Dataset Information

Phase 1 dose escalation study of FGFR4 inhibitor in combination with pembrolizumab in advanced solid tumors patients.

ABSTRACT:

Objective

Inhibition of fibroblast growth factor (FGF) 19-FGF Receptor 4 (FGFR4) signaling demonstrates potent anticancer activity. EVER4010001 is a highly selective FGFR4 inhibitor and pembrolizumab is approved for the treatment of several solid tumors. This study determined the maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), pharmacokinetics, safety, and preliminary efficacy of EVER4010001 plus pembrolizumab in patients with advanced solid tumors.

Methods

This Phase 1, multicenter, open-label study enrolled 19 Asian-Chinese patients (57.9% male: median age 58 years) with advanced solid tumors. For "3+3" dose escalation, 3-6 patients received treatment at each dose level (EVER4010001 40, 60, 80, or 100 mg twice daily [BID] plus pembrolizumab 200 mg every 3 weeks).

Results

At the data cutoff (August 12, 2021), no dose-limiting toxicities (DLTs) were reported at 40 mg-80 mg. At 100 mg, 2 (40.0%) patients had 3 DLTs within the 28-day DLT observation period after first administration. Median time to peak EVER4010001 concentration (T_max ) was 0.55-1.03 hours. Mean terminal EVER4010001 half-life (T_1/2 ) was 4.00-4.92 hours. The area under the concentration-time curve (AUC_0-t ) and maximum observed concentration (C_max ) ranged from 2370.87-5475.77 hour*ng/ml and 606.07-1348.86 ng/ml, respectively. The most common EVER4010001-related treatment-emergent adverse events were diarrhea (94.7%), increased aspartate aminotransferase (57.9%), and increased alanine aminotransferase (47.4%).

Conclusion

Eighty milligrams BID was the MTD and RP2D for EVER4010001 plus pembrolizumab. Efficacy results were promising, and no new safety risks were reported, justifying the Phase 2 portion of this study.

SUBMITTER: Xu J

PROVIDER: S-EPMC10134273 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Publications

Phase 1 dose escalation study of FGFR4 inhibitor in combination with pembrolizumab in advanced solid tumors patients.

Xu Jianming J Cui Jiuwei J Jiang Haiping H Zeng Yan Y Cong Xiuyu X

Cancer medicine 20230109 7

<h4>Objective</h4>Inhibition of fibroblast growth factor (FGF) 19-FGF Receptor 4 (FGFR4) signaling demonstrates potent anticancer activity. EVER4010001 is a highly selective FGFR4 inhibitor and pembrolizumab is approved for the treatment of several solid tumors. This study determined the maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), pharmacokinetics, safety, and preliminary efficacy of EVER4010001 plus pembrolizumab in patients with advanced solid tumors.<h4>Methods</h4>This Pha ...[more]

PMID: 36622048

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Project description:BackgroundData suggest that immunomodulation induced by DNA hypomethylating agents can sensitize tumors to immune checkpoint inhibitors. We conducted a phase 1 dose-escalation trial (NCT02998567) of guadecitabine and pembrolizumab in patients with advanced solid tumors. We hypothesized that guadecitabine will overcome pembrolizumab resistance.MethodsPatients received guadecitabine (45 mg/m2 or 30 mg/m2, administered subcutaneously on days 1-4), with pembrolizumab (200 mg administered intravenously starting from cycle 2 onwards) every 3 weeks. Primary endpoints were safety, tolerability and maximum tolerated dose; secondary and exploratory endpoints included objective response rate (ORR), changes in methylome, transcriptome, immune contextures in pre-treatment and on-treatment tumor biopsies.ResultsBetween January 2017 and January 2020, 34 patients were enrolled. The recommended phase II dose was guadecitabine 30 mg/m2, days 1-4, and pembrolizumab 200 mg on day 1 every 3 weeks. Two dose-limiting toxicities (neutropenia, febrile neutropenia) were reported at guadecitabine 45 mg/m2 with none reported at guadecitabine 30 mg/m2. The most common treatment-related adverse events (TRAEs) were neutropenia (58.8%), fatigue (17.6%), febrile neutropenia (11.8%) and nausea (11.8%). Common, grade 3+ TRAEs were neutropaenia (38.2%) and febrile neutropaenia (11.8%). There were no treatment-related deaths. Overall, 30 patients were evaluable for antitumor activity; ORR was 7% with 37% achieving disease control (progression-free survival) for ≥24 weeks. Of 12 evaluable patients with non-small cell lung cancer, 10 had been previously treated with immune checkpoint inhibitors with 5 (42%) having disease control ≥24 weeks (clinical benefit). Reduction in LINE-1 DNA methylation following treatment in blood (peripheral blood mononuclear cells) and tissue samples was demonstrated and methylation at transcriptional start site and 5' untranslated region gene regions showed enriched negative correlation with gene expression. Increases in intra-tumoural effector T-cells were seen in some responding patients. Patients having clinical benefit had high baseline inflammatory signature on RNAseq analyses.ConclusionsGuadecitabine in combination with pembrolizumab is tolerable with biological and anticancer activity. Reversal of previous resistance to immune checkpoint inhibitors is demonstrated.

Project description:BackgroundQuizartinib, an inhibitor of class III receptor tyrosine kinases (RTKs), is currently in phase 3 development for the treatment of acute myeloid leukemia (AML) bearing internal tandem duplications in the FLT3 gene. Aberrant RTK signaling is implicated in the pathogenesis of a variety of solid tumors, suggesting that inhibiting quizartinib-sensitive RTKs may be beneficial in precision cancer therapy.MethodsThis was a phase 1, open-label, modified Fibonacci dose-escalation study of orally administered quizartinib in patients with advanced solid tumors whose disease progressed despite standard therapy or for which there was no available standard treatment. Patients received quizartinib dihydrochloride (henceforth referred to as quizartinib) once daily throughout a 28-day treatment cycle. The primary endpoint was evaluation of the maximum tolerated dose (MTD) of quizartinib. Secondary endpoints included preliminary evidence of antitumor activity and determination of the pharmacokinetic and pharmacodynamic parameters of quizartinib.ResultsThirteen patients were enrolled. Five patients received a starting dose of quizartinib 135 mg/day; dose-limiting toxicities (DLTs) of grade 3 pancytopenia, asymptomatic grade 3 QTc prolongation, and febrile neutropenia were observed in 1 patient each at this dose. A lower dose of quizartinib (90 mg/day [n = 8]) was administered without DLTs. The most common treatment-related treatment-emergent adverse events (AEs) were fatigue (n = 7, 54%), dysgeusia (n = 5, 38%), neutropenia (n = 3, 23%), and QTc prolongation (n = 3, 23%). Overall, all patients experienced at least 1 AE, and 4 experienced serious AEs (2 patients each in the 135-mg and 90-mg dose groups) including hematologic AEs, infections, and gastrointestinal disorders. Six patients (including 3 patients with gastrointestinal stromal tumors [GIST]) had a best response of stable disease.ConclusionThe MTD of quizartinib in patients with advanced solid tumors was 90 mg/day. Overall, the safety and tolerability of quizartinib were manageable, with no unexpected AEs. Quizartinib monotherapy had limited evidence of activity in this small group of patients with advanced solid tumors.Trial registrationClinical Trials Registration Number: NCT01049893 ; First Posted: January 15, 2010.

Dataset Information

Phase 1 dose escalation study of FGFR4 inhibitor in combination with pembrolizumab in advanced solid tumors patients.

Objective

Methods

Results

Conclusion

Publications

Phase 1 dose escalation study of FGFR4 inhibitor in combination with pembrolizumab in advanced solid tumors patients.

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