Dataset Information

A phase I study of afatinib combined with paclitaxel and bevacizumab in patients with advanced solid tumors.

ABSTRACT:

Purpose

The combination of afatinib, an irreversible ErbB family blocker, with paclitaxel and bevacizumab was assessed in patients with advanced solid tumors.

Methods

This phase I study used a 3 + 3 design to determine the maximum tolerated dose (MTD) of afatinib combined with paclitaxel and bevacizumab. Safety, pharmacokinetics, and anti-tumor activity were also assessed. The starting dose was oral afatinib 40 mg once daily plus intravenous paclitaxel (fixed dose 80 mg/m², Days 1, 8, and 15 of a 4-week cycle) and intravenous bevacizumab 5 mg/kg every 2 weeks.

Results

Twenty-nine patients were enroled. The afatinib dose was de-escalated to 30 mg and then 20 mg after 2/6 and 2/5 evaluable patients developed dose-limiting toxicities at 40 and 30 mg, respectively, when combined with paclitaxel and bevacizumab 5 mg/kg. The bevacizumab dose was subsequently escalated to 10 mg/kg, and MTD was defined as afatinib 20 mg plus paclitaxel 80 mg/m² and bevacizumab 10 mg/kg. Frequent (any grade) treatment-related adverse events (AEs) included diarrhea (83%), rash/acne (83%), fatigue (79%), mucosal inflammation (59%), and nausea (59%). Based on overall safety, bevacizumab was amended to 7.5 mg/kg for the recommended phase II dose. Pharmacokinetic analyses suggested no relevant drug-drug interactions. Three (10%) confirmed partial responses were observed; 15 (52%) patients had stable disease.

Conclusions

The recommended phase II dose schedule was afatinib 20 mg/day with paclitaxel 80 mg/m² (Days 1, 8, and 15 every 4 weeks) and bevacizumab 7.5 mg/kg every 2 weeks. At this dose schedule, AEs were manageable, and anti-tumor activity was observed.

SUBMITTER: Spicer J

PROVIDER: S-EPMC5225194 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Publications

A phase I study of afatinib combined with paclitaxel and bevacizumab in patients with advanced solid tumors.

Spicer James J Irshad Sheeba S Ang Joo Ern JE Enting Deborah D Kristeleit Rebecca R Uttenreuther-Fischer Martina M Pemberton Karine K Pelling Katy K Schnell David D de Bono Johann J

Cancer chemotherapy and pharmacology 20161121 1

<h4>Purpose</h4>The combination of afatinib, an irreversible ErbB family blocker, with paclitaxel and bevacizumab was assessed in patients with advanced solid tumors.<h4>Methods</h4>This phase I study used a 3 + 3 design to determine the maximum tolerated dose (MTD) of afatinib combined with paclitaxel and bevacizumab. Safety, pharmacokinetics, and anti-tumor activity were also assessed. The starting dose was oral afatinib 40 mg once daily plus intravenous paclitaxel (fixed dose 80 mg/m<sup>2</s ...[more]

PMID: 27872953

Similar Datasets

Project description:PurposeAfatinib, an irreversible ErbB family blocker, has demonstrated preclinical antitumor activity with chemotherapy.MethodsAs part of a phase I trial in patients with advanced solid tumors (NCT00809133; 3 + 3 dose-escalation design), we determined the maximum tolerated dose (MTD) of afatinib with carboplatin (A/C) or with carboplatin plus paclitaxel (A/C/P). Starting doses: afatinib 20 mg/day, carboplatin AUC6 (A/C) with paclitaxel 175 mg/m2 (A/C/P) (chemotherapy: Day 1 of 21-day cycles). The primary objective was to determine the MTDs; safety, pharmacokinetics and antitumor activity were also evaluated.ResultsThirty-eight patients received A/C (n = 12) or A/C/P (n = 26). No dose-limiting toxicities (DLTs) were reported with A(20 mg)/C(AUC6). One patient experienced DLT in the A(40 mg)/C(AUC6) cohort (grade 3 acneiform rash); A(40 mg)/C(AUC6) was determined as the recommended phase II dose (RP2D) for A/C. Two patients each had DLTs with A(20 mg/day)/C(AUC6)/P(175 mg/m2): fatigue, infection, diarrhea, small intestine hemorrhage, dehydration, renal impairment, neutropenic sepsis (n = 1), mucositis (n = 1); A(40 mg)/C(AUC5)/P(175 mg/m2): febrile neutropenia (n = 1), mucositis, fatigue (n = 1); and A(30 mg)/C(AUC5)/P(175 mg/m2): stomatitis (n = 1), mucositis (n = 1). No DLT was observed with A(20 mg)/C(AUC5)/P(175 mg/m2), determined as the RP2D for A/C/P. The most frequent drug-related adverse events were (A/C; A/C/P): rash (75%; 73%), fatigue (67%; 69%), and diarrhea (58%; 88%). Drug plasma concentrations were similar between cycles, suggesting no drug-drug interactions. Objective response rates in these heavily pretreated patients were A/C, 3/12 (25%); A/C/P, 5/26 (19%).ConclusionsAfatinib 40 mg/day (approved monotherapy dose) with carboplatin AUC6, and afatinib 20 mg/day with carboplatin AUC5 and paclitaxel 175 mg/m2 demonstrated manageable safety and antitumor activity. Afatinib > 20 mg/day in the triple combination was not well tolerated.

Dataset Information

A phase I study of afatinib combined with paclitaxel and bevacizumab in patients with advanced solid tumors.

Purpose

Methods

Results

Conclusions

Publications

A phase I study of afatinib combined with paclitaxel and bevacizumab in patients with advanced solid tumors.

Similar Datasets

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