Determinants of patient screen failures in Phase 1 clinical trials.

OBJECTIVE: Certain eligibility criteria for Phase 1 cancer clinical trials may impede successful patient enrollment onto a study. We evaluated patient-specific or study-specific reasons for screen failures on Phase 1 oncology clinical trials and discuss factors which may inhibit subject enrollment. METHODS: Thirty-eight Phase 1 clinical trials for solid tumors meeting eligibility criteria and opened for enrollment between February 2006 and February 2011 at one oncology Phase 1 program were examined. Categorical reasons for screen failures and patients' demographics were examined and compared to characteristics of patients that successfully enrolled on a Phase 1 trial. RESULTS: There were a total of 583 successful Phase 1 enrollment and dose administration events out of 773 Phase 1 consent events (75.4 % dose success rate). The three most common reasons for screen failure were: out of protocol-specified range for chemistry, development of an interval medical issue that precluded proceeding with study participation, and subject declining participation after signing consent. Living further away from the Phase 1 program and receipt of fewer prior lines of systemic chemotherapy were significantly associated with increased screen failures. CONCLUSION: Screen failures for Phase 1 studies are not uncommon (24.6 %). When a protocol required tumor or host analyte is not required, most screen failures are due to out of protocol-specified range for chemistry or the development of an interval medical issue. Screen failure rates were increased when patients had longer travel distances and fewer prior lines of systemic chemotherapy.

Examining the effect of teleconferences on oncology phase 1 trials.

OBJECTIVE: Phase 1 clinical trials are the first stage of clinical development of an investigational agent. Because the trials often take place at several geographically dispersed sites, safety teleconferences are held to update investigators and the drug sponsor on safety information and other pertinent business related to the trial conduct. Here we examine associations between the frequency of teleconferences and other clinical trial factors on trial conduct efficiency. METHODS: We examined Phase 1 clinical trials for patients with solid tumors opened for enrollment at a single, non-profit cancer center in Arizona (Center) that had completed at least three dose levels. The following information was included: safety teleconference frequency, whether or not the sponsor or contract research organization sent follow-up requests for updates on patient accrual, and safety outside of scheduled safety teleconferences. The dose escalation scheme, route of study drug administration and formulation type (e.g. oral targeted therapy or monoclonal antibody) was also included. RESULTS: Forty-nine Phase 1 studies were examined for inclusion. The majority of safety teleconferences were regularly scheduled (81.6%) with most taking place bi-weekly (46.9%). Additional solicitation for updates outside of scheduled safety teleconferences were requested during the conduct of 31 (63.3%) studies. None of the factors analyzed were significantly associated with accrual, subject dosing, and dose escalation. CONCLUSION: We found that the frequency of teleconferences does not appear to expedite phase 1 study accrual, subject dosing, or dose escalation in the first 3 cohorts of a phase 1 clinical trial.

Factors influencing time to determination of the recommended phase 2 dose in phase 1 clinical trials.

OBJECTIVE: Cancer clinical trials are the means to develop safe and effective novel treatment options for patients. The longer it takes for these trials to reach the recommended phase 2 dose (RP2D), the fewer therapy options are available to patients and physicians. The purpose of this study is to examine the factors that delay RP2D determination in phase 1 clinical trials. METHODS: Thirty-five consecutive phase 1 clinical trials for advanced solid tumors that started between February 2006 and March 2009 in a single institution were examined for inclusion. Factors potentially contributing to trial delays were analyzed against time to determination of an RP2D (TDR). RESULTS: Thirty-one phase 1 clinical trials met the inclusion criteria and were included in the statistical analysis. Investigational agents under evaluation included single agent cytotoxic (N=4), monoclonal antibody (N=3), single agent cytostatic/targeted (N=16), or combination of an investigational agent and commercially available systemic chemotherapy (N=8). A protocol defined phase 2 dose decreased the TDR (P<0.001). Other factors that significantly increased TDR included a larger minimum estimated patient sample size (P=0.022), a greater number of predefined dose levels (P<0.001), and a higher number of expansion cohorts (P=0.038). CONCLUSIONS: Including a predefined phase 2 dose and reducing the number of dose levels and expansion cohorts may shorten phase 1 trial TDR.

Progression-free Survival Decreases with Each Subsequent Therapy in Patients Presenting for Phase I Clinical Trials.

BACKGROUND: There is often a finite progression-free interval of time between one systemic therapy and the next when treating patients with advanced cancer. While it appears that progression-free survival (PFS) between systemic therapies tends to get shorter for a number of factors, there has not been a formal evaluation of diverse tumor types in an advanced cancer population treated with commercially-available systemic therapies. METHODS: In an attempt to clarify the relationship between PFS between subsequent systemic therapies, we analyzed the records of 165 advanced cancer patients coming to our clinic for consideration for participation in six different phase I clinical trials requiring detailed and extensive past medical treatment history documentation. RESULTS: There were 77 men and 65 women meeting inclusion criteria with a median age at diagnosis of 55.3 years (range 9.4-81.6). The most common cancer types were colorectal (13.9%), other gastrointestinal (11.8%), prostate (11.8%). A median of 3 (range 1-11) systemic therapies were received prior to phase I evaluation. There was a significant decrease in PFS in systemic therapy for advanced disease from treatment 1 to treatment 2 to treatment 3 (p = 0.002), as well as, from treatment 1 through treatment 5 (p < 0.001). CONCLUSIONS: In an advanced cancer population of diverse tumor types, we observe a statistically significant decrease in PFS with each successive standard therapy. Identification of new therapies that reverse this trend of decreasing PFS may lead to improved clinical outcomes.