Investigational New Drugs

, Volume 32, Issue 1, pp 135–144 | Cite as

Safety, pharmacokinetics, and pharmacodynamics of the DR5 antibody LBY135 alone and in combination with capecitabine in patients with advanced solid tumors

  • Sunil SharmaEmail author
  • Elisabeth G. de Vries
  • Jeffrey R. Infante
  • Corina N. Oldenhuis
  • Jourik A. Gietema
  • Lin Yang
  • Sanela Bilic
  • Katie Parker
  • Michael Goldbrunner
  • Jeffrey W. Scott
  • Howard A. BurrisIII


Purpose We evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, biologic activity, and antitumor efficacy of the DR5 antibody, LBY135 ± capecitabine. Experimental design Escalating LBY135 was administered every 21 days, alone (Arm1) or with capecitabine (Arm2), to patients with advanced solid tumors. Results In Arm1 (n = 40), LBY135 (0.3–40 mg/kg) resulted in no dose-limiting toxicities (DLTs); adverse events (AEs) included fatigue, hypotension, abdominal pain, dyspnea, and nausea. Stable disease (SD) was observed in 21/38 (55.3 %) patients. In Arm2 (n = 33), LBY135 (1–40 mg/kg) plus capecitabine resulted in 3 DLTs (each grade 3): dehydration and mucosal inflammation (1 mg/kg), colitis (20 mg/kg), and diarrhea (40 mg/kg). AEs included fatigue, nausea, dyspnea, and vomiting. Partial response was observed in 2 patients (rectal and breast cancer) and SD in 12/27 (44.4 %) patients. Mean elimination half-life of LBY135 ± capecitabine at saturation of clearance (≥10 mg/kg) ranged between 146 h and 492 h. Immunogenicity was detected in 16/73 (22 %) patients, of which 6 patients experienced reduced LBY135 exposure with repeat dosing. M30/M65 levels were not predictive for LBY135 response. FDG-PET responses were not consistently associated with RECIST responses. Conclusions LBY135 was well tolerated up to 40 mg/kg, the maximal dose administered; no MTD for LBY135 ± capecitabine was defined. Clearance was saturated at doses ≥10 mg/kg.


LBY135 Dose escalation Capecitabine DR5 Death receptor TNF-related apoptosis-inducing ligand 



The authors thank Syntaxx Communications, Inc. (Laura Jung and Lisa Holle who provided manuscript development and medical writing services), with the support of Novartis Pharmaceuticals Corporation.


This work was supported by Novartis Pharmaceuticals Corporation, East Hanover, NJ. USA.

Conflicts of interest

LY, SB, KP, MG, and JWS are employees of Novartis Pharmaceuticals Corporation. SB, MG, KP, and JWS own stock in Novartis Pharmaceuticals, the sponsor of this study. SS has received clinical research support and consulting fees from Novartis Pharmaceuticals.


  1. 1.
    Ghobrial IM, Witzig TE, Adjei AA (2005) Targeting apoptosis pathways in cancer therapy. CA Cancer J Clin 55:178–194CrossRefPubMedGoogle Scholar
  2. 2.
    Ashkenazi A (2002) Targeting death and decoy receptors or the tumour-necrosis factor superfamily. Nat Rev Cancer 2:420–430CrossRefPubMedGoogle Scholar
  3. 3.
    Pan G, O’Rourke K, Chinnaiyan AM, Gentz R, Ebner R, Ni J, Dixit VM (1997) The receptor for the cytotoxic ligand TRAIL. Science 276:111–113CrossRefPubMedGoogle Scholar
  4. 4.
    Almasan A, Ashkenazi A (2003) Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy. Cytokine Growth Factor Rev 14:337–348CrossRefPubMedGoogle Scholar
  5. 5.
    Baetu TM, Hiscott J (2002) On the TRAIL to apoptosis. Cytokine Growth Factor Rev 13:199–207CrossRefPubMedGoogle Scholar
  6. 6.
    Duiker EW, Mom CH, de Jong S, Willemse PH, Gietema JA, van der Zee AG, de Vries EG (2006) The clinical trail of TRAIL. Eur J Cancer 42:2233–2240Google Scholar
  7. 7.
    Walczak H, Miller RE, Ariail K, Gliniak B, Griffith TS, Kubin M et al (1999) Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat Med 5:157–163CrossRefPubMedGoogle Scholar
  8. 8.
    Roth W, Isenmann S, Naumann U, Kügler S, Bähr M, Dichgans J, Ashkenazi A, Weller M (1999) Locoregional Apo2L/TRAIL eradicates intracranial human malignant glioma xenografts in athymic mice in the absence of neurotoxicity. Biochem Biophys Res Commun 265:479–483CrossRefPubMedGoogle Scholar
  9. 9.
    Mitsiades CS, Treon SP, Mitsiades N, Shima Y, Richardson P, Schlossman R, Hideshima T, Anderson KC (2001) TRAIL/Apo2L ligand selectively induces apoptosis and overcomes drug resistance in multiple myeloma: therapeutic applications. Blood 98:795–804CrossRefPubMedGoogle Scholar
  10. 10.
    Kelley SK, Harris LA, Xie D, Deforge L, Totpal K, Bussiere J, Fox JA (2001) Preclinical studies to predict the disposition of Apo2L/tumor necrosis factor-related apoptosis-inducing ligand in humans: characterization of in vivo efficacy, pharmacokinetics, and safety. J Pharmacol Exp Ther 299:31–38PubMedGoogle Scholar
  11. 11.
    Kruyt FA (2008) TRAIL and cancer therapy. Cancer Lett 263:14–25CrossRefPubMedGoogle Scholar
  12. 12.
    Greco FA, Bonomi P, Crawford J, Kelly K, Oh Y, Halpern W, Lo L, Gallant G, Klein J (2008) Phase 2 study of mapatumumab, a fully human agonistic monoclonal antibody which targets and activates the TRAIL receptor-1, in patients with advanced non-small cell lung cancer. Lung Cancer 61:82–90CrossRefPubMedGoogle Scholar
  13. 13.
    Trarbach T, Moehler M, Heinemann V, Köhne CH, Przyborek M, Schulz C, Sneller V, Gallant G, Kanzler S (2010) Phase II trial of mapatumumab, a fully human agonistic monoclonal antibody that targets and activates the tumour necrosis factor apoptosis-inducing ligand receptor-1 (TRAIL-R1), in patients with refractory colorectal cancer. Br J Cancer 102:506–512PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Wakelee HA, Patnaik A, Sikic BI, Mita M, Fox NL, Miceli R, Ullrich SJ, Fisher GA, Tolcher AW (2010) Phase I and pharmacokinetic study of lexatumumab (HGS-ETR2) given every 2 weeks in patients with advanced solid tumors. Ann Oncol 21:376–381PubMedCentralCrossRefPubMedGoogle Scholar
  15. 15.
    Babb J, Rogatko A, Zacks S (1998) Cancer phase I clinical trials: efficient dose escalation with overdose control. Stat Med 17:1103–1120CrossRefPubMedGoogle Scholar
  16. 16.
    Thall PF, Millikan RE, Mueller P, Lee SJ (2003) Dose-finding with two agents in phase I oncology trials. Biometrics 59:487–496CrossRefPubMedGoogle Scholar
  17. 17.
    Evans TRJ, Pentheroudakis G, Paul J, McInnes A, Blackie R, Raby N, Morrison R, Fullarton GM, Soukop M, McDonald AC (2002) A phase I and pharmacokinetic study of capecitabine in combination with epirubicin and cisplatin in patients with inoperable oesophago-gastric adenocarcinoma. Ann Oncol 13:1469–1478CrossRefPubMedGoogle Scholar
  18. 18.
    Demetri GD, Le Cesne A, Chawla SP, Brodowicz T, Maki RG, Bach BA, Smethurst DP, Bray S, Hei YJ, Blay JY (2012) First-line treatment of metastatic or locally advanced unresectable soft tissue sarcomas with conatumumab in combination with doxorubicin or doxorubicin alone: a phase I/II open-label and double-blind study. Eur J Cancer 48:547–563CrossRefPubMedGoogle Scholar
  19. 19.
    Leong S, Cohen RB, Gustafson DL, Langer CJ, Camidge DR, Padavic K, Gore L, Smith M, Chow LQ, von Mehren M, O’Bryant C, Hariharan S, Diab S, Fox NL, Miceli R, Eckhardt SG (2009) Mapatumumab, an antibody targeting TRAIL-R1, in combination with paclitaxel and carboplatin in patients with advanced solid malignancies: results of a phase I and pharmacokinetic study. J Clin Oncol 27:4413–4421CrossRefPubMedGoogle Scholar
  20. 20.
    Fox NL, Humphreys R, Luster TA, Klein J, Gallant G (2010) Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-1 and receptor-2 agonists for cancer therapy. Expert Opin Biol Ther 10:1–18CrossRefPubMedGoogle Scholar
  21. 21.
    Demiray M, Ulukaya EE, Arslan M, Gokgoz S, Saraydaroglu O, Ercan I, Evrensel T, Manavoglu O (2006) Response to neoadjuvant chemotherapy in breast cancer could be predictable by measuring a novel serum apoptosis product, caspase-cleaved cytokeratin 18: a prospective pilot study. Cancer Invest 24:669–676CrossRefPubMedGoogle Scholar
  22. 22.
    Olofsson MH, Ueno T, Pan Y, Xu R, Cai F, van der Kuip H et al (2007) Cytokeratin-18 is useful serum biomarker for early determination of response of breast carcinomas to chemotherapy. Clin Cancer Res 13:3198–3206CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Sunil Sharma
    • 1
    Email author
  • Elisabeth G. de Vries
    • 2
  • Jeffrey R. Infante
    • 3
  • Corina N. Oldenhuis
    • 2
  • Jourik A. Gietema
    • 2
  • Lin Yang
    • 4
  • Sanela Bilic
    • 4
  • Katie Parker
    • 4
  • Michael Goldbrunner
    • 4
  • Jeffrey W. Scott
    • 4
  • Howard A. BurrisIII
    • 3
  1. 1.Huntsman Cancer Institute, Division of Medical OncologyUniversity of UtahSalt Lake CityUSA
  2. 2.University Medical Center GroningenGroningenThe Netherlands
  3. 3.Sarah Cannon Research Institute/ Tennessee OncologyPLLC (Drug Development Unit)NashvilleUSA
  4. 4.Novartis Pharmaceuticals CorporationEast HanoverUSA

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