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Phase IB Trial of the Anti-Cancer Stem Cell DLL4-Binding Agent Demcizumab with Pemetrexed and Carboplatin as First-Line Treatment of Metastatic Non-Squamous NSCLC

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Abstract

Background

Delta-like ligand 4-Notch (DLL4-Notch) signaling contributes to the maintenance of chemotherapy-resistant cancer stem cells and tumor vasculature.

Objective

This phase IB trial of demcizumab, an IgG2 humanized monoclonal antibody directed against DLL4, was undertaken to determine its maximum tolerated dose, safety, immunogenicity, preliminary efficacy, pharmacokinetics, and pharmacodynamics, combined with standard chemotherapy.

Patients and Methods

Forty-six treatment-naive patients with metastatic non-squamous non-small cell lung cancer (NSCLC) were enrolled in this open-label, dose-escalation study using a standard 6 + 6 design. Demcizumab (2.5, 5.0, and 7.5 mg/kg) was given once every 3 weeks with standard doses of pemetrexed and carboplatin using a continuous (six cycles followed by demcizumab maintenance) or a truncated demcizumab regimen (four cycles followed by pemetrexed maintenance).

Results

Initially, continuous demcizumab was given until progression but two patients developed grade 3 pulmonary hypertension and congestive heart failure after eight or more infusions. Thereafter, 23 patients were treated with a truncated regimen of demcizumab, which was not associated with any grade 3 or greater cardiopulmonary toxicity. Common adverse events were hypertension, raised brain natriuretic peptide, and those expected from carboplatin and pemetrexed alone. Twenty of 40 evaluable patients (50%) had objective tumor responses. In peripheral blood, demcizumab treatment modulated the expression of genes regulating Notch signaling and angiogenesis, and achieved concentrations exceeding those saturating DLL4 binding.

Conclusions

This study has identified a truncated dosing regimen and recommended phase II dose of demcizumab (5 mg/kg q3-weekly ×4) for subsequent clinical evaluation in combination with standard carboplatin and pemetrexed chemotherapy. NCT01189968.

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Notes

  1. http://www.oncomed.com/invest/releasedetail.cfm?releaseid=1025195

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Author information

Authors and Affiliations

  1. University of Auckland and Auckland City Hospital, Auckland, New Zealand

    Mark J. McKeage

  2. Department of Pharmacology and Clinical Pharmacology and Auckland Cancer Society Research Centre, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Room 504-236A, 85 Park Road Grafton, Private Bag 92019, Auckland, 1142, New Zealand

    Mark J. McKeage

  3. Adelaide Cancer Centre, Adelaide, Australia

    Dusan Kotasek

  4. Monash Health and Monash University, Melbourne, Australia

    Ben Markman

  5. START, Madrid, Spain

    Manuel Hidalgo

  6. Sir Charles Gairdner Hospital, Perth, Australia

    Michael J. Millward

  7. Waikato Hospital and University of Auckland, Hamilton, New Zealand

    Michael B. Jameson

  8. Christchurch Hospital, Christchurch, New Zealand

    Dean L. Harris

  9. OncoMed, Redwood City, CA, USA

    Robert J. Stagg, Ann M. Kapoun & Lu Xu

  10. Royal Brisbane & Women’s Hospital and University of Queensland, Brisbane, Australia

    Brett G. M. Hughes

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  1. Mark J. McKeage
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Corresponding author

Correspondence to Mark J. McKeage.

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Funding

The study was funded by Oncomed Pharmaceuticals.

Conflict of Interest

AK, LX, and RS disclosed interests related to employment and stock ownership/options in Oncomed. MMcK, DK, BM, MH, MMil, MJ, DH, and BH had no interests to declare other than the funding of the study by Oncomed.

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McKeage, M.J., Kotasek, D., Markman, B. et al. Phase IB Trial of the Anti-Cancer Stem Cell DLL4-Binding Agent Demcizumab with Pemetrexed and Carboplatin as First-Line Treatment of Metastatic Non-Squamous NSCLC. Targ Oncol 13, 89–98 (2018). https://doi.org/10.1007/s11523-017-0543-0

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  • DOI: https://doi.org/10.1007/s11523-017-0543-0

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