Abstract A104: Safety and effectiveness of phase I solid tumor trial designs of molecularly targeted combination therapies
Authors: Soria Jean-Charles , Massard christophe , Paoletti Xavier , Dancey Janet 
Published: June 2012

Abstract
Background: Tumors depend on more than one signaling pathway for their growth and survival. As a consequence, different strategies are developed to inhibit multiple signaling pathways or multiple steps in the same pathway either by the development of multi-targeted agents or the combination of single targeted molecular therapies (MTT). We reviewed the strategies used to conduct phase I trials of MTT combination.
Material and Methods: We systemically reviewed the Journal of Clinical Oncology, Clinical Cancer Research and the ASCO, TAT, AACR-NCI-AACR meeting abstracts for phase 1 MTT published between 2004 and 2009. For each publication, we extracted data on study population, drug class (tyrosine kinase inhibitor, TKI; monoclonal antibody, mAB), primary and secondary endpoints, starting dose (SD), dose escalation methods, determination of maximum administered dose (MAD), dose limiting toxicities (DLT) and recommended phase II dose (RP2D), inclusion of pharmacokinetics (PK), correlative studies, and antitumor activity.
Results: We identified 95 phase 1 MTT trials (11 final reports and 84 abstracts), testing 67 combinations of 48 different drugs. XX trials evaluated two drugs and YY trials evaluated 3 drugs. Trials combined mAB and TKI (n=37), TKI and TKI (n=48), mAB and mAB (n=2) and others (n=9). The most common combinations were with HER (n=51 trials), VEGF-VEGFR (n=51) or mTOR inhibitors (n=29).
The study populations were tumor-site-specific (n=46), advanced solid cancers (n=39), or target-specific (n=10). All trials were designed to identify the RP2D based on DLTs. In most trials (n=62), one drug was given at full dose (100% of its RP2D in n=58 trials). The median SD of the escalated compound was 50% (range=15–100%) of the RP2D. When both drugs were escalated (n=33), the median SDs were 50% (ranges 15–75%) of each drug. The most common trial design was the 3+3 design(n=59). The median numbers of dose levels and patients per trial were 3 (range: 0–8) and 22 (range 2–61) respectively. The MTD was reached in 38 of the completed trials (n=80). The RP2D was clearly reported in 34 trials. On average, first DLTs were observed at the 2nd dose level (range 1–5).
89 trials reported antitumor activity with a median 6 complete responses (CRs) and 3 partial responses (PRs) (range 1–21) per trial. The most common tumor responses were in renal cancer, NSCLC, thyroid or breast cancers. PK data were available in 49 studies, and 9 trials reported PK drug interactions. 32 trials incorporated translational research based on tumor biopsy or functional imaging.
Conclusion: Phase I studies of MTT combination have generally used traditional endpoints for the selection of the R2PD . In general SDs of 100% and 50% or 50% and 50% of single agent RP2D is safe and active. High starting doses limited the number of evaluated dose levels. The details of the dose finding designs were often not assessable from the given material. The high clinical response rates observed in these combination trials is uncommon in phase I of monotherapy therapies, likely reflecting that the individual drugs had established single agent activity in specific disease settings. Few trials have incorporated translational research studies to identify mechanisms of additivity or synergy.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A104.