Hans-Joachim Schmoll1, Lars H Lindner2, Peter Reichardt3, Klaus Heißner4, Hans-Georg Kopp5, Torsten Kessler6, Regine Mayer-Steinacker7, Jörn Rüssel1, Gerlinde Egerer8, Martina Crysandt9, Bernd Kasper10, Dietger Niederwieser11, Annegret Kunitz12, Ekkehard Eigendorff13, Iver Petersen13,14, Jörg Steighardt15, Franziska Cygon1, Fabian Meinert1, Alexander Stein16. 1. Clinic for Internal Medicine IV-Hematology/Oncology, University Clinic, Martin Luther University, Halle-Wittenberg, Germany. 2. Department of Medicine III, University Hospital, Ludwig Maximilians University, Munich, Germany. 3. HELIOS Clinic Berlin Buch, Berlin, Germany. 4. Paracelsus Medical University, Nuremberg, Germany. 5. University Hospital Tuebingen, Tuebingen, Germany. 6. University Hospital Muenster, Muenster, Germany. 7. University Hospital Ulm, Ulm, Germany. 8. Department of Internal Medicine V, University Hospital, University of Heidelberg, Heidelberg, Germany. 9. Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, University Hospital RWTH Aachen University, Aachen, Germany. 10. Interdisciplinary Tumor Center Mannheim, Mannheim University Medical Center, Mannheim, Germany. 11. University of Leipzig, Leipzig, Germany. 12. University Hospital Charité Campus Virchow, Berlin, Germany. 13. University Hospital Jena, Jena, Germany. 14. SRH Wald Klinikum, Gera, Germany. 15. Coordination Center for Clinical Trials Halle, Martin Luther University, Halle-Wittenberg, Germany. 16. University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Abstract
IMPORTANCE: Pazopanib and gemcitabine have shown good tolerability, albeit modest single-agent activity in pretreated soft tissue sarcoma. A combined regimen to improve outcomes is required. OBJECTIVE: To determine the efficacy of gemcitabine and pazopanib compared with pazopanib alone. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, randomized phase 2 clinical trial was conducted in Germany from September 2011 to July 2014 and included patients with an Eastern Cooperative Oncology Group performance status score of 0 to 2, adequate organ function, measurable lesion, and progression after at least 1 prior treatment with anthracyclines and/or ifosfamide. Data analysis was performed during 2019 and 2020. INTERVENTIONS: Patients were randomized to pazopanib with gemcitabine (A) or without gemcitabine (B). MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival rate (PFSR) at 12 weeks; secondary end points included toxicity, quality of life, overall survival, and response rates. RESULTS: A total of 90 patients were randomized, and 86 eligible patients (43 women [50%]) were evaluable, with a median age of 57 (range, 22-84) years and Eastern Cooperative Oncology Group performance status score of 0/1 in 77 participants (90%). The predominant histological subtypes were leiomyosarcoma (22 [26%]) and liposarcoma (16 [19%]). After a median follow-up of 12.4 (range, 1-48) months, the primary end point was met, with a PFSR at 12 weeks of 74% (A) vs 47% (B) (hazard ratio [HR], 1.60; 90% CI, 1.15-2.23; P = .01). In the combination arm, PFSR was significantly longer, with a median of 5.6 vs 2.0 months (HR, 0.58; 95% CI, 0.36-0.92; P = .02) compared with single-agent pazopanib, whereas overall survival was similar, with 13.1 vs 11.2 months (HR, 0.98; 95% CI, 0.60-1.58; P = .83). The objective response rate was overall low, with 11% (A) vs 5% (B) (P = .10). The toxicity of the combination of pazopanib and gemcitabine was increased, but it was manageable and mainly hematological. CONCLUSIONS AND RELEVANCE: This phase 2 randomized clinical trial of patients with soft tissue sarcoma found that the addition of gemcitabine to pazopanib was tolerable, and PFSR at 12 weeks was significantly higher compared with pazopanib alone. These results suggest clinical activity of the combination, but they should be confirmed in a phase 3 trial in a more homogeneous population (eg, leiomyosarcoma). TRIAL REGISTRATION: German Clinical Trials Identifier: DRKS00003139.
IMPORTANCE: Pazopanib and gemcitabine have shown good tolerability, albeit modest single-agent activity in pretreated soft tissue sarcoma. A combined regimen to improve outcomes is required. OBJECTIVE: To determine the efficacy of gemcitabine and pazopanib compared with pazopanib alone. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, randomized phase 2 clinical trial was conducted in Germany from September 2011 to July 2014 and included patients with an Eastern Cooperative Oncology Group performance status score of 0 to 2, adequate organ function, measurable lesion, and progression after at least 1 prior treatment with anthracyclines and/or ifosfamide. Data analysis was performed during 2019 and 2020. INTERVENTIONS: Patients were randomized to pazopanib with gemcitabine (A) or without gemcitabine (B). MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival rate (PFSR) at 12 weeks; secondary end points included toxicity, quality of life, overall survival, and response rates. RESULTS: A total of 90 patients were randomized, and 86 eligible patients (43 women [50%]) were evaluable, with a median age of 57 (range, 22-84) years and Eastern Cooperative Oncology Group performance status score of 0/1 in 77 participants (90%). The predominant histological subtypes were leiomyosarcoma (22 [26%]) and liposarcoma (16 [19%]). After a median follow-up of 12.4 (range, 1-48) months, the primary end point was met, with a PFSR at 12 weeks of 74% (A) vs 47% (B) (hazard ratio [HR], 1.60; 90% CI, 1.15-2.23; P = .01). In the combination arm, PFSR was significantly longer, with a median of 5.6 vs 2.0 months (HR, 0.58; 95% CI, 0.36-0.92; P = .02) compared with single-agent pazopanib, whereas overall survival was similar, with 13.1 vs 11.2 months (HR, 0.98; 95% CI, 0.60-1.58; P = .83). The objective response rate was overall low, with 11% (A) vs 5% (B) (P = .10). The toxicity of the combination of pazopanib and gemcitabine was increased, but it was manageable and mainly hematological. CONCLUSIONS AND RELEVANCE: This phase 2 randomized clinical trial of patients with soft tissue sarcoma found that the addition of gemcitabine to pazopanib was tolerable, and PFSR at 12 weeks was significantly higher compared with pazopanib alone. These results suggest clinical activity of the combination, but they should be confirmed in a phase 3 trial in a more homogeneous population (eg, leiomyosarcoma). TRIAL REGISTRATION: German Clinical Trials Identifier: DRKS00003139.
Authors: Brian Schulte; Nisha Mohindra; Mohammed Milhem; Steven Attia; Steven Robinson; Varun Monga; Angela C Hirbe; Peter Oppelt; John Charlson; Irene Helenowski; Susan Abbinanti; Rasima Cehic; Scott Okuno; Brian A Van Tine; Mark Agulnik Journal: Br J Cancer Date: 2021-05-28 Impact factor: 9.075