77771a24b3bad709921c4e55dc9e2f00 pmc_10251876.pdf 96f2d9ae1f09ea02bc46d80147e58108f682a53a pmc_10251876.pdf d629fee34a5059892c62b1e4516f144251b5760e351f3e237a35e6e48d3b16f0 pmc_10251876.pdf Title: Results from a Phase 1b/2 Study of Ibrutinib Combination Therapy in Advanced Urothelial Carcinoma Subject: Ibrutinib is a first-in-class Bruton’s tyrosine kinase inhibitor approved for the treatment of various B-cell malignancies and chronic graft-versus-host disease. We evaluated the safety and efficacy of ibrutinib, alone or combined with standard-of-care regimens, in adults with advanced urothelial carcinoma (UC). Once-daily ibrutinib was administered orally at 840 mg (single-agent or with paclitaxel) or at 560 mg (with pembrolizumab). Phase 1b determined the recommended phase 2 dose (RP2D) of ibrutinib, and phase 2 assessed progression-free survival (PFS), overall response rate (ORR), and safety. Thirty-five, eighteen, and fifty-nine patients received ibrutinib, ibrutinib plus pembrolizumab, and ibrutinib plus paclitaxel at the RP2D, respectively. Safety profiles were consistent with those of the individual agents. The best-confirmed ORRs were 7% (two partial responses) with single-agent ibrutinib and 36% (five partial responses) with ibrutinib plus pembrolizumab. Median PFS was 4.1 months (range, 1.0–37.4+) with ibrutinib plus paclitaxel. The best-confirmed ORR was 26% (two complete responses). In previously treated patients with UC, ORR was higher with ibrutinib plus pembrolizumab than with either agent alone (historical data in the intent-to-treat population). ORR with ibrutinib plus paclitaxel was greater than historical values for single-agent paclitaxel or ibrutinib. These data warrant further evaluation of ibrutinib combinations in UC. Keywords: urothelial carcinoma; ibrutinib; paclitaxel; pembrolizumab Author: Nataliya Mar, Yousef Zakharia, Alejandro Falcon, Rafael Morales-Barrera, Begona Mellado, Ignacio Duran, Do-Youn Oh, Stephen K. Williamson, Pablo Gajate, Hendrik-Tobias Arkenau, Robert J. Jones, Min Yuen Teo, Tolga Turan, Robert T. McLaughlin, Hillary M. Peltier, Elizabeth Chong, Harisha Atluri, James P. Dean and Daniel Castellano Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Fri Jun 9 10:12:28 2023 CEST ModDate: Fri Jun 9 11:07:30 2023 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 16 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1386545 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- HCRKXL+VnURWPalladioL Type 1 Custom yes yes no 10 0 TVBCEG+URWPalladioL-Bold Type 1 Custom yes yes no 15 0 KZGDWO+URWPalladioL-Roma Type 1 Custom yes yes no 20 0 DAWIXO+URWPalladioL-Ital Type 1 Custom yes yes no 24 0 LCJEVJ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 43 0 VBAQIR+CMSY10 Type 1 Builtin yes yes no 68 0 LDSSDS+EURM10 Type 1 Builtin yes yes no 72 0 NKZTII+URWPalladioL-BoldItal Type 1 Custom yes yes no 82 0 BCDEEE+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 100 0 BCDFEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 104 0 BCDGEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 108 0 BCDIEE+PalatinoLinotype-Bold CID TrueType Identity-H yes yes yes 112 0 BCDJEE+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 119 0 BCDEEE+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 135 0 BCDFEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 139 0 BCDGEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 143 0 BCDIEE+PalatinoLinotype-Bold CID TrueType Identity-H yes yes yes 147 0 BCDJEE+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 154 0 BCDEEE+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 177 0 BCDFEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 181 0 BCDGEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 185 0 BCDHEE+PalatinoLinotype-Italic CID TrueType Identity-H yes yes yes 189 0 BCDJEE+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 196 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-02-02 02:34:04 CET RepresentationInformation: pmc_10251876.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2023-10-02 02:27:20 CEST Size: 1386545 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 346 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Materials and Methods Destination: section.2 Children: Item: Title: Study Design and Patients Destination: subsection.2.1 Item: Title: Assessments and Analyses Destination: subsection.2.2 Item: Title: Statistical Considerations and Analysis Populations Destination: subsection.2.3 Item: Title: Data Availability Destination: subsection.2.4 Item: Title: Results Destination: section.3 Children: Item: Title: Phase 1b Destination: subsection.3.1 Item: Title: Phase 1b/2 at RP2D Destination: subsection.3.2 Item: Title: Efficacy at RP2D Destination: subsection.3.3 Item: Title: Phase 1b Safety Destination: subsection.3.4 Item: Title: Safety at RP2D Destination: subsection.3.5 Item: Title: Pharmacokinetics Destination: subsection.3.6 Item: Title: Biomarkers Destination: subsection.3.7 Item: Title: Discussion Destination: section.4 Item: Title: Conclusions Destination: section.5 Item: Title: References Destination: section.A. Info: Title: Results from a Phase 1b/2 Study of Ibrutinib Combination Therapy in Advanced Urothelial Carcinoma Author: Nataliya Mar, Yousef Zakharia, Alejandro Falcon, Rafael Morales-Barrera, Begona Mellado, Ignacio Duran, Do-Youn Oh, Stephen K. Williamson, Pablo Gajate, Hendrik-Tobias Arkenau, Robert J. Jones, Min Yuen Teo, Tolga Turan, Robert T. McLaughlin, Hillary M. Peltier, Elizabeth Chong, Harisha Atluri, James P. Dean and Daniel Castellano Subject: Ibrutinib is a first-in-class Bruton’s tyrosine kinase inhibitor approved for the treatment of various B-cell malignancies and chronic graft-versus-host disease. We evaluated the safety and efficacy of ibrutinib, alone or combined with standard-of-care regimens, in adults with advanced urothelial carcinoma (UC). Once-daily ibrutinib was administered orally at 840 mg (single-agent or with paclitaxel) or at 560 mg (with pembrolizumab). Phase 1b determined the recommended phase 2 dose (RP2D) of ibrutinib, and phase 2 assessed progression-free survival (PFS), overall response rate (ORR), and safety. Thirty-five, eighteen, and fifty-nine patients received ibrutinib, ibrutinib plus pembrolizumab, and ibrutinib plus paclitaxel at the RP2D, respectively. Safety profiles were consistent with those of the individual agents. The best-confirmed ORRs were 7% (two partial responses) with single-agent ibrutinib and 36% (five partial responses) with ibrutinib plus pembrolizumab. Median PFS was 4.1 months (range, 1.0 37.4+) with ibrutinib plus paclitaxel. The best-confirmed ORR was 26% (two complete responses). In previously treated patients with UC, ORR was higher with ibrutinib plus pembrolizumab than with either agent alone (historical data in the intent-to-treat population). ORR with ibrutinib plus paclitaxel was greater than historical values for single-agent paclitaxel or ibrutinib. These data warrant further evaluation of ibrutinib combinations in UC. 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