title: Phase I study of pazopanib plus TH-302 in advanced solid tumors.
abstract: 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/m2TH-302 cohort and 6 patients in the 480 mg/m2TH-302 cohort. Ten patients were evaluable for DLT. DLTs included grade 2 intolerable esophagitis (n = 1) in the 340 mg/m2TH-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/m2TH-302 cohort. The 340 mg/m2TH-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/m2on 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.
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Seeley G. Mudd Building, 10 Bryan Searle Drive, Box 3052, Durham, NC, 27710, USA.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Riedel
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Seeley G. Mudd Building, 10 Bryan Searle Drive, Box 3052, Durham, NC, 27710, USA.
authors.forename: Kellen L
authors.initials: KL
authors.lastname: Meadows
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Seeley G. Mudd Building, 10 Bryan Searle Drive, Box 3052, Durham, NC, 27710, USA.
authors.forename: Paula H
authors.initials: PH
authors.lastname: Lee
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Seeley G. Mudd Building, 10 Bryan Searle Drive, Box 3052, Durham, NC, 27710, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Morse
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Seeley G. Mudd Building, 10 Bryan Searle Drive, Box 3052, Durham, NC, 27710, USA.
authors.forename: Hope E
authors.initials: HE
authors.lastname: Uronis
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Seeley G. Mudd Building, 10 Bryan Searle Drive, Box 3052, Durham, NC, 27710, USA.
authors.forename: Gerard C
authors.initials: GC
authors.lastname: Blobe
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Seeley G. Mudd Building, 10 Bryan Searle Drive, Box 3052, Durham, NC, 27710, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: George
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Seeley G. Mudd Building, 10 Bryan Searle Drive, Box 3052, Durham, NC, 27710, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Crawford
authors.affiliation: Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Niedzwiecki
authors.affiliation: Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, USA.
authors.forename: Christel N
authors.initials: CN
authors.lastname: Rushing
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Seeley G. Mudd Building, 10 Bryan Searle Drive, Box 3052, Durham, NC, 27710, USA.
authors.forename: Christy C
authors.initials: CC
authors.lastname: Arrowood
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Seeley G. Mudd Building, 10 Bryan Searle Drive, Box 3052, Durham, NC, 27710, USA. hurwi004@mc.duke.edu.
authors.forename: Herbert I
authors.initials: HI
authors.lastname: Hurwitz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D015331:Cohort Studies; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007191:Indazoles; D017567:Karnofsky Performance Status; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009593:Nitroimidazoles / Q000008:administration & dosage; D010752:Phosphoramide Mustards / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage; D055815:Young Adult
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D007191:Indazoles; D009593:Nitroimidazoles; D010752:Phosphoramide Mustards; D011743:Pyrimidines; D013449:Sulfonamides; C552526:TH 302; C516667:pazopanib
keywords: Advanced cancer; Hypoxia; Pazopanib; Phase I; TH-302