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Phase I study of pazopanib plus TH-302 in advanced solid tumors

  • Clinical Trial Report
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Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

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.

Methods

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.

Results

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).

Conclusions

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.

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Abbreviations

AE:

Adverse event(s)

ATP:

Adenosine tri-phosphate

DLT:

Dose limiting toxicity

EMT:

Epithelial-mesenchymal transition

HAP:

Hypoxia-activated prodrug(s)

HGF:

Hepatocyte growth factor

IL8:

Interleukin 8

IQR:

Interquartile range

MTD:

Maximum tolerated dose

PD:

Progressive disease

PDGFR:

Platelet derived growth factor receptor

PR:

Partial response

KPS:

Karnofsky performance status

RECIST:

Response evaluation criteria in solid tumors

RPTD:

Recommended phase two dose

SD:

Stable disease

SDF1:

Stem cell derived factor 1

UTI:

Urinary tract infection

VEGF:

Vascular endothelial growth factor

VEGFR:

Vascular endothelial growth factor receptor

WOCBP:

Women of childbearing potential

References

  1. Brown JM (2007) Tumor hypoxia in cancer therapy. Methods Enzymol 435:297–321

    CAS  PubMed  Google Scholar 

  2. Finger EC, Giaccia AJ (2010) Hypoxia, inflammation, and the tumor microenvironment in metastatic disease. Cancer Metastasis Rev 29:285–293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Azam F, Mehta S, Harris AL (2010) Mechanisms of resistance to antiangiogenesis therapy. Eur J Cancer 46:1323–1332

    Article  CAS  PubMed  Google Scholar 

  4. Ferrara N (2010) Pathways mediating VEGF-independent tumor angiogenesis. Cytokine Growth Factor Rev 21:21–26

    Article  CAS  PubMed  Google Scholar 

  5. Carmeliet P (2005) VEGF as a key mediator of angiogenesis in cancer. Int Soc Cell 69(Suppl 3):4–10

    CAS  Google Scholar 

  6. Staller P, Sulitkova J, Lisztwan J, Moch H, Oakeley EJ, Krek W (2003) Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Nature 425:307–311

    Article  CAS  PubMed  Google Scholar 

  7. Schioppa T, Uranchimeg B, Saccani A, Biswas SK, Doni A, Rapisarda A, Bernasconi S, Saccani S, Nebuloni M, Vago L, Mantovani A, Melillo G, Sica A (2003) Regulation of the chemokine receptor CXCR4 by hypoxia. J Exp Med 198:1391–1402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Massague J (2008) TGFbeta in cancer. Cell 134:215–230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F, Inoue M, Bergers G, Hanahan D, Casanovas O (2009) Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15:220–231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS (2009) Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15:232–239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ebos JM, Lee CR, Kerbel RS (2009) Tumor and host-mediated pathways of resistance and disease progression in response to antiangiogenic therapy. Clin Cancer Res 15:5020–5025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ebos JM, Lee CR, Christensen JG, Mutsaers AJ, Kerbel RS (2007) Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy. Proc Natl Acad Sci USA 104:17069–17074

    Article  CAS  PubMed  PubMed Central  Google 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 70:2171–2179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Herbst RS, Heymach JV, O’Reilly MS, Onn A, Ryan AJ (2007) Vandetanib (ZD6474): an orally available receptor tyrosine kinase inhibitor that selectively targets pathways critical for tumor growth and angiogenesis. Expert Opin Investig Drugs 16:239–249

    Article  CAS  PubMed  Google Scholar 

  15. Beaudry P, Nilsson M, Rioth M, Prox D, Poon D, Xu L, Zweidler-Mckay P, Ryan A, Folkman J, Ryeom S, Heymach J (2008) Potent antitumor effects of ZD6474 on neuroblastoma via dual targeting of tumor cells and tumor endothelium. Mol Cancer Ther 7:418–424

    Article  CAS  PubMed  Google 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 28:453–459

    Article  CAS  PubMed  Google Scholar 

  17. Jain RK, Duda DG, Willett CG, Sahani DV, Zhu AX, Loeffler JS, Batchelor TT, Sorensen AG (2009) Biomarkers of response and resistance to antiangiogenic therapy. Nat Rev Clin Oncol 6:327–338

    Article  CAS  PubMed  PubMed Central  Google 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):325–332

    Article  CAS  PubMed  Google 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 28:193–201

    Article  CAS  PubMed  Google 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 15:3600–3609

    Article  CAS  PubMed  Google 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):2012–2021

    Article  Google Scholar 

  22. Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW, Giaccia AJ (1996) Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 379(6560):88–91

    Article  CAS  PubMed  Google Scholar 

  23. Chang Q, Jurisica I, Do T, Hedley DW (2011) Hypoxia predicts aggressive growth and spontaneous metastasis formation from orthotopically grown primary xenografts of human pancreatic cancer. Cancer Res 71(8):3110–3120

    Article  CAS  PubMed  Google Scholar 

  24. Harris AL (2002) Hypoxia-a key regulatory factor in tumour growth. Nat Rev Cancer 2:38–47

    Article  CAS  PubMed  Google Scholar 

  25. Barsoum IB, Koti M, Siemens DR, Graham CH (2014) Mechanisms of hypoxia-mediated immune escape in cancer. Cancer Res 74(24):7185–7190

    Article  CAS  PubMed  Google Scholar 

  26. Sun JD, Ahluwalia D, Liu Q, Ferraro DJ, Wang Y, Jung D, Matteucci MD, Hart CP (2016) Comparison of hypoxia-activated prodrug evofosfamide (TH-302) and ifosfamide in preclinical non-small cell lung cancer models. Cancer Biol Ther 17(4):371–380

    Article  CAS  PubMed  PubMed Central  Google 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

    Article  CAS  PubMed  PubMed Central  Google 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)

    PubMed  PubMed Central  Google 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):438–449

    Article  CAS  PubMed  PubMed Central  Google 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)

    Article  CAS  PubMed  Google 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):50–56

    CAS  Google 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):3299–3306

    Article  CAS  PubMed  PubMed Central  Google 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):1475–1481

    Article  CAS  PubMed  Google 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.

  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; Copenhagen

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Acknowledgements

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.

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Authors and Affiliations

  1. Duke Cancer Institute, Duke University Medical Center, Seeley G. Mudd Building, 10 Bryan Searle Drive, Box 3052, Durham, NC, 27710, USA

    Richard F. Riedel, Kellen L. Meadows, Paula H. Lee, Michael A. Morse, Hope E. Uronis, Gerard C. Blobe, Daniel J. George, Jeffrey Crawford, Christy C. Arrowood & Herbert I. Hurwitz

  2. Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, USA

    Donna Niedzwiecki & Christel N. Rushing

Authors
  1. Richard F. Riedel
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  2. Kellen L. Meadows
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  3. Paula H. Lee
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  4. Michael A. Morse
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  5. Hope E. Uronis
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  6. Gerard C. Blobe
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  8. Jeffrey Crawford
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  9. Donna Niedzwiecki
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  11. Christy C. Arrowood
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  12. Herbert I. Hurwitz
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Corresponding author

Correspondence to Herbert I. Hurwitz.

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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.

Funding source

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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Riedel, R.F., Meadows, K.L., Lee, P.H. et al. Phase I study of pazopanib plus TH-302 in advanced solid tumors. Cancer Chemother Pharmacol 79, 611–619 (2017). https://doi.org/10.1007/s00280-017-3256-2

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  • DOI: https://doi.org/10.1007/s00280-017-3256-2

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