Factors Affecting Combination Trial Success (FACTS): Investigator Survey Results on Early-Phase Combination Trials.

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.

The Current Understanding of the Endocrine Effects From Immune Checkpoint Inhibitors and Recommendations for Management.

Clinical trials in the past decade have established the antitumor effects of immune checkpoint inhibition as a revolutionary treatment for cancer. Namely, blocking antibodies to cytotoxic T-lymphocyte antigen 4 and programmed death 1 or its ligand have reached routine clinical use. Manipulation of the immune system is not without side effects, and autoimmune toxicities often known as immune-related adverse events (IRAEs) are observed. Endocrine IRAEs, such as hypophysitis, thyroid dysfunction, and insulin-dependent diabetes mellitus, can present with unique profiles that are not seen with the use of traditional chemotherapeutics. In this Review, we discuss the current hypotheses regarding the mechanism of these endocrinopathies and their clinical presentations. Further, we suggest guidelines and algorithms for patient management and future clinical trials to optimize the detection and treatment of immune checkpoint-related endocrinopathies.

Challenges and Opportunities in Adapting Clinical Trial Design for Immunotherapies.

Immunotherapy adds an exciting new dimension to the treatment of cancer, joining other approaches as a key pillar in the oncotherapeutics armamentarium. Immuno-oncology agents harbor unique mechanisms of antitumor activity by leveraging the host immune system, which may result in response patterns, resistance kinetics, and toxicity profiles that differ from other systemic therapies. These features have led to many discussions on ways to optimally integrate immunotherapy into cancer clinical trials. This overview provides an introduction to the four CCR Focus articles that ensue, with special thoughts paid to clinical trial endpoints, biomarker development and validation, combination strategies, and limitations that arise with increasing use of these agents. In addition, this overview examines design concepts that may be applied to invigorate clinical trials and to maximize their impact in the immuno-oncology era.