A Study of Combination of Gemcitabine, Oxaliplatin (GEMOX)-Sorafenib in Patients With Advanced Biliary Tract Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of Combination of Gemcitabine, Oxaliplatin (GEMOX)-Sorafenib in Patients With Advanced Biliary Tract Cancer (NCT00955721), a non-randomized phase 1, phase 2 study. The primary outcome is Phase I: Recommended Phase II Dose (RPTD) of the Combination of Sorafenib and GEMOX in Patients With Advanced Biliary Tract Cancer (BTC)..

2. Clinical Question

3. Trial Design

This was a Phase I/II, non-randomized, parallel study with no masking. It was sponsored by the University of Miami. The registry lists a start date of 2009-08 and primary completion in 2014-07; the study status is terminated. Enrollment was 9, and the outcome description specifies that all 9 enrolled participants were in Phase I, of whom 6 were evaluable and analyzed for the primary outcome.

The Phase I component was intended as a safety run-in and dose-escalation stage. Its purpose was to identify a recommended Phase II dose (RPTD) for sorafenib combined with gemcitabine and oxaliplatin. Treatment descriptions specify gemcitabine and oxaliplatin dose options in Phase I and describe treatment in 14-day cycles. The sorafenib dose is not reported in the registry record. The Phase II arm was intended to use the dose determined in Phase I.

The study summary describes a plan to enroll 40 participants at the RPTD level within 2 years and to estimate progression-free survival. That planned Phase II evaluation is distinct from the trial's recorded enrollment: the registry lists no participants in the Phase II arm. The Phase I outcome description says dose escalation remained in progress when the study was terminated, so an RPTD could not be determined.

The registry also lists planned secondary aims: estimating overall response and clinical benefit rates, estimating overall survival, further evaluating safety, and exploring biomarkers of response. Results for those aims are not reported in the registry record. Because the trial was non-randomized and has no control arm, it cannot provide a randomized comparison of the combination against another treatment.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: A total of 9 participants were enrolled in Phase 1 of which 6 were evaluable and analyzed for this outcome measure. A recommended phase two dose (RPTD) of the combination of Sorafenib and GEMOX therapy could not be determined because dose escalation was still in progress when the study was terminated.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Phase I: Recommended Phase II Dose (RPTD) of the Combination of Sorafenib and GEMOX in Patients With Advanced Biliary Tract Cancer (BTC)., measured over First two 14-day Phase I cycles.

The registry's primary outcome is the recommended Phase II dose of sorafenib with GEMOX, expressed as a dose in mg over the first two 14-day Phase I cycles. This is a dose-finding endpoint, not a measure of tumor response or survival. In an early-phase study, a dose-finding endpoint is used to guide the dose selected for later evaluation, with safety and tolerability informing whether a dose can be taken forward.

The record says that 9 participants enrolled in Phase I and 6 were evaluable and analyzed for this outcome. It also states that an RPTD could not be determined because dose escalation was still in progress when the study was terminated. Thus, the primary outcome does not yield a selected Phase II dose in the registry results.

The study summary describes progression-free survival as the planned primary endpoint for the later Phase II component. The primary outcome measure recorded in the results, however, is the Phase I dose determination. No Phase II participants are listed, and Phase II progression-free survival results are not reported in the registry record. The distinction matters: a stated future endpoint is not an observed result, and the dose-finding result cannot be read as an estimate of clinical benefit.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does dose finding mean?

General statistical explanation: Early-phase dose finding seeks a dose or dose range that can be taken forward for further study while monitoring safety and tolerability. It is not the same inferential task as testing whether a treatment improves an outcome compared with a control. The registry identifies dose determination as the primary Phase I outcome and specifies the first two 14-day cycles as its timeframe. It does not report the dose-escalation rules, decision thresholds, or statistical model used to select a dose. Those details are not reported in the registry record.

The dose-finding result is incomplete: the record says that dose escalation remained in progress at termination, so a recommended Phase II dose could not be determined. This is not evidence that a particular dose was selected, nor does it show that a dose was found unacceptable. It means the registry does not report a completed dose recommendation.

What can a confidence interval tell a reader?

General statistical explanation: A confidence interval describes uncertainty around an estimate under the assumptions of the analysis. A narrow interval indicates greater precision than a wide interval, while an interval that spans many plausible values may leave substantial uncertainty. The registry record contains no reported efficacy estimates or confidence intervals for this trial. Consequently, there is no interval-based precision assessment for progression-free survival, response, or another treatment-effect outcome.

The absence of a confidence interval is especially important when an estimate might otherwise be interpreted as conclusive. A point estimate alone can conceal substantial uncertainty; without an estimate and its uncertainty, the magnitude and precision of an effect cannot be judged. No such treatment-effect estimate is reported for this study.

Why does the non-randomized design matter?

General statistical explanation: Random allocation helps make groups comparable, on average, with respect to measured and unmeasured factors at baseline. A non-randomized design does not provide that protection. Differences between groups, if they exist, can reflect who entered each group, differences in care, disease characteristics, or other factors as well as treatment. Here, the registry records non-randomized allocation and no masking. It does not describe a randomized comparator; the two listed arms represent Phase I and planned Phase II stages of the combination.

As a result, this record does not support a like-for-like causal comparison between GEMOX-sorafenib and another treatment. Further, no participants are listed in Phase II, so the two stages do not form populated groups that could be compared. The absence of a comparator is not repaired by descriptive counts from Phase I.

How should the sample-size illustrations be understood?

General statistical explanation: A sample-size calculation asks how much information a future study might need under stated assumptions, including the effect it is intended to detect, the significance level, allocation, and statistical method. Such calculations are planning illustrations. They are not observed outcomes and do not indicate the probability that the trial actually found an effect.

The registry's sample-size assumptions describe a two-sided significance level of 0.05, equal allocation, and a normal approximation, with calculations based on fractions of an observed effect. For time-to-event outcomes, the stated illustrations concern total events; for other outcomes, they concern participants per arm. Those assumptions do not establish the study's original design rationale. The registry's own sample-size justification is not reported in the registry record. Because no treatment-effect analyses are listed and the Phase II arm has no participants, the illustrations should not be interpreted as observed power or evidence that the trial was adequately sized for its planned endpoint.

Why can over-dispersion matter?

General statistical explanation: For count outcomes, a statistical model may assume a particular relationship between the average count and its variability. Over-dispersion occurs when observed variability exceeds what a simpler model assumes. If it is ignored, standard errors can be too small and confidence intervals or tests can appear more certain than warranted. The registry's primary outcome is a dose determination rather than a reported count comparison, and it does not provide a count-outcome analysis or model details. Whether over-dispersion is relevant to any analysis in this trial is not reported in the registry record.

What analyses are available?

The registry lists 6 outcome measures and 0 analyses. It does not report an analysis plan, interim analyses, adjustment methods, or inferential results. The statistical methods used for any analysis beyond the brief outcome descriptions are not reported in the registry record. Without those details, readers cannot assess whether analyses followed a prespecified plan or how uncertainty and multiple outcomes were handled.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists multiple planned outcomes, including Phase I dose determination and Phase II objectives involving response, clinical benefit, overall survival, safety, and biomarkers. It does not report a statistical analysis plan describing which outcomes were confirmatory, how hypotheses were ordered, or whether any adjustment for multiple testing was planned. Multiplicity methods are not reported in the registry record. General statistical explanation: When many outcomes or hypotheses are examined, the chance of at least one apparently unusual result can increase; a prespecified approach helps readers understand how that risk was handled.

The record lists 0 analyses. It does not report hypothesis tests, effect estimates, confidence intervals, or interim analyses. Whether interim monitoring or any stopping rules were prespecified is not reported in the registry record. The record does state that dose escalation remained in progress when the study was terminated, but it does not provide a statistical stopping rationale.

For the primary outcome, 9 participants enrolled in Phase I and 6 were evaluable and analyzed. Reasons for the difference between enrolled and evaluable populations, the handling of participants without evaluable dose information, and any missing-data methods are not reported in the registry record. The analysis population for the secondary outcomes is also not reported in the registry record. The Phase II arm lists 0 participants, so the planned Phase II outcomes have no recorded enrolled population from which to calculate results.

These omissions limit assessment of selection, missingness, and analysis choices. They do not establish that missing data or multiplicity were mishandled; they mean the registry does not report enough information to evaluate those issues.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: dehydration (22.2%), peritoneal infection (11.1%), diarrhea (11.1%), dizziness (11.1%), dyspnea (11.1%).

The registry reports Phase I safety counts for 9 participants at risk: 3 affected by serious adverse events, 8 affected by other adverse events, and 4 deaths. The Phase II arm lists 0 participants at risk and 0 affected. These are descriptive registry counts, not comparisons with another treatment group.

The serious-event terms listed include dehydration (22.2%), peritoneal infection (11.1%), diarrhea (11.1%), dizziness (11.1%), dyspnea (11.1%), and fever (11.1%). The registry presents these as terms associated with serious adverse events; the percentages should not be added together to infer a total, since the record does not clarify whether participants could have multiple terms. Nor do the figures establish that the study drugs caused an event. Attribution details, event-level timing, and the basis for judging relatedness are not reported in the registry record.

These figures should be interpreted in the context of the small Phase I group and the absence of a randomized comparator. The counts describe reported safety experience in the enrolled Phase I participants, but they cannot estimate how those events compare with another treatment or with the underlying risk in a comparable population.

12. What the Result Does, and Does Not, Mean

The result has a clear but narrow meaning: the registry does not record a recommended Phase II dose for GEMOX with sorafenib. It reports that dose escalation was still in progress when the study was terminated. Phase I enrolled 9 participants, and 6 were evaluable for the primary dose-determination outcome.

This does not establish whether the combination is effective or ineffective. The primary outcome is a dose-finding result, not a treatment-effect estimate. The planned Phase II progression-free survival endpoint has no recorded Phase II participants, and no survival or response results are reported in the registry record. Likewise, the safety counts are descriptive and do not show that an adverse event was caused by the treatment.

The non-randomized design also matters. There is no like-for-like control comparison, and the registry does not report a comparator arm receiving a different treatment. Therefore the record cannot isolate a treatment effect from other explanations. The Phase I and Phase II arms should not be interpreted as comparative treatment groups: Phase II has no participants recorded.

Nor does termination by itself identify why the study stopped or whether the combination could be used at a particular dose. The record explains that the RPTD was not determined because escalation was ongoing at termination, but does not report a more detailed reason for termination or a completed dose-selection decision. The evidence in the record is thus limited to the study's design, enrollment, incomplete dose-finding outcome, and descriptive safety counts.

13. Why This Trial Matters Statistically

This trial illustrates how the intended question can change across phases. The Phase I objective was to establish a recommended dose for a three-drug combination; the planned Phase II objective was to estimate progression-free survival at the dose selected in Phase I. Those objectives require different interpretations. A dose-finding outcome is not an efficacy endpoint, and an intended Phase II endpoint is not an observed estimate when no Phase II participants are recorded.

It also shows why enrollment and analysis populations need to be read together. The record reports 9 Phase I enrollees and 6 evaluable participants for the primary outcome. Without information on why some participants were not evaluable or how their data were handled, the reach of the primary result cannot be fully assessed. The registry does not report a completed dose recommendation, so even the early-phase objective remains unresolved.

The non-randomized design makes clear the difference between observing events and estimating comparative effects. Safety counts can describe what was recorded among enrolled participants, but without a control group they cannot establish comparative risk or attribution. In the same way, a sample-size planning illustration cannot stand in for outcome data or demonstrate observed power.

For clinical researchers and statisticians, the record is a useful reminder to distinguish planned outcomes from completed analyses, and descriptive safety reporting from causal evidence. It also highlights the value of reporting dose-escalation rules, analysis populations, missing-data handling, and reasons for study termination. Those details are not reported in the registry record, so interpretation remains constrained to the documented enrollment and outcome status.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The main trial-specific limitation is that the primary Phase I dose-finding objective was not completed: the registry reports that dose escalation was ongoing at termination and an RPTD could not be determined. This leaves no selected dose to carry into the planned Phase II evaluation. Although the study summary describes a Phase II plan to enroll 40 participants and estimate progression-free survival, no Phase II participants are recorded, and Phase II results are not reported in the registry record.

Phase I enrollment was 9, and 6 participants were evaluable for the primary outcome. The reasons for non-evaluability and the handling of participants who were not analyzed are not reported in the registry record. The registry does not report an analysis plan, the specific dose-escalation method, decision criteria, interim analyses, or statistical stopping rules. A detailed explanation for termination is not reported in the registry record.

The non-randomized design and absence of a populated comparator group preclude a direct treatment comparison. No masking was used. The registry's safety counts are descriptive, and attribution of adverse events to treatment is not established by those counts. Further information on event timing, severity definitions, and relatedness is not reported in the registry record.

Finally, the record lists no analyses and does not report effect estimates, confidence intervals, hypothesis tests, missing-data methods, or multiplicity procedures. The sorafenib dose is not reported in the registry record. These gaps limit both statistical appraisal and interpretation of the treatment regimen, without implying that unreported procedures were or were not performed.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study of Combination of Gemcitabine, Oxaliplatin (GEMOX)-Sorafenib in Patients With Advanced Biliary Tract Cancer — NCT00955721.
• Registry record last updated 2018-01-03; status last verified 2017-12.
• Results first posted 2015-02-13.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

NCT00955721 is a University of Miami-sponsored, non-randomized, unmasked Phase I/II study of gemcitabine, oxaliplatin, and sorafenib in advanced biliary tract cancer. The registry lists a start date of 2009-08, primary completion in 2014-07, terminated status, and enrollment of 9.

All 9 enrolled participants were in Phase I; 6 were evaluable for the primary outcome, which was to establish a recommended Phase II dose. The record says no dose was determined because escalation was still in progress at termination. The planned Phase II arm has no participants recorded. The registry lists 0 analyses, and efficacy results are not reported in the registry record.

Phase I safety reporting lists 3 participants affected by serious adverse events, 8 affected by other adverse events, and 4 deaths among 9 at risk. These descriptive counts do not establish treatment causation or provide a randomized comparison.