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Zhang, Danmei ORCID logoORCID: https://orcid.org/0000-0001-6048-4711; Westphalen, Christoph Benedikt; Quante, Michael; Waldschmidt, Dirk T.; Held, Swantje ORCID logoORCID: https://orcid.org/0000-0002-1344-9056; Kütting, Fabian; Dorman, Klara; Heinrich, Kathrin ORCID logoORCID: https://orcid.org/0000-0003-3580-2313; Weiss, Lena; Boukovala, Myrto; Haas, Michael; Boeck, Stefan; Heinemann, Volker ORCID logoORCID: https://orcid.org/0000-0002-1349-3321 und Probst, Victoria (2024): Gemcitabine and nab-paclitaxel combined with afatinib in metastatic pancreatic cancer. Results of a phase 1b clinical trial. In: European Journal of Cancer, Bd. 201, 113926 [PDF, 1MB]

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/m2 (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/m2) and afatinib (30 mg) was established. In a cohort of 11 patients, the combination showed an acceptable safety profile.

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