A Phase II Study of GSK1363089 (Formerly XL880) for Papillary Renal-Cell Carcinoma (PRC): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Phase II Study of GSK1363089 (Formerly XL880) for Papillary Renal-Cell Carcinoma (PRC) (NCT00726323), a non-randomized phase 2 study. The primary outcome is Overall Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Criteria Version 1.0.

2. Clinical Question

The study was conducted at multiple sites to assess best confirmed response rate, safety, and tolerability. The registry record accepted participants with either hereditary or sporadic papillary renal-cell carcinoma. Its primary endpoint description refers to the safety population, rather than to a separately named efficacy population.

Other listed outcomes include disease stabilization, progression-free survival, time to response, duration of response, duration of stable disease, overall survival, and changes in clinical chemistry and hematological parameters by CTCAE grade. The record lists 10 outcome measures, but does not report analysis results for them. Consequently, the stated clinical question can be described from the planned measures, but its answer cannot be recovered from the registry record's posted results.

3. Trial Design

This was a Phase II study with a parallel, non-randomized design and no masking. The registry lists 74 enrolled participants and two dosing regimens: intermittent 240 mg foretinib on a 5 day on / 9 day off schedule every 14 days, and 80 mg foretinib daily. The registry record does not describe randomized assignment, so the groups are not a like-for-like control comparison. Differences between their outcomes, if reported, could reflect differences in who entered each regimen as well as differences in dosing.

The study is listed as completed. Its recorded start date is 2006-06-30, and its primary completion date is 2010-08-18. GlaxoSmithKline is named as sponsor. The brief description states that the study took place at multiple sites and sought to assess confirmed response, safety, and tolerability in papillary renal-cell carcinoma.

The primary endpoint was a percentage based on best overall response, with a confirmed complete or partial response counted as a response. The record specifies investigator assessment of target and non-target lesions using RECIST Version 1.0. It gives the endpoint timeframe as “At the end of forth year.” The registry record does not provide further detail to clarify that wording or explain how assessments were scheduled.

The primary endpoint population is described as all participants who passed screening, enrolled, and received at least one dose. Although this is called the safety population in the record, it is also the population named for the primary endpoint. Whether every enrolled participant received treatment, and how participants with missing or unevaluable response assessments were handled, is not reported in the registry record.

The record lists secondary outcome topics, including time-to-event outcomes and laboratory safety measures. It does not report numerical results or analysis details for those outcomes. Further information about allocation procedures, regimen selection, protocol amendments, site-level conduct, and the statistical plan is not reported in the registry record.

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.

Before assignment: A total of 74 participants with PRC were enrolled in the study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Safety population included all participants who passed the screening criteria, were enrolled in the study and received at least one dose of the study drug.

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.

Population: The Safety population included all participants who passed the screening criteria, were enrolled in the study and received at least one dose of the study drug.

6. Primary Endpoint

The registry lists the primary outcome as Overall Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Criteria Version 1.0, measured over At the end of forth year.

The primary endpoint is the overall response rate, expressed as the percentage of participants whose best overall response was a confirmed partial response or confirmed complete response. In this study, response classification was based on investigator assessment of target and non-target lesions under RECIST Version 1.0. The endpoint description specifies confirmation, so an initial response alone would not meet the stated definition unless it was confirmed.

General: A response-rate endpoint reduces a participant's observed tumor-response history to a category for a defined period of assessment. The percentage communicates how common the defined response category was in the population being analyzed. It does not, on its own, describe how long a response lasted, whether disease remained stable, or what happened after progression. Those are distinct questions, reflected in the separately listed duration of response, duration of stable disease, progression-free survival, and overall survival outcomes.

The registry gives the timeframe as “At the end of forth year” and names the safety population as the endpoint population. It also specifies a 95% confidence interval as the dispersion measure. However, neither the percentage nor its confidence interval is reported in the registry record. The record therefore identifies what the endpoint was intended to measure, but does not permit an estimate of the observed response frequency or its precision.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the response percentage represent?

The primary measure is a binary response outcome at the participant level: the best overall response either met the confirmed complete or partial response definition, or it did not. The overall response rate expresses the number of participants meeting that definition as a percentage of the endpoint population. The registry defines that population as participants who passed screening, enrolled, and received at least one dose. The actual count meeting the definition, the percentage, and the confidence interval are not reported in the registry record.

General: Turning a clinical assessment into a binary endpoint makes the outcome straightforward to summarize, but it discards detail. A participant classified as a responder and a participant who did not respond can have different assessment histories that are not conveyed by that single category. The endpoint also does not encode response duration. That is why response rate is conceptually distinct from the separately listed duration of response, duration of stable disease, and time-to-event outcomes.

Why specify confirmation and response criteria?

The registry defines response as a confirmed complete or partial response using RECIST Version 1.0, with investigator assessment of target and non-target lesions. Confirmation is part of the endpoint definition, not an optional interpretation of the result. Standardized criteria can make response categories more reproducible by specifying how lesion assessments map to response classifications. The record does not provide additional operational details about assessment timing, confirmation intervals, independent review, or handling of unevaluable assessments.

How should a confidence interval be understood?

The endpoint names a 95% confidence interval as its measure of dispersion, but no interval is posted. General: A confidence interval is a range calculated from data under a statistical procedure. It conveys uncertainty around an estimate; it is not a guarantee that the true value lies in the particular reported interval, nor does it address every source of uncertainty. Its interpretation depends on the analysis population, endpoint definition, data completeness, and method used. Because the registry record contains no interval or numerical response estimate, the response result's precision cannot be evaluated.

What does non-randomized allocation mean for regimen comparisons?

The record describes a parallel design with non-randomized allocation and no masking. Participants were assigned to one of two dosing regimens, but random assignment is not reported. General: Randomization is commonly used to balance measured and unmeasured participant characteristics across treatment groups in expectation. Without randomization, groups can differ at baseline, and those differences can complicate interpretation of outcome contrasts. Masking can reduce some measurement or conduct biases, but no masking was used. The registry record does not describe adjustments or other analytic approaches for group differences.

The two regimens are therefore not randomized treatment and control arms. If outcomes are compared across them, the comparison should be interpreted as descriptive unless the record reports an appropriate analysis and supports stronger assumptions. No such comparative analysis is reported in the registry record. The sample-size illustration assumptions described for the statistical material are planning assumptions, including a two-sided significance level of 0.05, equal allocation, and a normal approximation. Those assumptions are not evidence that the trial used that design or analysis. Planning illustrations are not observed power.

Why can event rates be more variable than a simple model expects?

General: A basic statistical model may assume that observations vary independently and that the variability follows a specified distribution. Over-dispersion means the observed variability is greater than that model expects. It can occur when participants differ in underlying risk or when outcomes cluster in ways the model does not capture. If over-dispersion is present but ignored, uncertainty estimates can be too optimistic. This is a general consideration; the registry record does not report an over-dispersion assessment or identify a model for the response endpoint.

What information is missing for a full methods appraisal?

The registry record does not report the numerical primary result, analysis methods, covariate adjustments, handling of missing response assessments, sensitivity analyses, interim analyses, or a sample-size justification. It lists 10 outcome measures and no analyses. Therefore, the endpoint definition can be described, but the statistical method used to estimate the result and the robustness of any result cannot be assessed. The record does not establish whether a particular method was used merely by naming an endpoint or a confidence-interval measure.

The record includes planning illustrations based on a stated fraction of an observed effect, with equal allocation between arms and a normal approximation. Such illustrations describe hypothetical sample-size planning under their stated assumptions; they do not report actual trial power and cannot substitute for a trial-specific design rationale. The registry record does not report a sample-size justification, and the primary effect estimate needed to interpret an illustration is not reported as a result.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Intermittent 5 & 9 Dosing Regimen", "Daily Dosing Regimen")
n      <- c(37, 37)
events <- c(5, 5)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Intermittent 5 & 9 Dosing Regimen  37  5  13.5  4.5  28.8  5.9  28.0  6.0  28.1
ARM  Daily Dosing Regimen  37  5  13.5  4.5  28.8  5.9  28.0  6.0  28.1

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 10 outcome measures, including response, disease stabilization, progression-free survival, time to response, duration of response, duration of stable disease, overall survival, and laboratory safety outcomes. It reports no analyses. The registry record does not describe a multiplicity strategy, such as a prespecified hierarchy or adjustment across outcomes. It is therefore not possible to determine how testing across multiple outcomes was handled, or whether any reported finding was intended to be confirmatory. No numerical outcome findings are posted for interpretation.

The primary endpoint population is described as participants who passed screening, enrolled, and received at least one dose. This is called the safety population in the record. The registry does not report whether all participants in that population had an evaluable response assessment, how missing assessments were handled, or whether any additional analysis populations were defined. The numbers excluded from an endpoint analysis, if any, are not reported in the registry record.

General: Missing outcome data can affect both the number of participants contributing to an estimate and the interpretation of that estimate. The consequences depend on why data are missing and on the assumptions used to handle them. A complete-case analysis, an imputation approach, and other strategies can produce different estimates under different assumptions. Since the registry record does not state the approach, none should be inferred.

The record also does not report a statistical analysis plan, interim analyses, or a sample-size justification. Those omissions limit assessment of whether outcome definitions and analysis choices were specified before results were observed. They should not be filled in by assuming standard practice.

12. 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: night blindness (10.8%), pulmonary embolism (10.8%), diplopia (5.4%), diarrhoea (5.4%), dehydration (5.4%).

The registry reports serious adverse event counts separately by dosing regimen. For the intermittent 5 & 9 dosing regimen, 20 participants were affected among 37 at risk; for the daily dosing regimen, 22 were affected among 37 at risk. These are registry counts, not randomized comparative estimates. The record also lists 14 deaths in the intermittent regimen and 6 in the daily regimen. It does not state that these deaths were caused by foretinib.

The listed top serious adverse event terms include Night blindness and Pulmonary embolism, each at 10.8%; Diplopia, Diarrhoea, Dehydration, and Renal cancer are each listed at 5.4%. The denominator and counting method for these term-specific percentages are not reported in the registry record, so they should not be converted into participant counts or compared with the overall affected counts. The record separately indicates that 37 participants were at risk for other adverse events in each regimen and that 37 were affected in each.

General: An adverse event occurring during a study is not, by that fact alone, evidence that the study drug caused it. The registry record's counts describe events recorded in the study; interpretation of causation requires information about attribution and context, which is not reported. Since allocation was non-randomized, differences between regimen counts should not be treated as causal evidence about dose schedules.

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

The registry record establishes that a Phase II study evaluated foretinib in papillary renal-cell carcinoma using two dosing regimens and defined a primary endpoint based on confirmed complete or partial response. It also identifies a safety population and lists additional disease, survival, and laboratory outcomes. These details explain what the study set out to measure.

The record does not report the numerical primary response result or its 95% confidence interval. It therefore cannot establish from the posted results how often confirmed responses occurred or how precisely that rate was estimated. The presence of an endpoint definition is not itself evidence of a particular result. Similarly, the names of secondary outcomes do not reveal their values.

The serious adverse event counts and listed terms describe registry safety reporting, but do not establish causation. The record does not state that the events or deaths were caused by treatment. Nor can the two non-randomized regimens be treated as a randomized comparison. Any apparent contrast would be subject to possible differences between the participants assigned to each regimen.

General: Clinical trial results are interpreted in relation to their population, endpoint definitions, study design, and uncertainty. A response rate alone does not answer questions about durability, disease progression, survival, or the balance of benefits and harms. Those questions require their own reported outcome estimates and adequate context. For this record, those numerical findings and relevant analysis details are not reported in the registry record.

Accordingly, the most defensible interpretation is descriptive: the registry describes the study design, intended response measure, and certain safety counts. It does not provide enough posted efficacy results to quantify response or compare regimens, and it does not provide enough methodological detail to assess missing-data handling, multiplicity, or adjusted analyses.

14. Why This Trial Matters Statistically

This trial is statistically notable for the distinction between a defined clinical endpoint and a reported endpoint result. The registry specifies a confirmed response definition under RECIST Version 1.0 and identifies the population to which the primary endpoint refers. Yet it does not report the response percentage or its confidence interval. This illustrates why endpoint definitions alone cannot answer a study's clinical question: an estimate and its uncertainty are also needed.

The non-randomized parallel design is another important feature. Two dosing regimens are listed, but without randomized allocation, their outcomes would not automatically support a causal comparison. The distinction matters because treatment-group contrasts can reflect participant differences as well as regimen differences. The registry record does not report an adjustment strategy that would permit a more specific comparative interpretation.

The listed outcomes also span distinct statistical questions. A response percentage describes the occurrence of a defined best response, while response duration, progression-free survival, and overall survival concern time-related outcomes. Laboratory grade changes and adverse events concern safety. Each outcome requires its own definition and analysis; listing them does not substitute for reporting results.

Finally, the safety counts demonstrate why event descriptions need careful context. Counts by regimen and term are informative as registry reporting, but the available record does not establish causality or explain the denominator for the term-specific percentages. The absence of analyses, numerical efficacy results, and key statistical-plan details limits what can be inferred. These limitations are relevant to interpreting the record, rather than evidence for a particular treatment effect.

15. 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 central trial-specific limitation is that the registry record does not report the primary endpoint estimate or its 95% confidence interval. It consequently provides no numerical basis for assessing the observed response frequency or its precision. Although 74 participants were enrolled, the record does not report the number with evaluable primary endpoint data or the number meeting the response definition.

Allocation was non-randomized and masking was absent. The regimens therefore do not constitute a randomized comparison, and potential differences between their participants cannot be ruled out from the information reported. The registry record does not describe baseline comparability, adjusted analyses, or methods for controlling confounding.

The endpoint timeframe is recorded as “At the end of forth year,” but the registry record does not clarify that wording or provide a detailed assessment schedule. It does not report how missing, unevaluable, or unconfirmed responses were handled. Although the endpoint population is defined, the record does not give participant flow or analysis-population counts beyond enrollment and the safety population description.

The record lists secondary outcomes but no analyses, and does not report a multiplicity approach, interim analyses, a statistical analysis plan, or sample-size justification. For the serious adverse event term percentages, the denominator and counting method are not reported. The record also does not attribute the listed events or deaths to treatment. These omissions constrain interpretation of efficacy, safety, and comparisons between regimens.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Phase II Study of GSK1363089 (Formerly XL880) for Papillary Renal-Cell Carcinoma (PRC) — NCT00726323.
• Registry record last updated 2017-12-11; status last verified 2017-09.
• Results first posted 2017-12-11.
• 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.

19. Record Summary

NCT00726323 is a completed Phase II, parallel, non-randomized, unmasked study sponsored by GlaxoSmithKline. It enrolled 74 participants with papillary renal-cell carcinoma, including hereditary or sporadic forms. Foretinib was studied using an intermittent 240 mg regimen and a daily 80 mg regimen.

The primary endpoint was the percentage of participants with a confirmed complete or partial response under RECIST Version 1.0, based on investigator assessment. The registry record does not report a numerical primary result or confidence interval. It lists 10 outcome measures and no analyses.

Serious adverse event counts are reported by regimen, along with deaths and selected serious event terms. The record does not establish causation or provide enough information to treat regimen groups as a randomized comparison. Details on the statistical plan, missing data, multiplicity, and sample-size justification are not reported in the registry record.