal cancer, and a genomically selected disease-agnostic population. This article is highlighted in the In This Issue feature, p. 275 ., (©2021 The Authors; Published by the American Association for Cancer Research.)

TAS0728 is an oral covalent binding inhibitor of human epidermal growth factor receptor 2 (HER2). A first-in-human open-label, dose-escalation, phase I study (NCT03410927) was initiated to investigate the safety and dose-limiting toxicity (DLT) and to determine the maximum tolerated dose (MTD) and/or recommended phase II dose of TAS0728 in adults with advanced solid tumors with HER2 or HER3 overexpression, amplification or mutation. In total, 19 patients received TAS0728 at escalating doses from 50 to 200 mg BID for 21-day cycles. Following escalation of the dose to 200 mg BID, a total of two DLTs were observed, both cases of Grade 3 diarrhea (lasting >48 h and not responsive to aggressive antidiarrheal treatment). Following de-escalation of the dose to 150 mg BID, another DLT of Grade 3 diarrhea was observed in one patient. Additionally, at 150 mg BID, one patient had a fatal cardiac arrest after receiving 1 cycle (21 days) of TAS0728. The etiology of the cardiac arrest event was not clear, however causal relationship to TAS0728 could not be excluded due to the temporal association observed. Partial responses were observed in 2 of 14 patients evaluable for TAS0728 treatment response. The study was stopped due to unacceptable toxicity during the dose-escalation as the overall risk-benefit ratio no longer favored the dose level being tested, therefore the MTD was not determined. ClinicalTrials.gov registration number: https://clinicaltrials.gov/ct2/show/NCT03410927 ; registered on January 25, 2018., (© 2021. The Author(s).)

Purpose: Trifluridine/tipiracil (FTD/TPI) is approved for advanced colorectal and gastric/gastroesophageal cancer; however, data in patients with renal impairment (RI) are limited. This phase I study evaluated FTD/TPI in patients with advanced solid tumors and varying degrees of RI to develop dosing guidance., Methods: Patients were enrolled into normal renal function (CrCl ≥ 90 mL/min), mild RI (CrCl 60-89 mL/min), or moderate RI (CrCl 30-59 mL/min) cohorts and administered the recommended FTD/TPI dose (35 mg/m 2 twice daily, days 1-5 and 8-12; 28-day cycle). Based on interim pharmacokinetics/safety data, patients with severe RI (CrCl 15-29 mL/min) were enrolled and received FTD/TPI 20 mg/m 2 twice daily., Results: Forty-three patients (normal renal function [n = 12]; mild RI [n = 12]; moderate RI [n = 11]; severe RI [n = 8]) were enrolled and treated. At steady state, compared to values in patients with normal renal function, FTD area under the curve (AUC) was not significantly different in patients with RI, but TPI AUC was significantly higher and increased with RI severity. FTD/TPI safety profile was consistent with prior experience, but grade ≥ 3 adverse events (AEs) were more frequent in the RI cohorts (83.3% [mild], 90.9% [moderate], 75.0% [severe], and normal [50.0%]). Hematologic AEs (anemia and neutropenia) were more frequent with RI. Overall, seven patients discontinued because of unrelated, nonhematologic AEs., Conclusion: FTD/TPI is safe and tolerable at the recommended 35 mg/m 2 dose in patients with mild/moderate RI and at the reduced 20 mg/m 2 dose in patients with severe RI., Trial Registration: NCT02301117, registration date: November 21, 2014., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

LY3381916 is an orally available, highly selective, potent inhibitor of indoleamine 2,3-dioxygenase 1. This study explored the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of LY3381916 monotherapy and in combination with a programmed death-ligand 1 (PD-L1) inhibitor (LY3300054) in patients with advanced solid tumors. During dose escalation, patients received escalating doses of LY3381916 at 60-600 mg once daily (qd) and 240 mg twice daily in monotherapy (n=21) and in combination with PD-L1 inhibitor at 700 mg every 2 weeks (n=21). A modified toxicity probability interval method was used to guide dose escalation. Dose-limiting toxicities occurred in 3 patients; 1 at LY3381916 240 mg twice daily (alanine aminotransferase/aspartate aminotransferase increase and systemic inflammatory response syndrome) and 2 at LY3381916 240 mg qd in combination with PD-L1 inhibitor (fatigue and immune-related hepatitis). LY3381916, at the recommended phase II dose, 240 mg qd, in combination with PD-L1 inhibitor, produced maximal inhibition of indoleamine 2,3-dioxygenase 1 activity in plasma and tumor tissue, and led to an increase of CD8 T cells in tumor tissue. In the combination dose expansion cohorts, 14 triple-negative breast cancer and 4 non-small cell lung cancer patients were enrolled. Treatment-related liver toxicity (grade ≥2 alanine aminotransferase/aspartate aminotransferase increase or immune-related hepatitis) was the most prominent adverse event in triple-negative breast cancer patients (n=5, 35.7%). Best response was stable disease. These preliminary data suggest an alternative dose level of LY3381916 is needed for the combination with PD-L1 inhibitor. The combination clinical activity was limited in this study., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Notch signaling plays an important role in development and tissue homeostasis. Deregulation of Notch signaling has been implicated in multiple malignancies. Crenigacestat (LY3039478), a potent Notch inhibitor, decreases Notch signaling and its downstream biologic effects. I6F-MC-JJCD was a multicenter, nonrandomized, open-label, Phase 1b study with 5 separate, parallel dose-escalations in patients with advanced or metastatic cancer from a variety of solid tumors, followed by a dose-confirmation phase in prespecified tumor types. This manuscript reports on 3 of 5 groups. The primary objective was to determine the recommended Phase 2 dose of crenigacestat in combination with other anticancer agents (taladegib, LY3023414 [dual inhibitor of phosphoinositide 3-kinase; mechanistic target of rapamycin], or abemaciclib). Secondary objectives included evaluation of safety, tolerability, efficacy, and pharmacokinetics. Patients (N = 63) received treatment between November 2016 and July 2019. Dose-limiting toxicities occurred in 12 patients, mostly gastrointestinal (diarrhea, nausea, vomiting). The maximum-tolerated dose of crenigacestat was 25 mg in Part B (LY3023414), 50 mg in Part C (abemaciclib), and not established in Part A (taladegib) due to toxicities. Patients had at least 1 adverse event (AE) and 75.0-82.6% were ≥ Grade 3 all-causality AEs. No patient had complete or partial response. Disease control rates were 18.8% (Part B) and 26.1% (Part C). The study was terminated before dose confirmation cohorts were triggered. This study demonstrated that crenigacestat combined with different anticancer agents (taladegib, LY3023414, or abemaciclib) was poorly tolerated, leading to lowered dosing and disappointing clinical activity in patients with advanced or metastatic solid tumors. NCT02784795 and date of registration: May 27, 2016., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Patients with advanced gastroesophageal junction cancer (GEJC) have poor survival outcomes, and GEJC-specific data from trials evaluating agents in gastric cancers (GCs) as a whole are lacking. Trifluridine/tipiracil (FTD/TPI) was approved for previously treated metastatic GC or GEJC (mGC/mGEJC) based on results of the phase 3 TAGS trial. Subgroup analyses by primary tumor type (GC or GEJC) in TAGS are reported here., Methods: Pa tients with mGC/mGEJC treated with  ≥ 2 prior chemotherapy regimens were randomized (2:1) to receive FTD/TPI or placebo, plus best supportive care. A pre-planned sub-analysis was performed to evaluate efficacy and safety outcomes by primary tumor type (GEJC or GC)., Results: Of 507 randomized patients, 145 (29%) had GEJC and 360 (71%) had GC as the primary disease site. Baseline characteristics were generally similar between the GEJC and GC subgroups, except that more patients in the GEJC subgroup had received  ≥ 3 prior regimens (72 vs. 59% in the GC subgroup). Survival benefit with FTD/TPI was observed in both subgroups. The overall survival hazard ratio for FTD/TPI vs placebo was 0.75 (95% CI 0.50-1.11) and 0.67 (95% CI 0.52-0.87) in the GEJC and GC subgroups, respectively. Grade ≥ 3 adverse events of any cause were reported in 75 (77%) and 192 (81%) FTD/TPI-treated patients in the GEJC and GC subgroups, respectively. No new safety concerns were noted with FTD/TPI., Conclusion: As in patients with GC, FTD/TPI showed an efficacy benefit in patients with GEJC in the TAGS trial, along with demonstrating a manageable safety profile.

Background: Preclinical data suggest that vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-β signaling interact to stimulate angiogenesis and suppress antitumor immune responses. Thus, combined inhibition of both pathways may offer greater antitumor activity compared with VEGF-targeted antiangiogenic monotherapy against hepatocellular carcinoma (HCC)., Methods: This is a multicenter, open-label, phase 1b study of galunisertib, an inhibitor of TGF-β receptor 1, and ramucirumab, an anti-VEGF receptor 2 antibody, in patients with advanced HCC aiming to define the maximum tolerated dose (MTD). Secondary objectives included safety, pharmacokinetics (PK), antitumor efficacy, and plasma alpha-fetoprotein and TGF-β kinetics. Dose escalation employed a 3 + 3 design. Patients received galunisertib at 80 mg (cohort 1) or 150 mg (cohort 2) orally twice a day on days 1-14 of a 28-day cycle combined with ramucirumab 8 mg/kg intravenously every 2 weeks., Results: Eight patients were enrolled: three in cohort 1 and five in cohort 2 (two patients were unevaluable due to rapid disease progression and replaced). No dose-limiting toxicities were observed. Treatment-related adverse events (AEs) of any grade in ≥2 patients included nausea (25%) and vomiting (25%). There was one Grade 3 treatment-related AE, a cerebrovascular accident possibly related to ramucirumab. Galunisertib exposure was dose-proportional and not affected by ramucirumab. The RECIST version 1.1 objective response rate and disease control rate were 0% and 12.5%, respectively., Conclusion: Combination therapy was safe and tolerable and displayed favorable PK. The MTD was established at galunisertib at 150 mg orally twice a day and ramucirumab 8 mg/kg intravenously every 2 weeks. The results do not support the preclinical hypothesis that blocking TGFβ signaling enhances efficacy of VEGF-targeted therapy; thus further clinical development was halted for the combination of galunisertib and ramucirumab., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background This phase 1, single-center, nonrandomized, single-arm, open-label, dose-escalation study, evaluated the tolerability of crenigacestat, a γ-secretase inhibitor as an oral Notch inhibitor in Japanese patients with advanced solid tumors. Methods The study consisted of 2 dose levels of crenigacestat (25 mg and 50 mg), administered orally 3 times per week (TIW) over a 28-day cycle until disease progression, development of unacceptable toxicity, or any other discontinuation criteria were met. The primary objective was to evaluate the tolerability and determine the recommended dose of crenigacestat for Japanese patients. Secondary objectives were to characterize the safety and toxicity, the pharmacokinetic parameters, and to document any antitumor activity of crenigacestat. Results Eleven Japanese patients with advanced solid tumors were enrolled; 4 patients (median age of 64 years) received 25 mg of crenigacestat, and 7 patients (median age of 72 years) received 50 mg of crenigacestat. Median treatment duration was 8 weeks in the 25-mg treatment arm and 4 weeks in the 50-mg treatment arm. There were no dose-limiting toxicities or dose-limiting equivalent toxicities observed. None of the patients had a complete or partial response to the treatment. One patient (14.3%) with a desmoid tumor in the 50-mg treatment arm showed tumor size shrinkage of 22.4% and had stable disease for 22.5 months. Frequent (>14%) treatment-related-adverse events in both treatment arms included diarrhea, malaise, and vomiting. Conclusions Crenigacestat was tolerated in Japanese patients but with limited clinical activity. The recommended crenigacestat dose in Japanese patients is 50 mg TIW.Trial registration: NCT02836600 ( ClinicalTrials.gov ) registered on July 19, 2016.

Background: We assessed the safety, efficacy, and pharmacokinetics of the transforming growth factor beta (TGFβ) receptor inhibitor galunisertib co-administered with the anti-programmed death-ligand 1 (PD-L1) antibody durvalumab in recurrent/refractory metastatic pancreatic cancer previously treated with ≤2 systemic regimens., Methods: This was a two-part, single-arm, multinational, phase Ib study. In a dose-finding phase, escalating oral doses of galunisertib were co-administered on days 1-14 with fixed-dose intravenous durvalumab 1500 mg on day 1 every 4 weeks (Q4W), followed by an expansion cohort phase., Results: The galunisertib recommended phase II dose (RP2D) when co-administered with durvalumab 1500 mg Q4W was 150 mg two times per day. No dose-limiting toxicities were recorded. Among 32 patients treated with galunisertib RP2D, 1 patient had partial response, 7 had stable disease, 15 had objective progressive disease, and 9 were not evaluable. Disease control rate was 25.0%. Median overall survival and progression-free survival were 5.72 months (95% CI: 4.01 to 8.38) and 1.87 months (95% CI: 1.58 to 3.09), respectively. Pharmacokinetic profiles for combination therapy were comparable to those published for each drug. There was no association between potential biomarkers and treatment outcomes., Conclusion: Galunisertib 150 mg two times per day co-administered with durvalumab 1500 mg Q4W was tolerable. Clinical activity was limited. Studying this combination in patients in an earlier line of treatment or selected for predictive biomarkers of TGFβ inhibition might be a more suitable approach., Trial Registration Number: ClinicalTrials.gov identifier: NCT02734160., Competing Interests: Competing interests: DM has received research funding from Celgene, Incyte, and Shire, and has a consulting role with Baxter, Eli Lilly and Company, Incyte, and Shire. D-YO has received research funding from Array, AstraZeneca, Eli Lilly and Company, and Novartis, and has a consulting/advisory role with ASLAN, AstraZeneca, Bayer, Celgene, Genentech/Roche, Halozyme, Merck Serono, Novartis, Taiho, and Zymeworks. AH has received travel and accommodation expenses from Eli Lilly and Company. EC has received research funding from AbbVie, Amcure, Amgen, AstraZeneca, BeiGene, BMS, Boehringer-Ingelheim, CytomX, Eli Lilly and Company, H3, Incyte, Kura, LOXO, Macrogenics, Menarini, Merck, Merck Serono, Merus, Millennium Pharmaceuticals, Nanobiotix Janssen, Nektar, Novartis, Pfizer, PharmaMar, Principia Bayer, PsiOxus Therapeutics, PUMA, Rigontec, Roche/Genentech, Sanofi, Tahio, Tesaro; has a consulting/advisory role with AbbVie, Amcure, AstraZeneca, Boehringer-Ingelheim, Celgene, Cerulean Pharma, EUSA, GLG, Guidepoint Global, Janssen-Cilag, Nanobiotix Janssen, Novartis, Pfizer, Pierre Pharma, PsiOxus Therapeutics, Roche/Genentech, Seattle Genetics, Servier; is employed by HM Hospitals Group and START; has shares in HM Hospitals Group, International Cancer Consultants, Oncoart Associated, and START; and is president and founder of NPO Foundation Intheos (Investigational Therapeutics in Oncological Sciences). AMV has participated in clinical trials funded by Bristol Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, Silenseed, and Verastem. EB has received honoraria for consultancy from Corcept Therapeutics and Invitae, is on the speaker bureau for Ipsen, and his institution has received research funding from Biontech, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly and Company, Helix, Mabvax, Merck, Minneamrita Therapeutics, Pharmacyclics, and Samumed. TM has received honoraria for consultancy from Baxalta, Baxter, Celgene, Genzyme, Roche, Sanofi, Shire Pharmaceuticals, Tesaro, and QED Therapeutics, and has received travel/accommodation compensation from Bayer, H3 Biomedicine, Merck, and Sanofi. VM and CZ have no conflicts of interest to disclose. YZ, IG, MM, LG, STE, and EA are employees and stock holders of Eli Lilly and Company. KAB was an employee of Eli Lilly and Company at the time this research was conducted and is a stock holder of Eli Lilly and Company and a current employee of Taiho Oncology. MCL is a current employee and stock holder of AstraZeneca. SCG was an employee of Eli Lilly and Company at the time this research was conducted and is a stock holder of Eli Lilly and Company. RG-C declares having provided scientific advice and/or received honoraria from AAA, Advanz Pharma, Amgen, Bayer, BMS, Eli Lilly and Company, HMP, Ipsen, Merck, Midatech Pharma, MSD, Novartis, PharmaMar, Pfizer, Roche, and Sanofi, and has received research support from Pfizer and BMS. Work in the unit of DM was partially supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) Investigator Grant n°23719 and 5x1000 Grant n°12182, by the Italian Ministry of Health Ricerca Finalizzata 2016 GR-2016- 02361134 grant, and by the patients associations 'Nastro Viola' and 'Voglio il Massimo' donations., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background Crenigacestat is a potent Notch inhibitor that decreases Notch signaling and its downstream biological effects. Here, we report the results from Part F of study 16F-MC-JJCA designed to evaluate the safety, pharmacokinetics (PK), and antitumor activity of crenigacestat with prednisone in advanced or metastatic cancer. The combination was planned to mitigate gastrointestinal toxicities. Methods Eligible patients (Study Part F) received crenigacestat loading dose (75 mg, escalating to 150 mg) administered thrice weekly (TIW) (F1) or twice weekly (BIW) (F2) for 2 weeks during Cycle 1, followed by 50 mg TIW from week 3 onwards. Prednisone was co-administered for 2 weeks in Cycle 1. Results Twenty-eight patients were enrolled; 11 in F1 (median age, 63 years), 17 in F2 (median age, 50 years). Dose-limiting toxicities were Grade 3 increased serum amylase and Grade 2 fatigue in F1, and Grade 4 hypophosphatemia and Grade 3 rash maculo-papular in F2. The maximum tolerated dose was 75 mg in F1 and 100 mg in F2. Best overall response was stable disease (F1, 6 [54.5%] patients; F2, 11 [64.7%] patients). Pharmacokinetic was dose proportional. Prednisone did not modify PK of crenigacestat, and both F1 and F2 achieved pharmacodynamics effects on evaluable tumor tissue samples. Conclusions This study demonstrated the potential use of prednisone to reduce gastrointestinal (GI) toxicities of a Notch inhibitor without affecting its PK. The safety profile observed was consistent with Notch pathway inhibitors, and the maximum tolerated dose was 75 mg TIW and 100 mg BIW in F1 and F2, respectively. ClinicalTrials.gov: NCT01695005.

Background: Deregulated Notch signaling is implicated in T-cell acute lymphoblastic leukemia (T-ALL)/T-cell lymphoblastic lymphoma (T-LBL). Crenigacestat (LY3039478) prevents cleavage of Notch proteins and may benefit patients with relapsed/refractory T-ALL/T-LBL., Methods: JJCB was a multicenter, nonrandomized, open-label, dose-escalation, phase 1 study in adult patients with relapsed/refractory T-ALL/T-LBL. Eligible patients received Crenigacestat orally 3 times per week plus dexamethasone at 24 mg twice daily on days 1 to 5 every other week in a 28-day cycle. The starting level of Crenigacestat was 50 mg, and dose escalation was performed with a modified 3+3 scheme for the estimation of dose-limiting toxicity (DLT) at the recommended dose level., Results: In total, 36 patients with T-ALL (n = 31 [86.1%]) or T-LBL (n = 5 [13.9%]) were treated with Crenigacestat and dexamethasone. Six patients (16.7%) experienced DLTs: 2 of 12 (16.7%) in the 75-mg cohort (grade 4 gastrointestinal hemorrhage and grade 3 nausea, vomiting, and diarrhea), 1 of 15 (6.7%) in the 100-mg cohort (grade 3 diarrhea), and 3 of 3 (100%) in the 125-mg cohort (grade 3 diarrhea, nausea, and vomiting). The maximum tolerated dosewas 75 mg plus 24 mg of dexamethasone daily on days 1 to 5. Twenty-eight patients (77.8%) experienced 1 or more treatment-emergent adverse events related to the study treatment. The best overall response was a confirmed response, with 1 patient (2.8%) having a duration of response of 10.51 months. Six patients (16.7%) achieved stable disease, and 12 patients (33.3%) experienced progressive disease. The remaining 17 patients (47.2%) were not evaluable. The median event-free survival was 1.18 months (95% confidence interval, 0.76-2.14 months) among all groups. A pharmacodynamic analysis showed decreased plasma amyloid β levels., Conclusions: Crenigacestat demonstrated limited clinical activity at the recommended dose in adult patients with relapsed/refractory T-ALL/T-LBL., (© 2020 American Cancer Society.)

Introduction TAS-114 is a potent inhibitor of deoxyuridine triphosphatase, which is a gatekeeper protein preventing uracil and 5-fluorouracil (5-FU) misincorporation into DNA. TAS-114 has been suggested to enhance the antitumor activity of 5-FU. This randomized, phase 2 study investigated TAS-114 plus S-1 (TAS-114/S-1) vs. S-1 in non-small-cell lung cancer (NSCLC) patients. Methods Patients with advanced NSCLC, previously treated with ≥ 2 regimens, were randomized 1:1 to receive TAS-114 (400 mg)/S-1 (30 mg/m 2 ) or S-1 (30 mg/m 2 ). Progression-free survival (PFS, independent central review) was the primary endpoint. Secondary endpoints included disease control rate (DCR), overall survival (OS), overall response rate (ORR), and safety. Results In total, 127 patients received treatment. Median PFS was 3.65 and 4.17 months in the TAS-114/S-1 and S-1 groups, respectively (hazard ratio [HR] 1.16, 95% confidence interval [CI] 0.71-1.88; P = 0.2744). DCR was similar between groups (TAS-114/S-1 80.3%, S-1 75.9%) and median OS was 7.92 and 9.82 months for the TAS-114/S-1 and S-1 groups, respectively (HR 1.31, 95% CI 0.80-2.14; P = 0.1431). The ORR was higher in the TAS-114/S-1 group than the S-1 group (19.7% vs. 10.3%), and more patients with tumor shrinkage were observed in the TAS-114/S-1 group. Incidence rates of anemia, skin toxicities, and Grade ≥ 3 treatment-related adverse events were higher in the TAS-114/S-1 group compared with the monotherapy group. Conclusions Although the TAS-114/S-1 combination improved the response rate, this did not translate into improvements in PFS. Clinical Trial Registration No. NCT02855125 (ClinicalTrials.gov) registered on 4 August 2016.

Background: Futibatinib is an oral, irreversible, highly selective fibroblast growth factor receptor (FGFR)1-4 inhibitor with potent preclinical activity against tumors harboring FGFR aberrations. This first-in-human, phase I dose-escalation trial (NCT02052778) evaluates the safety and pharmacokinetics/pharmacodynamics of futibatinib in advanced solid tumors., Patients and Methods: Following a standard 3+3 dose-escalation design, eligible patients with advanced solid tumors refractory to standard therapies received 8-200 mg futibatinib three times a week (t.i.w.) or 4-24 mg once daily (q.d.)., Results: A total of 86 patients were enrolled in the nine t.i.w. (n = 42) and five q.d. cohorts (n = 44); 71 patients (83%) had tumors harboring FGF/FGFR aberrations. Three of nine patients in the 24-mg q.d. cohort experienced dose-limiting toxicities, including grade 3 increases in alanine transaminase, aspartate transaminase, and blood bilirubin (n = 1 each). The maximum tolerated dose (MTD) was determined to be 20 mg q.d.; no MTD was defined for the t.i.w. schedule. Across cohorts (n = 86), the most common treatment-emergent adverse events (TEAEs) were hyperphosphatemia (59%), diarrhea (37%), and constipation (34%); 48% experienced grade 3 TEAEs. TEAEs led to dose interruptions, dose reductions, and treatment discontinuations in 55%, 14%, and 3% of patients, respectively. Pharmacokinetics were dose proportional across all q.d. doses but not all t.i.w. doses evaluated, with saturation observed between 80 and 200 mg t.i.w. Serum phosphorus increased dose dependently with futibatinib on both schedules, but a stronger exposure-response relationship was observed with q.d. dosing, supporting 20 mg q.d. as the recommended phase II dose (RP2D). Overall, partial responses were observed in five patients [FGFR2 fusion-positive intrahepatic cholangiocarcinoma (n = 3) and FGFR1-mutant primary brain tumor (n = 2)], and stable disease in 41 (48%)., Conclusions: Futibatinib treatment resulted in manageable safety, pharmacodynamic activity, and preliminary responses in patients with advanced solid tumors. The results of this phase I dose-escalation trial support 20 mg q.d. futibatinib as the RP2D., Clinical Trial Registration: FOENIX-101 (ClinicalTrials.gov, NCT02052778)., Competing Interests: Disclosure RB does not have conflicts of interests to disclose. FM-B reports research support from Aileron Therapeutics, Inc., AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., K Group, Millennium Pharmaceuticals Inc., Novartis, Pfizer Inc., PPD Investigator Services LLC, Puma Biotechnology Inc., Seattle Genetics, Taiho Pharmaceutical Co., and Zymeworks Inc.; has served on the advisory committees of ClearLight Diagnostics, Darwin Health, Grail, Immunomedics, Inflection Biosciences, Mersana Therapeutics, Puma Biotechnology Inc., Seattle Genetics, and Silverback Therapeutics, Spectrum Pharmaceuticals; has a consulting role for eFFECTOR Therapeutics, PACT Pharma, Zymeworks, Jackson Laboratory, Genentech Inc., F. Hoffman-La Roche Ltd., Parexel International, Pfizer Inc., IBM Watson, Samsung Bioepis, Aduro Biotech Inc., Kolon Life Science, OrigiMed, Sumitomo Dainippon Pharma Co., Seattle Genetics Inc., DebioPharm, Dialectica, Piers Pharmaceuticals, Xencor, and Tyra Biosciences; and has received fees/honoraria from Chugai Biopharmaceuticals, Dialectica, Mayo Clinic, and Sumitomo Dainippon Pharma. LG has a consulting/advisory role for Debiopharm, H3 Biomedicine, Incyte, QED, Alentis, Pieres, Agios, and Sirtex; serves on the IDMC for AstraZeneca; has received research funding from Taiho; and has received reimbursement for travel, accommodation, and other expenses from Taiho. BT has served in an advisory role at Amgen, Astellas, Bayer, Sanofi, BMS, Janssen-Cilag, MSD, Novartis, Tolmar, Ipsen; has received research funding from Amgen, Astellas, AstraZeneca, Bayer, BMS, Ipsen, Janssen-Cilag, Pfizer, and Servier; has served on the Speaker Bureau for Amgen, Astellas, BMS, and Janssen-Cilag; and has received travel expenses from Amgen, Astellas, Bayer, and Sanofi. BT's institution receives funding from Amgen, Aslan, Akeso, AstraZeneca, Aptevo, GSK, MSD, Novartis, Servier, and Taiho. YH, KAB, and IY are full-time employees at Taiho Oncology. KAB was an employee at Eli Lilly and owns stock in Eli Lilly. HTA is an investigator in studies sponsored by Taiho and reports an advisory role in Guardant, Roche, and Servier. IM has no conflicts of interest to disclose., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background Deregulated Notch signaling is implicated in multiple cancers. The phase I trial (I6F-MC-JJCA) investigated the safety and anti-tumor activity of crenigacestat (LY3039478), a selective oral Notch inhibitor, in an expansion cohort of patients with adenoid cystic carcinoma (ACC) who received the dose-escalation-recommended phase 2 dose (RP2D), established previously (Massard C, et al., Annals Oncol 2018, 29:1911-17). Methods Patients with advanced or metastatic cancer, measurable disease, ECOG-PS ≤1, and baseline tumor tissue were enrolled. Primary objectives were to identify a safe RP2D, confirm this dose in expansion cohorts, and document anti-tumor activity. Secondary objectives included safety and progression-free survival (PFS). The ACC expansion cohort received the RP2D regimen of 50 mg crenigacestat thrice per week in a 28-day cycle until disease progression or other discontinuation criteria were met. Results Twenty-two patients with ACC were enrolled in the expansion cohort (median age of 60 years). Median treatment duration was 3 cycles with 6 patients remaining on treatment. There were no objective responses; 1 (5%) patient had an unconfirmed partial response. Disease control rate was 73% and 4 patients had stable disease ≥6 months. Median PFS was 5.3 months (95%CI: 2.4-NE)) for the 22 patients; and 7.7 months (95%CI: 4.0-NR) and 2.4 months (95%CI: 1.1-NE) in the subgroup of patients in second-line (n = 7) or ≥ third-line (n = 9), respectively. Frequent treatment-related-adverse events (all grades) included diarrhea, fatigue, vomiting, decreased appetite, dry mouth, and dry skin. There were no new safety signals. Conclusion The crenigacestat RP2D regimen induced manageable toxicity and limited clinical activity, without confirmed responses, in heavily pretreated patients with ACC.

Background: Transforming growth factor beta (TGF-β) signalling is involved in the development of hepatocellular carcinoma (HCC). We followed changes in biomarkers during treatment of patients with HCC with the TGF-βRI/ALK5 inhibitor galunisertib., Methods: This phase 2 study (NCT01246986) enrolled second-line patients with advanced HCC into one of two cohorts of baseline serum alpha-fetoprotein (AFP): Part A (AFP ≥1.5x ULN) or Part B (AFP <1.5x ULN). Baseline and postbaseline levels of AFP, TGF-β1, E-cadherin, selected miRNAs, and other plasma proteins were monitored., Results: The study enrolled 149 patients (Part A, 109; Part B, 40). Median OS was 7.3 months in Part A and 16.8 months in Part B. Baseline AFP, TGF-β1, E-cadherin, and an additional 16 plasma proteins (such as M-CSF, IL-6, ErbB3, ANG-2, neuropilin-1, MIP-3 alpha, KIM-1, uPA, IL-8, TIMP-1, ICAM-1, Apo A-1, CA-125, osteopontin, tetranectin, and IGFBP-1) were found to correlate with OS. In addition, a range of miRs were found to be associated with OS. In AFP responders (21% of patients in Part A with decrease of >20% from baseline) versus non-responders, median OS was 21.5 months versus 6.8 months (p = 0.0015). In TGF-β1 responders (51% of all patients) versus non-responders, median OS was 11.2 months versus 5.3 months (p = 0.0036)., Conclusions: Consistent with previous findings, both baseline levels and changes from baseline of circulating AFP and TGF-β1 function as prognostic indicators of survival. Future trials are needed to confirm and extend these results., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: KAB, STE, MM, and SW are employees and shareholders of Eli Lilly and Company. AC, MML, and CS are former employees and shareholders of Eli Lilly and Company. AS received fees as speaker or for Advisory boards from: Eli Lilly, Novartis, Roche, Servier, BMS, Gilead, Pfizer, Astra Zeneca, Bayer, Sandoz, Eisai, Takeda, MSD, and as consultant for Arqule. SF received consulting and research funding from BeiGene, Blueprint Medicine, Bristol-Myers Squibb, Bayer Pharma, Eli Lilly, Incyte, Ipsen, Merck Serono, MSD, and Novartis. RKK received research funding from Adaptimmune, Agios, Astra Zeneca, Bayer, BMS, Celgene, Exelixis, Novartis, QED, Taiho, Merck, and Medimmune, and is an advisor to Genentech/Roche and Target Pharma Solutions. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Mutations in ERK signaling drive a significant percentage of malignancies. LY3009120, a pan-RAF and dimer inhibitor, has preclinical activity in RAS - and BRAF -mutated cell lines including BRAF -mutant melanoma resistant to BRAF inhibitors. This multicenter, open-label, phase I clinical trial (NCT02014116) consisted of part A (dose escalation) and part B (dose confirmation) in patients with advanced/metastatic cancer. In part A, oral LY3009120 was dose escalated from 50 to 700 mg twice a day on a 28-day cycle. In part B, 300 mg LY3009120 was given twice a day. The primary objective was to identify a recommended phase II dose (RP2D). Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary efficacy. Identification of pharmacodynamic biomarkers was exploratory. In parts A and B, 35 and 16 patients were treated, respectively ( N = 51). In part A, 6 patients experienced eight dose-limiting toxicities. The RP2D was 300 mg twice a day. Common (>10%) any-grade drug-related treatment-emergent adverse events were fatigue ( n = 15), nausea ( n = 12), dermatitis acneiform ( n = 10), decreased appetite ( n = 7), and maculopapular rash ( n = 7). The median duration of treatment was 4 weeks; 84% of patients completed one or two cycles of treatment. Exposures observed at 300 mg twice a day were above the preclinical concentration associated with tumor regression. Eight patients had a best overall response of stable disease; there were no complete or partial clinical responses. Despite adequate plasma exposure levels, predicted pharmacodynamic effects were not observed., (©2019 American Association for Cancer Research.)

Purpose: To evaluate the exposure-overall survival (OS) relationship in patients with advanced pancreatic cancer treated with galunisertib plus gemcitabine (GG) or gemcitabine plus placebo (GP)., Methods: Galunisertib 300 mg/day was given orally as intermittent dosing and gemcitabine as per label. Galunisertib exposure metrics for each patient in the GG arm (n = 99) of a phase 2 study of pancreatic cancer were calculated. Parametric survival models were used to identify influential baseline and response covariates on OS., Results: The population pharmacokinetics dataset included data from 297 patients/healthy subjects (age: 22-84 years, weight: 39-126 kg) across multiple studies, including this pancreatic cancer study. Galunisertib was rapidly absorbed with peak concentrations attained within 0.5-2 h and had an elimination half-life of 8 h. Between-subject variance on apparent clearance was estimated to be 47%. Age was the only characteristic to have a statistically significant effect on apparent clearance. A parametric Weibull survival model with treatment effect (dose) estimated a hazard ratio of 0.796, after adjusting for patient baseline factors that were significantly associated with OS. There was also a flat daily exposure-OS relationship within the observed exposure range, once all significant baseline covariates were included. Response covariates, such as reduction in CA19-9, time on treatment, and cumulative exposure over treatment cycles were also identified as significant factors for OS for patients with pancreatic cancer., Conclusions: This analysis suggests that 300 mg/day galunisertib administered as 150 mg twice daily for 14 days on/14 days off treatment is an appropriate dosing regimen for patients with pancreatic cancer.

Background and Aims: We assessed the activity of galunisertib, a small molecule inhibitor of the transforming growth factor beta (TGF-β1) receptor I, in second-line patients with hepatocellular carcinoma (HCC) in two cohorts of baseline serum alpha fetoprotein (AFP)., Methods: Patients with advanced HCC who progressed on or were ineligible to receive sorafenib, Child-Pugh A/B7 and ECOG PS ≤1 were enrolled into Part A (AFP ≥ 1.5× ULN) or Part B (AFP < 1.5× ULN). Patients were treated with 80 or 150 mg galunisertib BID for 14 days per 28-day cycle. Endpoints were time-to-progression (TTP) and changes in circulating AFP and TGF-β1 levels, as well as safety, pharmacokinetics, progression-free survival and overall survival (OS)., Results: Patients (n = 149) were enrolled with median age 65 years. Median TTP was 2.7 months (95% CI: 1.5-2.9) in Part A (n = 109) and 4.2 months (95% CI: 1.7-5.5) in Part B (n = 40). Median OS was 7.3 months (95% CI: 4.9-10.5) in Part A and 16.8 months (95% CI: 10.5-24.4) in Part B. OS was longer in AFP responders (>20% decrease from baseline, Part A) compared to non-responders (21.5 months vs 6.8 months). OS was longer in TGF-β1 responders (>20% decrease from baseline, all patients) compared to non-responders. The most common Grade 3/4 treatment-related adverse events were neutropenia (n = 4) and fatigue, anaemia, increased bilirubin, hypoalbuminemia and embolism (each, n = 2)., Conclusions: Galunisertib treatment had a manageable safety profile in patients with HCC. Lower baseline AFP and a response in AFP or TGF-β1 levels (vs no response) correlated with longer survival., Trial Registration Number: NCT01246986 at ClinicalTrials.gov., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Inhibition of tumor growth factor-β (TGF-β) receptor type I potentiated the activity of sorafenib in preclinical models of hepatocellular carcinoma (HCC). Galunisertib is a small-molecule selective inhibitor of TGF-β1 receptor type I, which demonstrated activity in a phase 2 trial as second-line HCC treatment., Methods: The combination of galunisertib and sorafenib (400 mg BID) was tested in patients with advanced HCC and Child-Pugh A liver function without prior systemic therapy. Galunisertib dose was administered 80 or 150 mg b.i.d. orally for 14 days every 28 days in safety lead-in cohorts; in the expansion cohort, all patients received galunisertib 150 mg b.i.d. Objectives included time-to-tumor progression, changes in circulating alpha fetoprotein and TGF-β1, safety, overall survival (OS), response rate, and pharmacokinetics (PK)., Results: Patients (n = 47) were enrolled from 5 non-Asian countries; 3 and 44 patients received the 80 mg and 150 mg b.i.d. doses of galunisertib, respectively. The pharmacokinetics and safety profiles were consistent with monotherapy of each drug. For the 150 mg b.i.d. galunisertib cohort, the median time-to-tumor progression was 4.1 months; the median OS was 18.8 months. A partial response was seen in 2 patients, stable disease in 21, and progressive disease in 13. TGF-β1 responders (decrease of >20% from baseline) vs nonresponders had longer OS (22.8 vs 12.0 months, P = 0.038)., Discussion: The combination of galunisertib and sorafenib showed acceptable safety and a prolonged OS outcome.

Purpose: Galunisertib, the first small molecule transforming growth factor beta (TGFβ) receptor inhibitor, plus gemcitabine resulted in the improvement of survival in patients with unresectable pancreatic cancer, but markers to identify patients likely to respond are lacking., Methods: In the Phase 1b/2 JBAJ study, 156 patients were randomized 2:1 to galunisertib + gemcitabine (N = 104) or placebo + gemcitabine (N = 52). Clinical outcome data were integrated with baseline markers and pharmacodynamic markers while patients were on treatment, including circulating proteins using a multi-analyte panel, T cell subset evaluation, and miRNA profiling., Results: Baseline biomarkers associated with overall prognosis regardless of treatment included CA19-9 and TGF-β1. In addition, IP-10, FSH, MIP-1α, and PAI-1 were potential predictive proteins. Baseline proteins that were changed during treatment included amphiregulin, CA15-3, cathepsin D, P-selectin, RAGE, sortilin, COMP, eotaxin-2, N-BNP, osteopontin, and thrombospondin-4. Plasma miRNA with potential prognostic value included miR-21-5p, miR-301a-3p, miR-210-3p, and miR-141-3p, while those with potential predictive value included miR-424-5p, miR-483-3p, and miR-10b-5p., Conclusions: Galunisertib + gemcitabine resulted in improvement of overall survival, and 4 proteins (IP-10, FSH, MIP-1α, PAI-1) were potentially predictive for this combination treatment. Future studies should also include baseline evaluation of miR-424-5p, miR-483-3p, and miR-10b-5p., Trial Registration: Clinicaltrials.gov NCT01373164.

Background Galunisertib inhibits type I transforming growth factor-beta receptor serine/threonine kinase. The primary objective of this study was to evaluate the safety and tolerability of galunisertib in combination with sorafenib in Japanese patients with unresectable hepatocellular carcinoma. Patients and methods This open-label, dose-escalation, multicenter, nonrandomized phase 1b study consisted of two dose levels of galunisertib, 160 or 300 mg/day, in combination with sorafenib 800 mg/day. Galunisertib 80 mg or 150 mg was administered orally twice daily for 14 days followed by 14 days of rest plus sorafenib 400 mg administered orally twice daily for 28 days. The dose-limiting toxicity evaluation was 28 days after the first dose. Safety measures, pharmacokinetics, and antitumor activity were assessed. Results Fourteen patients, 7 at each galunisertib dose, were enrolled and treated. Three dose-limiting toxicities were reported for 2 patients. The most common treatment-emergent adverse events (TEAEs) were hypophosphatemia (14 patients [100%]), palmar-plantar erythrodysesthesia syndrome (12 patients [85.7%]), and decreased platelet count (10 patients [71.4%]). The most common grade ≥ 3 TEAEs were hypophosphatemia (10 patients [71.4%]) and palmar-plantar erythrodysesthesia syndrome (7 patients [50.0%]). No grade 5 TEAEs were reported. The pharmacokinetic profile of galunisertib in combination with sorafenib was similar to that previously reported for galunisertib. Eleven patients had a best overall response of stable disease, and 1 patient achieved a partial response by hepatocellular carcinoma-specific modified RECIST. Conclusions These data are consistent with the known safety profile for galunisertib and sorafenib and confirm tolerability of the recommended dose of galunisertib (150 mg twice daily for 14 days) in combination with sorafenib in Japanese patients with unresectable hepatocellular carcinoma.

Background: LY3039478 is an orally bioavailable selective Notch inhibitor. This phase 1a/b trial evaluated the safety, pharmacokinetics and antitumour activity of LY3039478 in patients with soft tissue sarcoma (STS) and gastrointestinal stromal tumour (GIST)., Methods: This multipart, phase 1 trial enrolled patients with refractory advanced/metastatic STS and GIST, measurable disease, Eastern Cooperative Oncology Group ≤1 and baseline tumour tissue. Eligible patients received LY3039478 50mg/75 mg three times per week, for 28-day cycle until disease progression. Safety assessments were based on Common Terminology Criteria for Adverse Events, V4.0. Tumour responses were assessed using Response Evaluation Criteria in Solid Tumours (RECIST 1.1) and Choi criteria. Primary objectives were to confirm the recommended phase 2 dose of LY3039478 and document the antitumour activity. Secondary objectives were safety and toxicity, pharmacokinetics (PK), progression-free survival (PFS) and overall survival (OS)., Results: Sixty-nine patients were enrolled and received LY3039478 (27 males, 42 females; median age 58, range 31-78). 16/37 (43%) patients with evaluable samples were positive for Notch 1 immunohistochemistry. Per RECIST 1.1, in leiomyosarcoma (LMS) group (n = 29), ten (36%) had stable disease (SD) and one (4%) had unconfirmed partial response (PR). In GIST group (n = 13), four (31%) had SD. Among other STS subtypes (n = 27), one patient with angiosarcoma had unconfirmed PR, six (21%) had SD. Median PFS was 1.9 months (95% confidence interval:1.6-3.3) for LMS, 1.9 months (0.3-6.1) for GIST and 1.7 months (1.4-2.2) for other STS groups. Median OS was 7.4 months (4.3-non-evaluable [NE]) for LMS, 16.5 months (3.9-16.5) for GIST and 5.6 months (3.4-NE) for other STS groups. Most common adverse events were diarrhoea, nausea, vomiting and decreased appetite., Conclusion: LY3039478 suggested a modest clinical activity in patients with STS and GIST and had a manageable safety profile., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Galunisertib is the first-in-class, first-in-human, oral small-molecule type I transforming growth factor-beta receptor (ALK5) serine/threonine kinase inhibitor to enter clinical development. The effect of galunisertib vs. placebo in patients with unresectable pancreatic cancer was determined., Methods: This was a two-part, multinational study: phase 1b was a non-randomised, open-label, multicentre, and dose-escalation study; phase 2 was a randomised, placebo- and Bayesian-augmented controlled, double-blind study in patients with locally advanced or metastatic pancreatic adenocarcinoma considered candidates for first-line chemotherapy with gemcitabine. Patients were randomised 2:1 to galunisertib-gemcitabine (N = 104) or placebo-gemcitabine (N = 52). Gemcitabine dose was 1000 mg/m 2 QW. Primary endpoints for phases 1b and 2, respectively, were phase 2 dose and overall survival. Secondary objectives included tolerability and biomarkers., Results: Dose-escalation suggested a 300-mg/day dose. Primary objective was met: median survival times were 8.9 and 7.1 months for galunisertib and placebo, respectively (hazard ratio [HR] = 0.79 [95% credible interval: 0.59-1.09] and posterior probability HR < 1 = 0.93). Lower baseline biomarkers macrophage inflammatory protein-1-alpha and interferon-gamma-induced protein 10 were associated with galunisertib benefit., Conclusions: Galunisertib-gemcitabine combination improved overall survival vs. gemcitabine in patients with unresectable pancreatic cancer, with minimal added toxicity. Future exploration of galunisertib in pancreatic cancer is ongoing in combination with durvalumab.

Background: Deregulated Notch signaling due to mutation or overexpression of ligands and/or receptors is implicated in various human malignancies. γ-Secretase inhibitors inhibit Notch signaling by preventing cleavage of transmembrane domain of Notch protein. LY3039478 is a novel, potent Notch inhibitor decreases Notch signaling and its downstream biologic effects. In this first-in-human study, we report the safety, pharmacokinetic (PK) profile, pharmacodynamic effects, and antitumor activity of LY3039478 in patients with advanced or metastatic cancer., Methods: This phase I, open-label, multicenter, nonrandomized, and dose-escalation phase study determined and confirmed the recommended phase II dose of LY3039478 (oral dose: 2.5-100 mg, thrice weekly (TIW) on a 28-day cycle). The primary objectives are to determine (part A) and confirm (part B) a recommended phase II dose that may be safely administered to patients with advanced or metastatic cancer, and secondary objectives include evaluation of safety, tolerability, PK parameters, and preliminary antitumor activity of LY3039478., Results: A total of 110 patients were treated with LY3039478 monotherapy between 31 October 2012 and 15 July 2016. Dose-limiting toxicities were thrombocytopenia, colitis, and nausea. Most adverse events were gastrointestinal. The recommended phase II dose was 50 mg TIW, because of its better tolerability compared with 75 mg. The PKs of LY3039478 appeared dose proportional. Pharmacodynamic data indicate an ∼80% inhibition of plasma Aβ, and >50% inhibition of Notch-regulated genes hairy and enhancer of split-1, cyclin D1, and Notch-regulated ankyrin repeat at 45-100-mg dose. Clinical activity (tumor necrosis, metabolic response, or tumor shrinkage) was observed in patients with breast cancer, leiomyosarcoma, and adenoid cystic carcinoma., Conclusion: Potent inhibition of Notch signaling by LY3039478 was well tolerated at doses associated with target engagement, and demonstrated evidence of clinical activity in heavily pretreated patients. Further investigation with LY3039478 as monotherapy and in combination with targeted agent or chemotherapy is ongoing., Clinicaltrials.gov Id: NCT01695005.

Background: The transforming growth factor β (TGF-β)-signaling pathway has emerged as a promising therapeutic target for many disease states including hepatocellular carcinoma (HCC). Because of the pleiotropic effects of this pathway, patient selection and monitoring may be important. TGF-β1 is the most prevalent isoform, and an assay to measure plasma levels of TGF-β1 would provide a rational biomarker to assist with patient selection. Therefore, the objective of this study was to analytically validate a colorimetric ELISA for the quantification of TGF-β1 in human plasma., Methods: A colorimetric sandwich ELISA for TGF-β1 was analytically validated per Clinical and Laboratory Standards Institute protocols by assessment of precision, linearity, interfering substances, and stability. A reference range for plasma TGF-β1 was established for apparently healthy individuals and potential applicability was demonstrated in HCC patients., Results: Precision was assessed for samples ranging from 633 to 10822 pg/mL, with total variance ranging from 28.4% to 7.2%. The assay was linear across the entire measuring range, and no interference of common blood components or similar molecules was observed. For apparently healthy individuals, the average TGF-β1 level was 1985 ± 1488 pg/mL compared to 4243 ± 2003 pg/mL for HCC patients. Additionally, the TGF-β1 level in plasma samples was demonstrated to be stable across all conditions tested, including multiple freeze-thaw cycles., Conclusions: The ELISA described in this report is suitable for the quantification of TGF-β1 in human plasma and for investigational use in an approved clinical study., (© 2018 American Association for Clinical Chemistry.)

Background: TGFβ signaling plays a pleotropic role in tumor biology, promoting tumor proliferation, invasion and metastasis, and escape from immune surveillance. Inhibiting TGFβ's immune suppressive effects has become of particular interest as a way to increase the benefit of cancer immunotherapy. Here we utilized preclinical models to explore the impact of the clinical stage TGFβ pathway inhibitor, galunisertib, on anti-tumor immunity at clinically relevant doses., Results: In vitro treatment with galunisertib reversed TGFβ and regulatory T cell mediated suppression of human T cell proliferation. In vivo treatment of mice with established 4T1-LP tumors resulted in strong dose-dependent anti-tumor activity with close to 100% inhibition of tumor growth and complete regressions upon cessation of treatment in 50% of animals. This effect was CD8+ T cell dependent, and led to increased T cell numbers in treated tumors. Mice with durable regressions rejected tumor rechallenge, demonstrating the establishment of immunological memory. Consequently, mice that rejected immunogenic 4T1-LP tumors were able to resist rechallenge with poorly immunogenic 4 T1 parental cells, suggesting the development of a secondary immune response via antigen spreading as a consequence of effective tumor targeting. Combination of galunisertib with PD-L1 blockade resulted in improved tumor growth inhibition and complete regressions in colon carcinoma models, demonstrating the potential synergy when cotargeting TGFβ and PD-1/PD-L1 pathways. Combination therapy was associated with enhanced anti-tumor immune related gene expression profile that was accelerated compared to anti-PD-L1 monotherapy., Conclusions: Together these data highlight the ability of galunisertib to modulate T cell immunity and the therapeutic potential of combining galunisertib with current PD-1/L1 immunotherapy.

Transforming growth factor-β (TGFβ) is an important driver of tumor growth via intrinsic and extrinsic mechanisms, and is therefore an attractive target for developing cancer therapeutics. Using preclinical models, we characterized the anti-tumor activity of a small molecule inhibitor of TGFβ receptor I (TGFβRI), galunisertib (LY2157299 monohydrate). Galunisertib demonstrated potent and selective inhibition of TGFβRI with corresponding inhibition of downstream signaling via inhibition of SMAD phosphorylation (pSMAD). Galunisertib also inhibited TGFβ-induced pSMAD in vivo, which enabled a pharmacokinetic/pharmacodynamic profile in Calu6 and EMT6-LM2 tumors. Galunisertib demonstrated anti-tumor activity including inhibition of tumor cell migration and mesenchymal phenotype, reversal of TGFβ-mediated immune-suppression, and tumor growth delay. A concentration-effect relationship was established with a dosing schedule to achieve the optimal level of target modulation. Finally, a rat model demonstrated a correlation between galunisertib-dependent inhibition of pSMAD in tumor tissues and in PBMCs, supporting the use of PBMCs for assessing pharmacodynamic effects. Galunisertib has been tested in several clinical studies with evidence of anti-tumor activity observed in subsets of patients. Here, we demonstrate that galunisertib inhibits a number of TGFβ-dependent functions leading to anti-tumor activity. The enhanced understanding of galunisertib provides rationale for further informed clinical development of TGFβ pathway inhibitors., Competing Interests: CONFLICTS OF INTEREST The authors disclose no potential conflicts of interest. All authors except HH and RAB, are current or former employees of Eli Lilly and Company.

Purpose: Transforming growth factor-beta inhibitors may enhance the antitumor activity of gemcitabine with acceptable safety and tolerability. This open-label, multicenter, non-randomized phase 1b study assessed the safety/tolerability, pharmacokinetics, and tumor response of galunisertib plus gemcitabine in Japanese patients with advanced or metastatic pancreatic cancer., Methods: During each 28-day cycle, galunisertib 150 mg was administered orally twice daily (300 mg/day) for 14 days, followed by 14 days of rest. Gemcitabine 1000 mg/m 2 was intravenously given on Days 8, 15, and 22. Safety was assessed by the incidence of dose-limiting toxicities (DLTs) in the first cycle and treatment-emergent adverse events (TEAEs). Efficacy was assessed by antitumor activity and changes in carbohydrate antigen 19-9 (CA19-9)., Results: No DLTs were reported. All 7 enrolled patients had ≥1 TEAE, of which the most common included anorexia, decreased neutrophil count, and decreased white blood cell count. Grade ≥3 TEAEs were observed in 6 patients; 4 patients had Grade ≥3 TEAEs (decreased neutrophil, white blood cell, and lymphocyte count; hypophosphatemia) considered possibly related to study drug(s). The pharmacokinetic profile of galunisertib in combination with gemcitabine was similar to that previously observed for galunisertib alone. The clinical response [complete response (CR), partial response (PR), or stable disease] rate was 42.9%, and the median progression-free survival was 64 days; no CR/PR were achieved., Conclusion: Galunisertib plus gemcitabine had an acceptable safety/tolerability profile with evidence of efficacy in Japanese patients with advanced or metastatic pancreatic cancer.

Background: Notch signalling regulates stem cell development and survival and is deregulated in multiple malignancies. LY900009 is a small molecule inhibitor of Notch signalling via selective inhibition of the γ-secretase protein. We report the first-in-human phase I trial of LY900009., Methods: Dose escalation (Part A) was performed in cohorts of three advanced cancer patients using a modified continual reassessment method and dose confirmation (Part B) was performed in ovarian cancer patients. LY900009 was taken orally thrice weekly (every Monday, Wednesday, and Friday) during a 28-d cycle. The primary objective determined the maximum tolerated dose (MTD); secondary end-points included toxicity, pharmacokinetics, pharmacodynamics, and antitumour activity., Results: Thirty-five patients received LY900009 at dose levels ranging from 2-60 mg. Study drug-related adverse events were diarrhoea (46%), vomiting (34%), anorexia (31%), nausea (31%), and fatigue (23%). At 30 mg, a dose-limiting toxicity (grade III mucosal inflammation) was observed. LY900009 absorption was rapid, with median tmax at 1-4 h post-dose. LY900009 inhibited plasma levels of amyloid-β peptide in a dose-dependent manner with 80-90% inhibition observed in the 30- to 60-mg cohorts. No responses were seen, but five patients had stable disease. Two patients (5.7%) with leiomyosarcoma and ovarian cancer received four cycles of therapy. One patient (15 mg) showed markedly increased glandular mucin consistent with pharmacologic inhibition of the Notch pathway., Conclusions: The recommended MTD schedule for future studies was 30 mg thrice weekly, which exceeds the target inhibition level observed in preclinical models to promote tumour regression in humans., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: This Phase-I-study aimed to determine the recommended Phase-II-dosing-schedule of LY2334737, an oral gemcitabine prodrug, in patients with advanced/metastatic solid tumors. Pharmacokinetics, cytokeratin-18 (CK18) levels, genetic polymorphisms, and antitumor activity were additionally evaluated., Methods: Patients received escalating doses of LY2334737 either every other day for 21 days (d) followed by 7 days-drug-free period (QoD-arm) or once daily for 7 days every other week (QD-arm). The 28 days-cycles were repeated until disease progression or unacceptable toxicity. Standard 3 + 3 dose-escalation was succeeded by a dose-confirmation phase (12 additional patients to be enrolled on the maximum tolerated dose [MTD])., Results: Forty-one patients received QoD- (40-100 mg) and 32 QD-dosing (40-90 mg). On QoD, 3/9 patients experienced dose-limiting toxicities (DLTs) on the 100 mg dose (2 × G3 diarrhea, 1 × G3 transaminase increase); 1 additional DLT (G3 diarrhea) occurred during dose confirmation at 90 mg (12 patients). On QD, 1 patient each experienced DLTs on 60 mg (G3 transaminase increase) and 80 mg (G3 prolonged QTcF-interval); 2/7 patients had 3 DLTs on the 90 mg dose (diarrhea, edema, liver-failure; all G3). The MTD was established at 90 mg for the QoD-arm. Seven patients on QoD and 4 on QD achieved SD (no CR + PR). Pharmacokinetics showed a dose-proportional increase in exposure of LY2334737 and dFdC without accumulation after repeated dosing. Significant increases in CK18 levels were observed. Genetic polymorphism of the cytidine deaminase gene (rs818202) could be associated with ≥ G3 hepatotoxicity., Conclusions: Both schedules displayed linear pharmacokinetics and acceptable safety profiles. The recommended dose and schedule of LY2334737 for subsequent Phase-II-studies is 90 mg given QoD for 21 day.

Galunisertib (LY2157299) is a selective ATP-mimetic inhibitor of TGF-β receptor (TβR)-I activation currently under clinical investigation in hepatocellular carcinoma (HCC) patients. Our study explored the effects of galunisertib in vitro in HCC cell lines and ex vivo on patient samples. Galunisertib was evaluated in HepG2, Hep3B, Huh7, JHH6 and SK-HEP1 cells as well as in SK-HEP1-derived cells tolerant to sorafenib (SK-Sora) and sunitinib (SK-Suni). Exogenous stimulation of all HCC cell lines with TGF-β yielded downstream activation of p-Smad2 and p-Smad3 that was potently inhibited with galunisertib treatment at micromolar concentrations. Despite limited antiproliferative effects, galunisertib yielded potent anti-invasive properties. Tumor slices from 13 patients with HCC surgically resected were exposed ex vivo to 1 µM and 10 µM galunisertib, 5 µM sorafenib or a combination of both drugs for 48 hours. Galunisertib but not sorafenib decreased p-Smad2/3 downstream TGF-β signaling. Immunohistochemistry analysis of galunisertib and sorafenib-exposed samples showed a significant decrease of the proliferative marker Ki67 and increase of the apoptotic marker caspase-3. In combination, galunisertib potentiated the effect of sorafenib efficiently by inhibiting proliferation and increasing apoptosis. Our data suggest that galunisertib may be active in patients with HCC and could potentiate the effects of sorafenib.

Transforming growth factor-beta (TGF-β) signaling regulates a wide range of biological processes. TGF-β plays an important role in tumorigenesis and contributes to the hallmarks of cancer, including tumor proliferation, invasion and metastasis, inflammation, angiogenesis, and escape of immune surveillance. There are several pharmacological approaches to block TGF-β signaling, such as monoclonal antibodies, vaccines, antisense oligonucleotides, and small molecule inhibitors. Galunisertib (LY2157299 monohydrate) is an oral small molecule inhibitor of the TGF-β receptor I kinase that specifically downregulates the phosphorylation of SMAD2, abrogating activation of the canonical pathway. Furthermore, galunisertib has antitumor activity in tumor-bearing animal models such as breast, colon, lung cancers, and hepatocellular carcinoma. Continuous long-term exposure to galunisertib caused cardiac toxicities in animals requiring adoption of a pharmacokinetic/pharmacodynamic-based dosing strategy to allow further development. The use of such a pharmacokinetic/pharmacodynamic model defined a therapeutic window with an appropriate safety profile that enabled the clinical investigation of galunisertib. These efforts resulted in an intermittent dosing regimen (14 days on/14 days off, on a 28-day cycle) of galunisertib for all ongoing trials. Galunisertib is being investigated either as monotherapy or in combination with standard antitumor regimens (including nivolumab) in patients with cancer with high unmet medical needs such as glioblastoma, pancreatic cancer, and hepatocellular carcinoma. The present review summarizes the past and current experiences with different pharmacological treatments that enabled galunisertib to be investigated in patients.