Abstract A98: Safety, efficacy and efficiency of phase 1 single agent trials using the accelerated titration (ATD) versus modified Fibonacci designs (STD)
Authors: Dancey Janet E. , Espinoza-Delgado Igor , Papaconstantinou Andriana , Saunders Joan , Rubinstein Larry 
Published: June 2012

Abstract
Background: Phase 1 trials of oncology drugs should balance safety, ethics and efficiency; however there is limited consensus on preferred designs for first-in-human studies (FIH).
Methods: We conducted a review of the major oncology journals to identify phase 1 oncology trials using ATD and the standard modified Fibonacci design (STD) published between 2000–08. Trials were limited to FIH, single agent, and patients with solid tumors, and used animal toxicology studies to determine starting dose. Data on agent, class, design, starting dose rationale, dose levels, toxicities and responses were abstracted and compared to determine the efficiency, safety, and response rate of the ATD and STD.
Results: We identified 46 ATD (1270 patients) and 90 SDT (3035 patients) trials published between 2000–8. Fewer patients were treated at low dose levels (mean difference = 6) and overall (mean n = 28 and 34), there was no significant increase in the number of patients treated above the recommended phase 2 dose (RP2D) or in the mean number of treatment related-deaths on trials using the ATD versus STD (1.3% vs. 1%). Between ATD and STD, the mean number of dose levels evaluated was the same; however, the mean fold dose range evaluated was greater with the ATD. The objective response rate (ORR) was significantly higher among evaluable patients on ATD versus STD trials (2.7% vs. 1.7%, p=.02 1-sided). These results suggest a gain in efficiency both by limiting numbers of patients and numbers of dose levels required to establish the RP2D and by improving the number of patients treated at biological active doses. Most ATD trials used designs 3 and 4, which utilize single patient cohorts and 100% dose escalations and 48% of the ATD trials utilized intra-patient dose escalation (IPDE); thus, more patients overall were treated closer to the RP2D. Both ORR and numbers of treatment-deaths were higher in trials using IPDE. Excess treatment-related deaths did not appear to occur for IPDE patients. Total death rates were 1.71% for STD trials and 1.42% for ATD trials (0.94% for trials without IPDE and 1.90% for trials with IPDE) suggesting either an increase in treatment- versus disease-related deaths in IPDE trials or potential bias in attribution. Proportionately more ATD versus STD trials used 1/10th the LD10 from murine models to determine the starting doses, tested agents that could be classified within traditional chemotherapy classes and reported dose-limiting hepatotoxicity and mucositis.
Conclusions: Our results support the safety, efficiency and efficacy of the ATD designs and suggest that the ATD is preferable to the STD. The role of IPDE requires further evaluation.
ATD versus STD Trials ATD STD 1-s. p-value Total Trials (n) 46 (22 with IPDE) 90 Total patients (n) 1270 3035 Mean patients/trial 27.6 33.7 p=.01 Overall response rate among evaluable pts [restricted to IPDE trials in ()] 2.73% 1.69% p=.02 (3.49%) (p=.005) Total treatment-related deaths 17 [1.34%] 30 p=.20 [IPDE trials in ()] (11 [1.75%]) [.99%] (p=.08) Mean dose levels/trial 7.8 7.3 Median dose fold-increase/trial 16.8 12.0 Mean pts &gt; recommended dose 8.2 7.2 Mean doses &gt; recommended dose 1.5 1.3
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A98.