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.
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.
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)|
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
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No funding was required as this was a retrospective study
All authors have declared no conflicts of interest.