Phase I study of pazopanib plus TH-302 in advanced solid tumors
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.
- 5.Carmeliet P (2005) VEGF as a key mediator of angiogenesis in cancer. Int Soc Cell 69(Suppl 3):4–10Google Scholar
- 13.Nikolinakos PG, Altorki N, Yankelevitz D, Tran HT, Yan S, Rajagopalan D, Bordogna W, Ottesen LH, Heymach JV (2010) Plasma cytokine and angiogenic factor profiling identifies markers associated with tumor shrinkage in early-stage non-small cell lung cancer patients treated with pazopanib. Cancer Res 70:2171–2179CrossRefPubMedPubMedCentralGoogle Scholar
- 16.Kopetz S, Hoff PM, Morris JS, Wolff RA, Eng C, Glover KY, Adinin R, Overman MJ, Valero V, Wen S, Lieu C, Yan S, Tran HT, Ellis LM, Abbruzzese JL, Heymach JV (2010) Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol 28:453–459CrossRefPubMedGoogle Scholar
- 18.Gerstner ER, Eichler AF, Plotkin SR, Drappatz J, Doyle CL, Xu L, Duda DG, Wen PY, Jain RK, Batchelor TT (2011) Phase I trial with biomarker studies of vatalanib (PTK787) in patients with newly diagnosed glioblastoma treated with enzyme inducing antiepileptic drugs and standard radiation and temozolomide. J Neurooncol 103(2):325–332CrossRefPubMedGoogle Scholar
- 19.Hanrahan EO, Lin HY, Kim ES, Yan S, Du DZ, McKee KS, Tran HT, Lee JJ, Ryan AJ, Langmuir P, Johnson BE, Heymach JV (2010) Distinct patterns of cytokine and angiogenic factor modulation and markers of benefit for vandetanib and/or chemotherapy in patients with non-small-cell lung cancer. J Clin Oncol 28:193–201CrossRefPubMedGoogle Scholar
- 20.Hanrahan EO, Ryan AJ, Mann H, Kennedy SJ, Langmuir P, Natale RB, Herbst RS, Johnson BE, Heymach JV (2009) Baseline vascular endothelial growth factor concentration as a potential predictive marker of benefit from vandetanib in non-small cell lung cancer. Clin Cancer Res 15:3600–3609CrossRefPubMedGoogle Scholar
- 21.Kumar R, Knick VB, Rudolph SK, Johnson JH, Crosby RM, Crouthamel MC, Hopper TM, Miller CG, Harrington LE, Onori JA, Mullin RJ, Gilmer TM, Truesdale AT, Epperly AH, Boloor A, Stafford JA, Luttrell DK, Cheung M (2007) Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol Cancer Ther 6(7):2012–2021CrossRefGoogle Scholar
- 27.Liapis V, Zinonos I, Labrinidis A, Hay S, Ponomarev V, Panagopoulos V, Zysk A, DeNichilo M, Ingman W, Atkins GJ, Findlay DM, Zannettino AC, Evdokiou A (2016) Anticancer efficacy of the hypoxia-activated prodrug evofosfamide (TH-302) in osteolytic breast cancer murine models. Cancer Med 5(3):534–545. doi: 10.1002/cam4.599 CrossRefPubMedPubMedCentralGoogle Scholar
- 28.Sun JD, Ahluwalia D, Liu Q, Li W, Wang Y, Meng F, Bhupathi D, Matteucci MD, Hart CP (2015) Combination tre2atment with hypoxia-activated prodrug evofosfamide (TH-302) and mTOR inhibitors results in enhanced antitumor efficacy in preclinical renal cell carcinoma models. Am J Cancer Res 5(7):2139–2155 (eCollection 2015) PubMedPubMedCentralGoogle Scholar
- 29.Sun JD, Liu Q, Ahluwalia D, Li W, Meng F, Wang Y, Bhupathi D, Ruprell AS, Hart CP (2015) Efficacy and safety of the hypoxia-activated prodrug TH-302 in combination with gemcitabine and nab-paclitaxel in human tumor xenograft models of pancreatic cancer. Cancer Biol Ther 16(3):438–449CrossRefPubMedPubMedCentralGoogle Scholar
- 30.Liapis V, Labrinidis A, Zinonos I, Hay S, Ponomarev V, Panagopoulos V, DeNichilo M, Ingman W, Atkins GJ, Findlay DM, Zannettino AC, Evdokiou A (2015) Hypoxia-activated pro-drug TH-302 exhibits potent tumor suppressive activity and cooperates with chemotherapy against osteosarcoma. Cancer Lett 357(1):160–169. doi: 10.1016/j.canlet.2014.11.020 (Epub 2014 Nov 15) CrossRefPubMedGoogle Scholar
- 31.Ganjoo KN, Cranmer LD, Butrynski JE, Rushing D, Adkins D, Okuno SH, Lorente G, Kroll S, Langmuir VK, Chawla SP (2011) A phase I study of the safety and pharmacokinetics of the hypoxia-activated prodrug TH-302 in combination with doxorubicin in patients with advanced soft tissue sarcoma. Int Soc Cell 80(1–2):50–56Google Scholar
- 32.Chawla SP, Cranmer LD, Van Tine BA, Reed DR, Okuno SH, Butrynski JE, Adkins DR, Hendifar AE, Kroll S, Ganjoo KN (2014) Phase II study of the safety and antitumor activity of the hypoxia-activated prodrug TH-302 in combination with doxorubicin in patients with advanced soft tissue sarcoma. J Clin Oncol 32(29):3299–3306CrossRefPubMedPubMedCentralGoogle Scholar
- 33.Borad MJ, Reddy SG, Bahary N, Uronis HE, Sigal D, Cohn AL, Schelman WR, Stephenson J Jr, Chiorean EG, Rosen PJ, Ulrich B, Dragovich T, Del Prete SA, Rarick M, Eng C, Kroll S, Ryan DP (2015) Randomized Phase II trial of Gemcitabine Plus TH-302 Versus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 33(13):1475–1481CrossRefPubMedGoogle Scholar
- 34.Van Cutsem E, Lenz HJ, Furuse J, Tabernero J, Heinemann V, Ioka T, Melichar B (2016) MAESTRO: a randomized, double-blind phase III study of evofosfamide (Evo) in combination with gemcitabine (Gem) in previously untreated patients (pts) with metastatic or locally advanced unresectable pancreatic ductal adenocarcinoma (PDAC). In ASCO Meeting Abstracts, vol 34, p 4007.Google Scholar
- 35.Tap W, Papai Z, Van Tine B, Attia S, Ganjoo K, Jones R, Schuetze S, Reed D, Chawla S, Riedel R, Krarup-Hansen A, Italiano A, Hohenberger P, Grignani G, Cranmer L, Alcindor T, Lopez-Pousa A, Pearce T, Kroll S, Schoffski P. Randomized phase 3, multicenter, open-label study comparing evofosfamide (Evo) in combination with doxorubicin (D) vs. D alone in patients (pts) with advanced soft tissue sarcoma (STS): study TH-CR-406/SARC021. Paper presented at: European Society for Medical Oncology (ESMO) 2016 Congress; October 7–11, 2016; CopenhagenGoogle Scholar