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
Mark J McKeage1, Dusan Kotasek2, Ben Markman3, Manuel Hidalgo4, Michael J Millward5, Michael B Jameson6, Dean L Harris7, Robert J Stagg8, Ann M Kapoun8, Lu Xu8, Brett GM Hughes9
1University of Auckland and Auckland City Hospital, Auckland, New Zealand; 2Adelaide Cancer Centre, Adelaide, Australia; 3Monash Health and Monash University, Melbourne, Australia; 4START, Madrid, Spain; 5Sir Charles Gairdner Hospital, Perth, Australia; 6Waikato Hospital and University of Auckland, Hamilton, New Zealand; 7Christchurch Hospital, Christchurch New Zealand; 8OncoMed, Redwood City, CA; & 9Royal Brisbane & Women’s Hospital and University of Queensland, Brisbane, Australia.
Supplementary materials
Supplementary Figure 1 Survival outcomes of patients treated with the truncated regimen
Supplementary Figure 2 Demcizumab Pharmacokinetics
Supplementary Table 1 Safety analysis
Supplementary Table 2 Treatment-emergent cardiac, pulmonary and vascular adverse events reported of grade 3 or greater severity
Supplementary Figure 1 Survival outcomes of patients treated with the truncated regimen
A total of 23 patients were included in an exploratory analysis of survival outcomes from the truncated regimen, including all patients from cohorts 5, 6 and 7 (n=20) plus 3 patients from cohort 4, who were on treatment at the time of the protocol amendment from the continuous to truncated regimen and were treated accordingly. Median progression-free survival was 5.8 months (95% CI 3.3-14.8 months). Median overall survival was 11.5 months (95% CI 5.8-NR months).
Supplementary Figure 2 Demcizumab Pharmacokinetics
Symbols: Observed patient concentration data in presence of carboplatin and pemetrexed, by nominal time; Line: simulated concentration-time profile with pharmacokinetic model constructed based on single agent phase 1a data
Supplementary Table 1 Safety analysis.
Continuous regimen / Truncated regimen / TotalCohort / 1 / 2 / 3 / 4 / 5 / 6 / 7
Demcizumab dose level / 5 / 2.5 / 5 / 5 / subtotal / 7.5 / 5 / 5 / subtotal / n / %
Number of patients / 6 / 6 / 8 / 6 / 26 / 6 / 7 / 7 / 20 / 46 / 100
One or more adverse event / 6 / 6 / 8 / 6 / 26 / 6 / 7 / 7 / 20 / 46 / 100
Related adverse events / 6 / 6 / 8 / 6 / 26 / 4 / 6 / 6 / 16 / 42 / 91
Serious adverse events / 1 / 3 / 4 / 4 / 12 / 6 / 2 / 2 / 10 / 22 / 48
Related serious adverse events / 1 / 3 / 3 / 0 / 7 / 0 / 0 / 0 / 0 / 7 / 15
Grade 3 or more adverse events / 5 / 6 / 6 / 6 / 23 / 6 / 7 / 6 / 19 / 42 / 91
Grade 5 adverse events / 0 / 1 / 1 / 1 / 3 / 1 / 0 / 0 / 1 / 4 / 9
Supplementary Table 2 Treatment-emergent cardiac, pulmonary and vascular adverse events reported of grade 3 or greater severity
Continuous regimen (n=26) / Truncated regimen (n=20)n / % / n / %
Hypertension / 7 / 27 / 6 / 30
Chest pain / 2 / 8 / 2 / 10
Pulmonary Embolism / 1 / 4 / 3 / 15
Respiratory infection / 2 / 8 / 2 / 10
Pleural effusion / 1 / 4 / 2 / 10
BNP increase / 2 / 8 / 0 / 0
Cerebrovascular accident / 2 / 8 / 0 / 0
Chronic obstructive pulmonary disease / 2 / 8 / 0 / 0
Pulmonary Hypertension / 2 / 8 / 0 / 0
Aspiration / 1 / 4 / 0 / 0
Atrial fibrillation / 1 / 4 / 0 / 0
Congestive heart failure / 1 / 4 / 0 / 0
Cough / 1 / 4 / 0 / 0
Dyspnoea / 1 / 4 / 0 / 0
Embolism arterial / 0 / 0 / 1 / 5
Hypotension / 0 / 0 / 1 / 5
Intra-cardiac thrombosis / 1 / 4 / 0 / 0
Right ventricular tachycardia / 1 / 4 / 0 / 0
Supraventricular tachycardia / 0 / 0 / 1 / 5
Thrombosis / 1 / 4 / 0 / 0
Troponin increase / 1 / 4 / 0 / 0