A phase I study of volasertib combined with afatinib, in advanced solid tumors
Jean-Pascal Machiels1, Marc Peeters2, Catherine Herremans3
1Department of Medical Oncology, Institut Roi Albert II, Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (Pole MIRO), Université Catholique de Louvain, Avenue Hippocrate 10, 1200, Brussels, Belgium. Jean-Pascal.Machiels@uclouvain.be.
Purpose:
To determine the maximum tolerated dose (MTD) of volasertib, a Polo-like kinase inhibitor, combined with afatinib, an oral irreversible ErbB family blocker, in patients with advanced solid tumors (NCT01206816; Study 1230.20).
Methods:
Patients with advanced non-resectable and/or metastatic disease following failure of conventional treatment received intravenous volasertib 150-300 mg on day 1 every 21 days, combined with oral afatinib 30-40 mg on days 2-21 of a 3-week cycle (Schedule A), or 50-90 mg on days 2-6 of a 3-week cycle (Schedule B). The primary objective was to determine the MTD of volasertib in combination with afatinib.
Results:
Fifty-seven patients (Schedule A, N = 29; Schedule B, N = 28) were treated. The MTDs were volasertib 300 mg plus afatinib 30 mg days 2-21 and 70 mg days 2-6 of a 3-week cycle for Schedules A and B, respectively. The most common Grade 3/4 adverse events were neutropenia (31.0 %), diarrhea (13.8 %), and thrombocytopenia (10.3 %) in Schedule A; neutropenia (39.3 %), thrombocytopenia (35.7 %), hypokalemia (14.3 %), febrile neutropenia, and nausea (each 10.7 %) in Schedule B. The best overall response was two partial responses (6.9 %; both in Schedule A); eight patients in each schedule achieved stable disease. Volasertib showed multi-exponential pharmacokinetic (PK) behavior; co-administration of volasertib and afatinib had no significant effects on the PK profile of either drug.
Conclusions:
Volasertib combined with afatinib had manageable adverse effects and limited antitumor activity in this heavily pretreated population.
Insights
This study determined the maximum tolerated dose of volasertib with afatinib in advanced solid tumors. The combination showed manageable side effects but limited antitumor activity in heavily pretreated patients.
Area of Science:
- Oncology
- Pharmacology
Background:
- Polo-like kinase inhibitors and ErbB family blockers represent targeted therapies for cancer.
- Combination therapies are being explored to improve treatment efficacy in advanced solid tumors.
Purpose of the Study:
- To determine the maximum tolerated dose (MTD) of volasertib, a Polo-like kinase inhibitor, in combination with afatinib, an ErbB family blocker.
- To evaluate the safety and tolerability of this combination in patients with advanced solid tumors.
Main Methods:
- A phase I clinical trial involving 57 patients with advanced solid tumors.
- Patients received intravenous volasertib and oral afatinib on different schedules (Schedule A and Schedule B).
- Dose escalation was used to determine the MTD.
Main Results:
- The MTDs were established as volasertib 300 mg (Schedule A) and 70 mg (Schedule B) combined with afatinib 30 mg (Schedule A) and 70 mg (Schedule B).
- Common Grade 3/4 adverse events included neutropenia, diarrhea, and thrombocytopenia.
- Limited antitumor activity was observed, with two partial responses and stable disease in 16 patients.
Conclusions:
- Volasertib combined with afatinib demonstrated manageable adverse effects in a heavily pretreated patient population.
- The combination exhibited limited antitumor efficacy, suggesting further investigation may be needed.
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