AUTHOR=Paller Channing J. , Huang Erich P. , Luechtefeld Thomas , Massett Holly A. , Williams Christopher C. , Zhao Jinxiu , Gravell Amy E. , Tamashiro Tami , Reeves Steven A. , Rosner Gary L. , Carducci Michael A. , Rubinstein Lawrence , Ivy S. Percy TITLE=Factors Affecting Combination Trial Success (FACTS): Investigator Survey Results on Early-Phase Combination Trials JOURNAL=Frontiers in Medicine VOLUME=6 YEAR=2019 URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2019.00122 DOI=10.3389/fmed.2019.00122 ISSN=2296-858X ABSTRACT=

Experimental therapeutic oncology agents are often combined to circumvent tumor resistance to individual agents. However, most combination trials fail to demonstrate sufficient safety and efficacy to advance to a later phase. This study collected survey data on phase 1 combination therapy trials identified from ClinicalTrials.gov between January 1, 2003 and November 30, 2017 to assess trial design and the progress of combinations toward regulatory approval. Online surveys (N = 289, 23 questions total) were emailed to Principal Investigators (PIs) of early-phase National Cancer Institute and/or industry trials; 263 emails (91%) were received and 113 surveys completed (43%). Among phase 1 combination trials, 24.9% (95%CI: 15.3%, 34.4%) progressed to phase 2 or further; 18.7% (95%CI: 5.90%, 31.4%) progressed to phase 3 or regulatory approval; and 12.4% (95%CI: 0.00%, 25.5%) achieved regulatory approval. Observations of “clinical promise” in phase 1 combination studies were associated with higher rates of advancement past each milestone toward regulatory approval (cumulative OR = 11.9; p = 0.0002). Phase 1 combination study designs were concordant with Clinical Trial Design Task Force (CTD-TF) Recommendations 79.6% of the time (95%CI: 72.2%, 87.1%). Most discordances occurred where no plausible pharmacokinetic or pharmacodynamic interactions were expected. Investigator-defined “clinical promise” of a combination is associated with progress toward regulatory approval. Although concordance between study designs of phase 1 combination trials and CTD-TF Recommendations was relatively high, it may be beneficial to raise awareness about the best study design to use when no plausible pharmacokinetic or pharmacodynamic interactions are expected.