학술논문
Gemcitabine and nab-paclitaxel combined with afatinib in metastatic pancreatic cancer - Results of a phase 1b clinical trial.
Document Type
Academic Journal
Author
Zhang D; Comprehensive Cancer Center Munich & Department of Medicine III, Ludwig-Maximilian University of Munich, Munich, Germany; German Cancer Consortium (DKTK partner site Munich), Heidelberg, Germany.; Benedikt Westphalen C; Comprehensive Cancer Center Munich & Department of Medicine III, Ludwig-Maximilian University of Munich, Munich, Germany; German Cancer Consortium (DKTK partner site Munich), Heidelberg, Germany.; Quante M; Medizinische Klinik II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany and Innere Medizin II, Universitätsklinik Freiburg, Universität Freiburg, Germany.; Waldschmidt DT; Clinic for Gastroenterology and Hepatology, University Hospital Cologne, Germany.; Held S; ClinAssess GmbH, Leverkusen, Germany.; Kütting F; Clinic for Gastroenterology and Hepatology, University Hospital Cologne, Germany.; Dorman K; Comprehensive Cancer Center Munich & Department of Medicine III, Ludwig-Maximilian University of Munich, Munich, Germany; German Cancer Consortium (DKTK partner site Munich), Heidelberg, Germany.; Heinrich K; Comprehensive Cancer Center Munich & Department of Medicine III, Ludwig-Maximilian University of Munich, Munich, Germany.; Weiss L; Comprehensive Cancer Center Munich & Department of Medicine III, Ludwig-Maximilian University of Munich, Munich, Germany.; Boukovala M; Comprehensive Cancer Center Munich & Department of Medicine III, Ludwig-Maximilian University of Munich, Munich, Germany.; Haas M; Comprehensive Cancer Center Munich & Department of Medicine III, Ludwig-Maximilian University of Munich, Munich, Germany; German Cancer Consortium (DKTK partner site Munich), Heidelberg, Germany; Department of Hematology and Oncology, München Klinik Neuperlach, Munich, Germany.; Boeck S; Comprehensive Cancer Center Munich & Department of Medicine III, Ludwig-Maximilian University of Munich, Munich, Germany; German Cancer Consortium (DKTK partner site Munich), Heidelberg, Germany; Department of Hematology and Oncology, München Klinik Neuperlach, Munich, Germany.; Heinemann V; Comprehensive Cancer Center Munich & Department of Medicine III, Ludwig-Maximilian University of Munich, Munich, Germany; German Cancer Consortium (DKTK partner site Munich), Heidelberg, Germany. Electronic address: Volker.Heineman@med.uni-muenchen.de.; Probst V; Comprehensive Cancer Center Munich & Department of Medicine III, Ludwig-Maximilian University of Munich, Munich, Germany. Electronic address: victoria.probst@med.uni-muenchen.de.
Source
Publisher: Elsevier Science Ltd Country of Publication: England NLM ID: 9005373 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0852 (Electronic) Linking ISSN: 09598049 NLM ISO Abbreviation: Eur J Cancer Subsets: MEDLINE
Subject
Language
English
Abstract
Purpose: The combination of gemcitabine/nab-paclitaxel is an established standard treatment in the first-line treatment of metastatic ductal adenocarcinoma of the pancreas (mPDAC). Afatinib, an oral second-generation pan ErbB family tyrosine kinase inhibitor, has shown promising pre-clinical signs in the treatment of pancreatic cancer. The aim of this phase 1b trial was to determine the maximum tolerated dose (MTD) of afatinib in combination with gemcitabine/nab-paclitaxel in patients with mPDAC.
Methods: Treatment naïve patients (≥18 years) with histologically proven mPDAC and good performance status (ECOG 0/1) were enrolled to receive gemcitabine/nab-paclitaxel in combination with afatinib. Treatment was continued until disease progression, or unacceptable toxicity. The primary endpoint MTD was determined using a 3 + 3 design. Treatment started at dose level 0 with intravenous gemcitabine/nab-paclitaxel 1000 mg/m2 / 125 mg/m 2 (day 1, 8, 15 of a 28-day cycle) + oral afatinib 30 mg daily. At dose level + 1 afatinib was increased to 40 mg. Secondary endpoints included safety parameters and exploratory endpoints evaluated treatment efficacy.
Results: Twelve patients were included in this trial, and 11 patients were treated and analysed in the safety and full analysis set (FAS). At dose level 0 the first three patients did not experience a dose-limiting toxicity (DLT). At dose leve (DL) + 1 two patients experienced a DLT. Accordingly, enrolment continued at DL 0 with three more patients, of which one experienced DLT (skin rash ≥ CTCAE grade 3). Seven patients (63.6%) experienced at least one treatment-emergent serious adverse event (TESAE), with four patients (36.4%) experiencing TESAEs grade 3-5 related to the study medication. In the FAS, the objective response rate (ORR) was 36.4%, median progression-free survival (PFS) was 3.5 months and median overall survival in nine evaluable patients was 7.5 months.
Conclusions: In this phase 1b clinical trial, the MTD of gemcitabine/nab-paclitaxel (1000 mg/m2 / 125 mg/m 2 ) and afatinib (30 mg) was established. In a cohort of 11 patients, the combination showed an acceptable safety profile.
Competing Interests: Declaration of Competing Interest DZ reported receiving honoraria from AstraZeneca, receiving research funding for the institution from Milteny and travel as well as accommodation expenses from AstraZeneca and Amgen. CBW has received honoraria from Amgen, Bayer, BMS, Chugai, Celgene, Falk, GSK, MSD, Merck, Janssen, Ipsen, Roche, Servier, SIRTeX, and Taiho; served on advisory boards for Bayer, BMS, Celgene, Janssen, MSD, Servier, Shire/Baxalta, Rafael Pharmaceuticals, RedHill, and Roche; has received travel support by Bayer, Celgene, Janssen, RedHill, Roche, Servier, and Taiho and research grants (institutional) by Roche. MQ, DTW, FK, KH and MB report no conflict of interest. SW reported being employee of ClinAssess GmbH KD has received travel support from Servier, GSK, and BMS, as well as honoraria from AstraZeneca. LW received honoraria for scientific presentations from Roche and Servier and travel accommodation expenses from Amgen. MH reported receiving travel support from Servier and honoraria for scientific presentations from Falk Foundation. SB had a consulting and advisory role for Celgene, Servier, Incyte, Fresenius, Janssen-Cilag, AstraZeneca, MSD, and BMS, and received honoraria for scientific presentations from Roche, Celgene, Servier, and MSD. VH received honoraria for talks and advisory board role for Merck, Amgen, Roche, Sanofi, Servier, Pfizer, Pierre-Fabre, AstraZeneca, BMS; MSD, Novartis, Terumo, On- cosil, NORDIC, Seagen, GSK. Research funding from Merck, Amgen, Roche, Sanofi, Boehringer-Ingelheim, SIRTEX, Servier. VP reported receiving travel support from Nordic Pharma.
(Copyright © 2024. Published by Elsevier Ltd.)
Methods: Treatment naïve patients (≥18 years) with histologically proven mPDAC and good performance status (ECOG 0/1) were enrolled to receive gemcitabine/nab-paclitaxel in combination with afatinib. Treatment was continued until disease progression, or unacceptable toxicity. The primary endpoint MTD was determined using a 3 + 3 design. Treatment started at dose level 0 with intravenous gemcitabine/nab-paclitaxel 1000 mg/m
Results: Twelve patients were included in this trial, and 11 patients were treated and analysed in the safety and full analysis set (FAS). At dose level 0 the first three patients did not experience a dose-limiting toxicity (DLT). At dose leve (DL) + 1 two patients experienced a DLT. Accordingly, enrolment continued at DL 0 with three more patients, of which one experienced DLT (skin rash ≥ CTCAE grade 3). Seven patients (63.6%) experienced at least one treatment-emergent serious adverse event (TESAE), with four patients (36.4%) experiencing TESAEs grade 3-5 related to the study medication. In the FAS, the objective response rate (ORR) was 36.4%, median progression-free survival (PFS) was 3.5 months and median overall survival in nine evaluable patients was 7.5 months.
Conclusions: In this phase 1b clinical trial, the MTD of gemcitabine/nab-paclitaxel (1000 mg/m
Competing Interests: Declaration of Competing Interest DZ reported receiving honoraria from AstraZeneca, receiving research funding for the institution from Milteny and travel as well as accommodation expenses from AstraZeneca and Amgen. CBW has received honoraria from Amgen, Bayer, BMS, Chugai, Celgene, Falk, GSK, MSD, Merck, Janssen, Ipsen, Roche, Servier, SIRTeX, and Taiho; served on advisory boards for Bayer, BMS, Celgene, Janssen, MSD, Servier, Shire/Baxalta, Rafael Pharmaceuticals, RedHill, and Roche; has received travel support by Bayer, Celgene, Janssen, RedHill, Roche, Servier, and Taiho and research grants (institutional) by Roche. MQ, DTW, FK, KH and MB report no conflict of interest. SW reported being employee of ClinAssess GmbH KD has received travel support from Servier, GSK, and BMS, as well as honoraria from AstraZeneca. LW received honoraria for scientific presentations from Roche and Servier and travel accommodation expenses from Amgen. MH reported receiving travel support from Servier and honoraria for scientific presentations from Falk Foundation. SB had a consulting and advisory role for Celgene, Servier, Incyte, Fresenius, Janssen-Cilag, AstraZeneca, MSD, and BMS, and received honoraria for scientific presentations from Roche, Celgene, Servier, and MSD. VH received honoraria for talks and advisory board role for Merck, Amgen, Roche, Sanofi, Servier, Pfizer, Pierre-Fabre, AstraZeneca, BMS; MSD, Novartis, Terumo, On- cosil, NORDIC, Seagen, GSK. Research funding from Merck, Amgen, Roche, Sanofi, Boehringer-Ingelheim, SIRTEX, Servier. VP reported receiving travel support from Nordic Pharma.
(Copyright © 2024. Published by Elsevier Ltd.)