Martin Forster1, Allan Hackshaw2, Tommaso De Pas3, Manuel Cobo4, Pilar Garrido5, Yvonne Summers6, Anne-Marie C Dingemans7, Michael Flynn8, David Schnell9, Ute von Wangenheim9, Arsene-Bienvenu Loembé10, Rolf Kaiser11, Siow Ming Lee12. 1. Department of Oncology, University College London Cancer Institute, London, UK; University College London Hospitals NHS Foundation Trust, London, UK. 2. Cancer Research UK & UCL Cancer Trials Centre, University College London Cancer Institute, London, UK. 3. Medical Oncology Department, Istituto Europeo di Oncologia, Milan, Italy. 4. Medical Oncology Department, Hospital Universitario Málaga General FIMABIS, Málaga, Spain. 5. Medical Oncology Department, University Hospital Ramón y Cajal, Madrid, Spain. 6. Medical Oncology Department, Christie Hospital NHS Foundation Trust, Manchester, UK. 7. Department of Pulmonology, Maastricht University Medical Center, Maastricht, The Netherlands. 8. University College London Hospitals NHS Foundation Trust, London, UK. 9. Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany. 10. Boehringer Ingelheim B.V., Alkmaar, The Netherlands. 11. Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; Institute of Pharmacology, University of Mainz, Mainz, Germany. 12. Department of Oncology, University College London Cancer Institute, London, UK; University College London Hospitals NHS Foundation Trust, London, UK. Electronic address: smlee@ucl.ac.uk.
Abstract
BACKGROUND: There are limited treatment options for squamous non-small cell lung cancer (sqNSCLC) and prognosis remains poor. The safety and pharmacokinetics (PK) of nintedanib, a triple angiokinase inhibitor, plus cisplatin/gemcitabine as first-line treatment for advanced sqNSCLC patients, were evaluated. MATERIALS AND METHODS: A phase I, dose-escalation study administering drugs in a 21-day cycle: cisplatin (75 mg/m2, Day 1), gemcitabine (1250 mg/m2, Days 1 and 8) and nintedanib (Days 2-7, 9-21) were given for 4-6 cycles, followed by monotherapy until disease progression or adverse events (AEs). Two nintedanib doses were tested, 150 mg twice daily (bid) and 200 mg bid, to determine maximum tolerated dose (MTD) based on occurrence of dose-limiting toxicities (DLTs) during Cycle 1. DLTs were primarily defined as drug-related non-hematologic (Grade ≥3) or hematologic (Grade 4) AEs. RESULTS: Sixteen patients were treated with nintedanib; n = 4 for 150 mg bid, n = 12 for 200 mg bid. No DLTs were observed in Cycle 1; therefore, the MTD was 200 mg bid. In subsequent cycles, two patients had DLTs: renal failure and reduced blood magnesium levels. The most common AEs were gastrointestinal. Three patients discontinued last study medication due to AEs and one had a nintedanib dose reduction. No relevant PK interactions were observed. Five patients had partial responses (31.3%) and eight had stable disease (50.0%); disease control rate was 81.3%. There were three long-term survivors (17-35 months). CONCLUSIONS: The safety profile of nintedanib 200 mg bid plus cisplatin/gemcitabine was manageable, with AEs consistent with previous observations. PK data demonstrated no interaction, and preliminary antitumor activity was observed.
BACKGROUND: There are limited treatment options for squamous non-small cell lung cancer (sqNSCLC) and prognosis remains poor. The safety and pharmacokinetics (PK) of nintedanib, a triple angiokinase inhibitor, plus cisplatin/gemcitabine as first-line treatment for advanced sqNSCLC patients, were evaluated. MATERIALS AND METHODS: A phase I, dose-escalation study administering drugs in a 21-day cycle: cisplatin (75 mg/m2, Day 1), gemcitabine (1250 mg/m2, Days 1 and 8) and nintedanib (Days 2-7, 9-21) were given for 4-6 cycles, followed by monotherapy until disease progression or adverse events (AEs). Two nintedanib doses were tested, 150 mg twice daily (bid) and 200 mg bid, to determine maximum tolerated dose (MTD) based on occurrence of dose-limiting toxicities (DLTs) during Cycle 1. DLTs were primarily defined as drug-related non-hematologic (Grade ≥3) or hematologic (Grade 4) AEs. RESULTS: Sixteen patients were treated with nintedanib; n = 4 for 150 mg bid, n = 12 for 200 mg bid. No DLTs were observed in Cycle 1; therefore, the MTD was 200 mg bid. In subsequent cycles, two patients had DLTs: renal failure and reduced blood magnesium levels. The most common AEs were gastrointestinal. Three patients discontinued last study medication due to AEs and one had a nintedanib dose reduction. No relevant PK interactions were observed. Five patients had partial responses (31.3%) and eight had stable disease (50.0%); disease control rate was 81.3%. There were three long-term survivors (17-35 months). CONCLUSIONS: The safety profile of nintedanib 200 mg bid plus cisplatin/gemcitabine was manageable, with AEs consistent with previous observations. PK data demonstrated no interaction, and preliminary antitumor activity was observed.