406P - Does dose affect tumour response in phase I oncology trials of non-cytotoxic agents?

Date 10 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Drug Development
Presenter Jaya Ghosh
Citation Annals of Oncology (2016) 27 (6): 114-135. 10.1093/annonc/mdw368
Authors J. Ghosh1, G. Lazaridis2, Z. Viney3, H. Verma3, I. Sheriff4, Y. Wang5, H. Moller6, J.F. Spicer7, D. Sarker7
  • 1Translational Cancer Medicine, King's College London, UK & Tata Memorial Centre, Mumbai, India, WC2R2LS - London/GB
  • 2Medical Oncology, Guy's and St. Thomas' Hospital NHS Trust, SE1 9RT - London/GB
  • 3Radiology, Guy's and St. Thomas' Hospital NHS Trust, SE1 9RT - London/GB
  • 4Gkt School Of Medical Education, Kings College London, London/GB
  • 5Primary Care And Public Health Sciences, Kings College London, London/GB
  • 6Cancer Epidemiology & Poulation Health, Kings College London, London/GB
  • 7Division Of Cancer Studies, King's College London & Guy’s and St Thomas’ NHS Foundation Trust, London/GB

Abstract

Background

Although phase I oncology trials have conventionally used the maximum tolerated dose (MTD) as the recommended dose for phase II studies (RP2D), there is conflicting data on how dose relates to response for non-cytotoxic agents. Also, patients achieving disease stabilisation have differing tumour growth rates (TGR). We retrospectively evaluated tumour response and kinetics at different dose levels in phase 1 trials.

Methods

All patients enrolled in phase I trials of non-cytotoxics in a single UK centre between 2007-2015 were evaluated. Patients were divided into four dose levels (60-80%, >80%) based on the percentage of the dose allocated compared to the maximum administered dose (MAD) on the trial. TGR was measured as the percentage change in tumour volume per unit time.

Results

A total of 151 patients were enrolled in 12 phase I trials (8 molecularly targeted agents, 3 immunotherapy and 1 steroid synthesis inhibitor). Median age was 59 years and 73% had low risk RMH score. There was no statistically significant difference in best response on treatment, progression free survival (PFS) or overall survival (OS) at different dose levels. Increased toxicity resulting in dose reduction or treatment discontinuation was seen at higher doses. However, when responders (complete or partial response, or stable disease) were analysed separately, higher doses were associated with of decreasing TGR, longer median PFS and OS (Table).

- Response, toxicity, progression free and overall survival at different dose levels

%MAD 60-80 n = 33 >80 n = 31
Best Response Complete/Partial Response Stable Disease 14% 27% 12% 48% 24% 30% 23% 16% p = 0.17
TGR at Best Response (Responders) 0% -14% -8% -30% p trend = 0.017
Toxicity Dose Reduction Drug Discontinuation 0 0 5% 15% 21% 9% 16% 13% p = 0.017
Median PFS (weeks) All Patients Responders 9 16 16 20 13 29 9 (p = 0.16) 36 (p = 0.002)
Median OS (weeks) All Patients Responders 27 44 47 54 43 73 32 (p = 0.137) 108 (p = 0.24)

Conclusions

Overall for non-cytotoxic agents there was no significant dose-response relationship but the subgroup of responding patients had longer survival at higher doses. Thus MTD should continue to be the RP2D though there is need for apriori identifying potential responders.

Clinical trial identification

Not Applicable

Legal entity responsible for the study

N/A

Funding

No funding was required as this was a retrospective study

Disclosure

All authors have declared no conflicts of interest.