Phase I study of pazopanib plus TH-302 in advanced solid tumors
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To define the maximum tolerated dose (MTD), recommended phase II dose (RPTD), and assess safety and tolerability for the combination of pazopanib plus TH-302, an investigational hypoxia-activated prodrug (HAP), in adult patients with advanced solid tumors.
This was an open-label, non-randomized, single-center, phase I trial consisting 2 stages. Stage 1 was a standard “3 + 3” dose escalation design to determine safety and the RPTD for TH-302 plus pazopanib combination. Stage 2 was an expanded cohort to better describe the tolerability and toxicity profile at the MTD. Pazopanib was orally dosed at 800 mg daily on days 1–28 for all cohorts. TH-302 was administered intravenously on days 1, 8 and 15 of a 28-day cycle at doses of 340 mg/m2 (cohort 1) or 480 mg/m2 (cohort 2). Dose limiting toxicity (DLT) was assessed in the first 28-day cycle. Efficacy was assessed every 2 cycles.
Thirty patients were enrolled between December 2011 and September 2013. In the dose escalation stage, 7 patients were enrolled in the 340 mg/m2 TH-302 cohort and 6 patients in the 480 mg/m2 TH-302 cohort. Ten patients were evaluable for DLT. DLTs included grade 2 intolerable esophagitis (n = 1) in the 340 mg/m2 TH-302 cohort, and grade 3 vaginal inflammation (n = 1) and grade 3 neutropenia with grade 3 thrombocytopenia (n = 1, same patient) in the 480 mg/m2 TH-302 cohort. The 340 mg/m2 TH-302 cohort was determined to be MTD and RPTD. The most common treatment-related adverse events were hematologic (anemia, neutropenia, and thrombocytopenia), nausea/vomiting, palmar-plantar erythrodysesthesia syndrome, constipation, fatigue, mucositis, anorexia, pain, and hypertension. Partial response (PR) was observed in 10% (n = 3) of patients, stable disease (SD) in 57% (n = 17), and progressive disease (PD) in 23% (n = 7). Due to toxicity, 3 patients were discontinued from study drug prior to first radiographic assessment but were included in these calculations. Disease control ≥6 months was observed in 37% of patients (n = 11).
The RPTD for this novel combination is pazopanib 800 mg daily on days 1–28 plus TH-302 340 mg/m2 on days 1, 8 and 15 of each 28-day cycle. Preliminary activity was seen in treatment-refractory cancers and supports potential value of co-targeting tumor angiogenesis and tumor hypoxia.
KeywordsPazopanib TH-302 Advanced cancer Phase I Hypoxia
Dose limiting toxicity
Hepatocyte growth factor
Maximum tolerated dose
Platelet derived growth factor receptor
Karnofsky performance status
Response evaluation criteria in solid tumors
Recommended phase two dose
Stem cell derived factor 1
Urinary tract infection
Vascular endothelial growth factor
Vascular endothelial growth factor receptor
Women of childbearing potential
We gratefully acknowledge the invaluable contributions of the patients and their families. We would also like to acknowledge the Duke University Phase I Oncology clinical trials team.
Compliance with ethical standards
Conflict of interest
Dr. Riedel serves as institutional PI for SARC021: A Trial of TH-302 in Combination with Doxorubicin versus Doxorubicin Alone to Treat Patients with Locally Advanced Unresectable or Metastatic Soft Tissue Sarcoma.
This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Novartis Pharmaceuticals Corporation (formerly GlaxoSmithKline, LLC) and research supported by Threshold Pharmaceuticals, Inc.
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