A Phase I, Open-Label, Multicenter, Dose-escalation Study of the Oral Selective FGFR Inhibitor Debio 1347 in Patients with Advanced Solid Tumors Harboring FGFR Gene Alterations
To investigate tolerability, efficacy, and pharmacokinetics/pharmacodynamics of Debio 1347, a selective FGFR inhibitor. This was a first-in-human, multicenter, open-label study in patients with advanced solid tumors harboring gene alterations. Eligible patients received oral Debio 1347 at escalating...
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| Published in: | Clinical cancer research Vol. 25; no. 9; p. 2699 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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| ISSN: | 1557-3265, 1557-3265 |
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| Abstract | To investigate tolerability, efficacy, and pharmacokinetics/pharmacodynamics of Debio 1347, a selective FGFR inhibitor.
This was a first-in-human, multicenter, open-label study in patients with advanced solid tumors harboring
gene alterations. Eligible patients received oral Debio 1347 at escalating doses once daily until disease progression or intolerable toxicity. Dose-limiting toxicities (DLT) were evaluated during the first 4 weeks on treatment, pharmacokinetics/pharmacodynamics postfirst dose and after 4 weeks.
A total of 71 patients were screened and 58 treated with Debio 1347 at doses from 10 to 150 mg/day. Predominant tumor types were breast and biliary duct cancer, most common gene alterations were
amplifications (40%) and mutations in
(12%) and
(17%); 12 patients (21%) showed
fusions. Five patients at three dose levels had six DLTs (dry mouth/eyes, hyperamylasemia, hypercalcemia, hyperbilirubinemia, hyperphosphatemia, and stomatitis). The maximum tolerated dose was not reached, but dermatologic toxicity became sometimes dose limiting beyond the DLT period at ≥80 mg/day. Adverse events required dose modifications in 52% of patients, mostly due to dose-dependent, asymptomatic hyperphosphatemia (22%). RECIST responses were seen across tumor types and mechanisms of FGFR activation. Six patients, 3 with
fusions, demonstrated partial responses, 10 additional patients' tumor size regressions of ≤30%. Plasma half-life was 11.5 hours. Serum phosphate increased with Debio 1347 plasma levels and confirmed target engagement at doses ≥60 mg/day.
Preliminary efficacy was encouraging and tolerability acceptable up to 80 mg/day, which is now used in an extension part of the study. |
|---|---|
| AbstractList | To investigate tolerability, efficacy, and pharmacokinetics/pharmacodynamics of Debio 1347, a selective FGFR inhibitor.PURPOSETo investigate tolerability, efficacy, and pharmacokinetics/pharmacodynamics of Debio 1347, a selective FGFR inhibitor.This was a first-in-human, multicenter, open-label study in patients with advanced solid tumors harboring FGFR1-3 gene alterations. Eligible patients received oral Debio 1347 at escalating doses once daily until disease progression or intolerable toxicity. Dose-limiting toxicities (DLT) were evaluated during the first 4 weeks on treatment, pharmacokinetics/pharmacodynamics postfirst dose and after 4 weeks.PATIENTS AND METHODSThis was a first-in-human, multicenter, open-label study in patients with advanced solid tumors harboring FGFR1-3 gene alterations. Eligible patients received oral Debio 1347 at escalating doses once daily until disease progression or intolerable toxicity. Dose-limiting toxicities (DLT) were evaluated during the first 4 weeks on treatment, pharmacokinetics/pharmacodynamics postfirst dose and after 4 weeks.A total of 71 patients were screened and 58 treated with Debio 1347 at doses from 10 to 150 mg/day. Predominant tumor types were breast and biliary duct cancer, most common gene alterations were FGFR1 amplifications (40%) and mutations in FGFR2 (12%) and FGFR3 (17%); 12 patients (21%) showed FGFR fusions. Five patients at three dose levels had six DLTs (dry mouth/eyes, hyperamylasemia, hypercalcemia, hyperbilirubinemia, hyperphosphatemia, and stomatitis). The maximum tolerated dose was not reached, but dermatologic toxicity became sometimes dose limiting beyond the DLT period at ≥80 mg/day. Adverse events required dose modifications in 52% of patients, mostly due to dose-dependent, asymptomatic hyperphosphatemia (22%). RECIST responses were seen across tumor types and mechanisms of FGFR activation. Six patients, 3 with FGFR fusions, demonstrated partial responses, 10 additional patients' tumor size regressions of ≤30%. Plasma half-life was 11.5 hours. Serum phosphate increased with Debio 1347 plasma levels and confirmed target engagement at doses ≥60 mg/day.RESULTSA total of 71 patients were screened and 58 treated with Debio 1347 at doses from 10 to 150 mg/day. Predominant tumor types were breast and biliary duct cancer, most common gene alterations were FGFR1 amplifications (40%) and mutations in FGFR2 (12%) and FGFR3 (17%); 12 patients (21%) showed FGFR fusions. Five patients at three dose levels had six DLTs (dry mouth/eyes, hyperamylasemia, hypercalcemia, hyperbilirubinemia, hyperphosphatemia, and stomatitis). The maximum tolerated dose was not reached, but dermatologic toxicity became sometimes dose limiting beyond the DLT period at ≥80 mg/day. Adverse events required dose modifications in 52% of patients, mostly due to dose-dependent, asymptomatic hyperphosphatemia (22%). RECIST responses were seen across tumor types and mechanisms of FGFR activation. Six patients, 3 with FGFR fusions, demonstrated partial responses, 10 additional patients' tumor size regressions of ≤30%. Plasma half-life was 11.5 hours. Serum phosphate increased with Debio 1347 plasma levels and confirmed target engagement at doses ≥60 mg/day.Preliminary efficacy was encouraging and tolerability acceptable up to 80 mg/day, which is now used in an extension part of the study.CONCLUSIONSPreliminary efficacy was encouraging and tolerability acceptable up to 80 mg/day, which is now used in an extension part of the study. To investigate tolerability, efficacy, and pharmacokinetics/pharmacodynamics of Debio 1347, a selective FGFR inhibitor. This was a first-in-human, multicenter, open-label study in patients with advanced solid tumors harboring gene alterations. Eligible patients received oral Debio 1347 at escalating doses once daily until disease progression or intolerable toxicity. Dose-limiting toxicities (DLT) were evaluated during the first 4 weeks on treatment, pharmacokinetics/pharmacodynamics postfirst dose and after 4 weeks. A total of 71 patients were screened and 58 treated with Debio 1347 at doses from 10 to 150 mg/day. Predominant tumor types were breast and biliary duct cancer, most common gene alterations were amplifications (40%) and mutations in (12%) and (17%); 12 patients (21%) showed fusions. Five patients at three dose levels had six DLTs (dry mouth/eyes, hyperamylasemia, hypercalcemia, hyperbilirubinemia, hyperphosphatemia, and stomatitis). The maximum tolerated dose was not reached, but dermatologic toxicity became sometimes dose limiting beyond the DLT period at ≥80 mg/day. Adverse events required dose modifications in 52% of patients, mostly due to dose-dependent, asymptomatic hyperphosphatemia (22%). RECIST responses were seen across tumor types and mechanisms of FGFR activation. Six patients, 3 with fusions, demonstrated partial responses, 10 additional patients' tumor size regressions of ≤30%. Plasma half-life was 11.5 hours. Serum phosphate increased with Debio 1347 plasma levels and confirmed target engagement at doses ≥60 mg/day. Preliminary efficacy was encouraging and tolerability acceptable up to 80 mg/day, which is now used in an extension part of the study. |
| Author | Borger, Darrell R Hierro, Cinta Cleary, James M Iafrate, A John Voss, Martin H Tabernero, Josep Ishii, Nobuya Vaslin Chessex, Anne Zanna, Claudio Gandhi, Leena Flaherty, Keith T Meric-Bernstam, Funda Janku, Filip Nicolas-Metral, Valerie Pokorska-Bocci, Anna Kirpicheva, Yulia Heist, Rebecca S Hu, Youyou Baselga, Jose |
| Author_xml | – sequence: 1 givenname: Martin H orcidid: 0000-0003-0551-5807 surname: Voss fullname: Voss, Martin H email: vossm@mskcc.org organization: Memorial Sloan Kettering Cancer Center, New York, New York. vossm@mskcc.org – sequence: 2 givenname: Cinta surname: Hierro fullname: Hierro, Cinta organization: Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain – sequence: 3 givenname: Rebecca S surname: Heist fullname: Heist, Rebecca S organization: Massachusetts General Hospital Cancer Center, Boston, Massachusetts – sequence: 4 givenname: James M surname: Cleary fullname: Cleary, James M organization: Dana-Farber Cancer Institute, Boston, Massachusetts – sequence: 5 givenname: Funda surname: Meric-Bernstam fullname: Meric-Bernstam, Funda organization: The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 6 givenname: Josep orcidid: 0000-0002-2495-8139 surname: Tabernero fullname: Tabernero, Josep organization: Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain – sequence: 7 givenname: Filip surname: Janku fullname: Janku, Filip organization: The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 8 givenname: Leena surname: Gandhi fullname: Gandhi, Leena organization: Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York, New York – sequence: 9 givenname: A John surname: Iafrate fullname: Iafrate, A John organization: Massachusetts General Hospital Cancer Center, Boston, Massachusetts – sequence: 10 givenname: Darrell R surname: Borger fullname: Borger, Darrell R organization: Massachusetts General Hospital Cancer Center, Boston, Massachusetts – sequence: 11 givenname: Nobuya surname: Ishii fullname: Ishii, Nobuya organization: Chugai Pharmaceutical Co., Ltd., Tokyo, Japan – sequence: 12 givenname: Youyou surname: Hu fullname: Hu, Youyou organization: Debiopharm International SA, Lausanne, Switzerland – sequence: 13 givenname: Yulia surname: Kirpicheva fullname: Kirpicheva, Yulia organization: Debiopharm International SA, Lausanne, Switzerland – sequence: 14 givenname: Valerie surname: Nicolas-Metral fullname: Nicolas-Metral, Valerie organization: Debiopharm International SA, Lausanne, Switzerland – sequence: 15 givenname: Anna surname: Pokorska-Bocci fullname: Pokorska-Bocci, Anna organization: Debiopharm International SA, Lausanne, Switzerland – sequence: 16 givenname: Anne surname: Vaslin Chessex fullname: Vaslin Chessex, Anne organization: Debiopharm International SA, Lausanne, Switzerland – sequence: 17 givenname: Claudio surname: Zanna fullname: Zanna, Claudio organization: Debiopharm International SA, Lausanne, Switzerland – sequence: 18 givenname: Keith T surname: Flaherty fullname: Flaherty, Keith T organization: Massachusetts General Hospital Cancer Center, Boston, Massachusetts – sequence: 19 givenname: Jose surname: Baselga fullname: Baselga, Jose organization: Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/30745300$$D View this record in MEDLINE/PubMed |
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| Snippet | To investigate tolerability, efficacy, and pharmacokinetics/pharmacodynamics of Debio 1347, a selective FGFR inhibitor.
This was a first-in-human, multicenter,... To investigate tolerability, efficacy, and pharmacokinetics/pharmacodynamics of Debio 1347, a selective FGFR inhibitor.PURPOSETo investigate tolerability,... |
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| SubjectTerms | Adult Aged Benzimidazoles - pharmacokinetics Benzimidazoles - therapeutic use Drug Administration Schedule Female Follow-Up Studies Gene Fusion Humans Male Maximum Tolerated Dose Middle Aged Mutation Neoplasms - drug therapy Neoplasms - genetics Neoplasms - pathology Prognosis Protein Kinase Inhibitors - pharmacokinetics Protein Kinase Inhibitors - therapeutic use Pyrazoles - pharmacokinetics Pyrazoles - therapeutic use Receptor, Fibroblast Growth Factor, Type 1 - antagonists & inhibitors Receptor, Fibroblast Growth Factor, Type 1 - genetics Receptor, Fibroblast Growth Factor, Type 2 - antagonists & inhibitors Receptor, Fibroblast Growth Factor, Type 2 - genetics Receptor, Fibroblast Growth Factor, Type 3 - antagonists & inhibitors Receptor, Fibroblast Growth Factor, Type 3 - genetics Signal Transduction Tissue Distribution |
| Title | A Phase I, Open-Label, Multicenter, Dose-escalation Study of the Oral Selective FGFR Inhibitor Debio 1347 in Patients with Advanced Solid Tumors Harboring FGFR Gene Alterations |
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