CCI-779 and Bevacizumab in Treating Patients With Metastatic or Unresectable Kidney Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for CCI-779 and Bevacizumab in Treating Patients With Metastatic or Unresectable Kidney Cancer (NCT00112840), a na phase 1, phase 2 study. The primary outcome is Dose-limiting Toxicity (DLT) (Phase I).

2. Clinical Question

3. Trial Design

This was a Phase I/II, completed, single-group study sponsored by the National Cancer Institute (NCI). The registry lists an enrollment of 60 and identifies the study as concerning metastatic or unresectable kidney cancer, including Stage IV renal cell cancer. The study began in 2005-05, and primary completion is recorded as 2010-08-09. No random allocation is described: allocation is listed as NA, and masking is listed as none. Accordingly, this design does not create a randomized control comparison.

The intervention was CCI-779 together with bevacizumab. The arm description says that patients received the drugs intravenously on scheduled treatment days, with courses repeating every 28 days in the absence of disease progression or unacceptable toxicity. In Phase I, cohorts of 3-6 patients received escalating doses. The purpose described in the record was to assess side effects and determine the best dose, with dose-limiting toxicity used to define the maximum tolerated dose. The available arm description ends before stating the final maximum tolerated dose.

The record identifies dose-limiting toxicity as the primary outcome for Phase I. Named secondary outcomes include clinical best response rate and time to progression in Phase II, and overall survival in both Phase I and Phase II. There are 5 outcome measures listed, but the registry record does not report estimates for these clinical outcomes in the information available. The record also lists 0 statistical analyses. That is a description of what is posted, not evidence that no analyses were performed outside the registry.

Phase I dose cohorts and the Phase II group serve different roles within this study. They do not constitute treatment and control groups. Any observed rates or counts across these cohorts should therefore be interpreted descriptively, with attention to differences in dose, phase, and the groups’ purposes. The registry record does not report the detailed statistical analysis plan, eligibility criteria, or a rationale for the enrollment target.

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: In Phase I, Dose Level 2, 2 subjects were unevaluable because they were removed from the study before completing cycle 1 of treatment for reasons other than toxicity. In Phase II, 5/46 patients were ineligible and one patient cancelled.

Overall Study

Reasons for not completing this period:

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 Dose-limiting Toxicity (DLT) (Phase I), measured over Patients observed a minimum of 4 weeks (one full course). The maximum number of cycles observed was 16 cycles..

The primary endpoint is dose-limiting toxicity (DLT) in Phase I, measured as a number of participants. The registry defines DLT as an adverse event attributed definitely, probably, or possibly to study treatment during the first four weeks of combination therapy and meeting specified severity criteria. Those criteria include prolonged Grade 4 low neutrophil count, Grade 4 anemia or thrombocytopenia, a specified creatinine increase, other qualifying Grade 3 or higher non-hematologic events with stated exceptions, and persistent Grade 3 triglycerides despite appropriate lipid-lowering therapy.

This endpoint is used in dose-escalation studies to identify whether toxicities at a dose level are sufficiently frequent or severe to limit further dose increases. The record defines the maximum tolerated dose as the highest safely tolerated dose where 1 or 0 out of 6 patients experience DLT with the next higher dose. This definition makes the endpoint part of a dose-finding decision, rather than a direct measure of tumor response or long-term clinical benefit.

Participants were observed for a minimum of 4 weeks, described as one full course; the maximum number of cycles observed was 16 cycles. The DLT window is specifically the first four weeks, even though some participants may have been observed over more treatment cycles. The registry record does not report the number of participants who experienced DLT, the dose level selected as the maximum tolerated dose, or an uncertainty estimate for the endpoint. Therefore, the endpoint definition can be described, but its observed result cannot be evaluated from the posted information.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a single-group design tell us?

In a single-group study, participants receive the study intervention without a concurrent control group specified in the design. Outcomes can be described within the treated group, and Phase I dose cohorts can support dose-finding decisions under the protocol’s rules. But a within-study event count does not estimate what would have happened to comparable participants under another treatment or no study treatment. Without randomization, differences across cohorts can reflect factors other than dose or intervention. This is why the Phase I dose levels and Phase II group should not be treated as if they were randomized comparison arms.

The record lists allocation as NA and masking as none, and identifies the model as single group. These design features do not establish that the study lacked all forms of clinical monitoring or assessment; they describe the registry’s design fields. The record does not report additional assessment procedures or a statistical plan that could clarify how outcomes were evaluated.

How is a dose-limiting toxicity endpoint used?

A DLT endpoint applies prespecified clinical criteria within a specified observation window. Here the registry defines qualifying events by treatment attribution, timing during the first four weeks, and severity criteria. A structured definition helps make dose-finding decisions more consistent than relying on an informal overall impression of tolerability. It also sets boundaries: an adverse event outside the definition, outside the stated window, or not meeting the specified severity criteria would not necessarily count as a DLT for this endpoint, even if it remained clinically relevant.

The record’s maximum tolerated dose rule connects the observed DLT count to dose escalation. The stated rule refers to the highest safely tolerated dose and whether 1 or 0 out of 6 patients experience DLT with the next higher dose. This is a protocol decision rule, not a claim that the selected dose is risk-free or optimal for every later purpose. The DLT result and the selected dose are not reported in the registry record, so the rule can be explained but not applied to the observed study results.

Why should event counts be read with denominators?

A count says how many participants experienced an event; its at-risk denominator indicates the group in which those events were recorded. Both are needed for a meaningful descriptive reading. Even when a denominator is available, an event count alone does not show the duration of observation, the timing of events, recurrence, severity distribution, or causal attribution. The registry’s serious-event figures are separate from the DLT endpoint. Serious adverse events and protocol-defined DLTs are not interchangeable categories: the registry uses different labels, and the DLT definition includes specific attribution, timing, and severity requirements.

The record also lists percentages for the most frequent serious-event terms. A percentage is interpretable only in relation to its denominator and the event-reporting rules. The denominator and detailed ascertainment information for these term percentages are not reported in the registry record. The listed percentages should therefore be read as posted descriptions, not recalculated or treated as estimates with known precision.

What does uncertainty add?

In general, a confidence interval describes a range of values compatible with the data under a stated statistical method and assumptions. It conveys precision as well as the direction or size of an estimate. A point estimate without an interval can obscure how uncertain the estimate is, particularly when the number of observed events is limited. No confidence intervals for the listed clinical outcomes or safety counts are reported in the registry record, so their statistical precision cannot be assessed from the posted information.

In general, statistical significance testing addresses how compatible data are with a specified null model, given its assumptions. A p-value is not the probability that a treatment works, nor does it measure clinical importance. The registry reports 0 statistical analyses, and it does not report p-values or a statistical plan. No significance-based conclusion should be inferred from the outcome names or descriptive event counts.

Why do dose cohorts and phases require separate interpretation?

Phase I and Phase II address different questions. This record describes Phase I as focused on side effects and finding a dose, with DLT as its primary endpoint. The Phase II outcomes include clinical best response rate and time to progression. Overall survival is listed for both phases. Pooling or directly comparing these outcomes across phases would require definitions, analysis methods, and population details that are not reported in the registry record. The different phase purposes also mean that the groups should not be assumed to have identical follow-up or eligibility.

For a time-to-event outcome, general statistical interpretation depends on when follow-up begins, how events and censoring are defined, and how incomplete follow-up is handled. The registry names time to progression and overall survival but does not report the analysis method, censoring rules, event counts, or estimates. Those results cannot be reconstructed from the endpoint labels.

What is a planning illustration?

General sample-size illustrations describe the number of participants that might be needed under stated assumptions about an effect, significance level, allocation, and statistical method. They are prospective planning calculations, not evidence about the trial’s actual power or the observed treatment effect. A calculation based on an observed effect is especially dependent on that estimate and its uncertainty. Such illustrations should not be mistaken for the trial’s design rationale or a substitute for reported results. The registry record does not report the study’s sample-size justification, and it does not report an inferential analysis from which the clinical outcome estimates could be evaluated.

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("Phase I, Dose Level 1", "Phase 1 , Dose Level 2")
n      <- c(6, 6)
events <- c(1, 1)
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  Phase I, Dose Level 1  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  Phase 1 , Dose Level 2  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9

11. Multiplicity, Missing Data and Analysis Populations

The registry names multiple outcomes: Phase I dose-limiting toxicity; Phase II clinical best response rate and time to progression; and overall survival in Phase I and Phase II. Considering multiple outcomes raises a general multiplicity issue: when many outcomes or analyses are tested, the chance of at least one apparently notable result can increase unless the analysis plan accounts for that possibility. The appropriate approach depends on which outcomes were prespecified as primary or secondary, which comparisons were intended, and how tests were conducted.

The registry identifies DLT as the primary Phase I endpoint and labels the other listed measures as secondary outcomes. It does not report a multiplicity strategy, a hierarchy among secondary outcomes, or results for those outcomes. The record reports 0 statistical analyses. This means inferential procedures and any multiplicity adjustment cannot be assessed from the registry record; it does not establish what analyses may have been carried out elsewhere.

Missing-data interpretation also depends on the outcome and analysis population. For binary outcomes, missing outcome status can change the denominator and the estimated event proportion. For time-to-event outcomes, incomplete follow-up may lead to censoring, whose handling and assumptions affect interpretation. These are general statistical considerations; the registry record does not report missing outcome counts, reasons for missingness, censoring rules, or analysis populations for the named clinical outcomes.

The safety groups report numbers at risk, but the record does not explain how those denominators were determined or whether all enrolled participants were represented in every outcome analysis. The DLT observation window is specified, but the observed DLT result and participant-level follow-up information are not reported. Without those details, the completeness and precision of the primary endpoint cannot be evaluated. The enrollment figure should not be assumed to be the denominator for each outcome.

The registry record also does not report an intention-to-treat or other named analysis population, rules for handling treatment discontinuation, or a protocol-specific approach to missing observations. Those details should not be inferred from the single-group design or the endpoint definitions.

12. Safety Results

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

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: anorexia (33.3%), dehydration (25.0%), anal fistula (16.7%), nausea (16.7%), vomiting (16.7%).

The registry reports serious adverse events by group. For Phase I, Dose Level 1, 3 participants were affected among 8 at risk; for Phase I, Dose Level 2, 2 were affected among 6 at risk; and for Phase II, 12 were affected among 45 at risk. These are descriptive counts for the groups as posted. They do not constitute a randomized safety comparison, because the study is single group and the cohorts differ by phase and dose context.

The record also lists serious adverse-event terms and percentages: anorexia, 33.3%; dehydration, 25.0%; anal fistula, nausea, vomiting, and injection site reaction, each 16.7%. The denominator and detailed event-counting rules behind these percentages are not reported in the registry record. The listed terms should not be interpreted as rates among all enrolled participants unless the denominator is established.

Serious adverse events should not be equated with the primary DLT endpoint. DLT has a specific treatment-attribution requirement, a first-four-weeks window, and protocol-defined severity criteria. The safety figures do not show how many participants met that definition. Nor do the posted counts establish that an event was caused by the combination. The record does not provide timing, recurrence, exposure duration, or a control group for causal comparison.

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

The registry record describes a combination study with a Phase I dose-finding component and a Phase II component. Its primary Phase I question concerns dose-limiting toxicity during the first four weeks, under a detailed protocol definition. This is a clinically relevant design question for dose escalation because safety observations inform the dose-selection rule. However, the posted information does not report the number of DLTs or the maximum tolerated dose. The central Phase I result therefore cannot be stated from this record.

The record names Phase II clinical best response rate and time to progression, and overall survival for both phases. It does not report numerical estimates or uncertainty for these outcomes. As a result, the registry information does not establish the size or precision of any tumor-response, progression, or survival result. The outcome labels indicate what was intended to be assessed, not what the findings were.

The serious adverse-event counts and listed terms provide descriptive safety information. They should be interpreted within their reported groups and denominators, without combining cohorts or treating the groups as controls. The record does not report enough detail to determine causal attribution or to compare these observations with what would have occurred under another treatment.

More generally, a single-group study can characterize observed events and support dose-finding, but it cannot provide the same controlled contrast as a randomized trial. This design limitation matters especially for efficacy interpretation: an outcome observed after treatment does not, by itself, demonstrate that treatment caused the outcome. No medical conclusion about benefit or lack of benefit follows from the absence of posted efficacy estimates. The appropriate statistical conclusion is narrower: the registry record documents the study’s design and selected safety information, while key primary and clinical outcome results are not reported in the registry record.

14. Why This Trial Matters Statistically

This study illustrates why a clearly defined endpoint and its observed result are both essential. The registry gives a detailed DLT definition, including attribution, timing, and severity criteria, and specifies how DLT observations relate to the maximum tolerated dose decision. That level of definition makes the intended dose-finding question understandable. But without the observed DLT count and selected dose, readers cannot determine how the rule was applied or what dose was supported by the Phase I findings.

It also demonstrates the distinction between dose-finding and comparative evaluation. The single-group design is suited to describing treatment experience and escalating doses under a protocol rule, but it does not create a randomized control contrast. Phase I dose levels and the Phase II group have different purposes and should not be read as equivalent treatment arms. This distinction prevents descriptive cohort differences from being mistaken for treatment effects.

Finally, the record shows why outcome names and adverse-event summaries need context. Clinical response, time to progression, and overall survival are listed, but estimates and uncertainty are not reported. Safety counts are available, yet they do not answer the separate DLT question and do not establish causality. Statistical interpretation depends not only on what was measured, but also on denominators, follow-up, analysis populations, and the methods used to handle uncertainty and missing data. Those details are not reported in the registry record.

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 principal limitation for interpreting outcomes is that the registry record does not report the observed result for the primary Phase I endpoint. The number of participants with DLT, the dose level selected as the maximum tolerated dose, and any uncertainty measure are absent from the posted information. The record also does not provide numerical results for the named response, progression, or survival outcomes.

The single-group design and absence of masking limit the kinds of comparisons that can be made from the study structure. There is no concurrent randomized control group, and dose cohorts should not be treated as controls for one another. Differences among groups could reflect factors beyond dose or treatment, and no adjusted comparative analysis is reported.

Additional details needed for a fuller appraisal are not reported in the registry record, including eligibility criteria, outcome analysis populations, statistical methods, missing-data handling, and the rationale for the enrollment target. The record does not describe confidence intervals, p-values, or a multiplicity strategy. For serious adverse-event terms, the denominator and ascertainment details behind the posted percentages are not reported. The at-risk counts are available by group, but the record does not explain their relationship to outcome-specific analysis populations or follow-up.

These limitations do not establish that analyses or information were absent outside the registry. They define what can be concluded from the registry record itself. In particular, the posted design and safety counts support description, but not a treatment-effect estimate or a complete assessment of the precision and generalizability of the clinical outcomes.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: CCI-779 and Bevacizumab in Treating Patients With Metastatic or Unresectable Kidney Cancer — NCT00112840.
• Registry record last updated 2022-02-01; status last verified 2022-01.
• Results first posted 2014-09-11.
• 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

NCT00112840 is a completed Phase I/II, single-group study of CCI-779 and bevacizumab in metastatic or unresectable kidney cancer. Enrollment is listed as 60. The record identifies dose-limiting toxicity in Phase I as the primary endpoint and names clinical best response rate, time to progression, and overall survival as secondary outcomes.

The registry defines DLT and its role in dose escalation, and reports serious adverse-event counts by Phase I dose level and Phase II group. It does not report the primary DLT result, the maximum tolerated dose, or estimates for the named clinical outcomes. The single-group design does not provide a randomized control comparison. Statistical analyses, missing-data methods, and analysis populations are not reported in the registry record.