Cixutumumab and Temsirolimus in Treating Patients With Locally Recurrent or Metastatic Breast Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Cixutumumab and Temsirolimus in Treating Patients With Locally Recurrent or Metastatic Breast Cancer (NCT00699491), a na phase 1, phase 2 study. The primary outcome is Recommended Dose Level for Phase II Testing (RPTD) (Phase I).

2. Clinical Question

3. Trial Design

This was a phase I/II, completed, single-group trial sponsored by the National Cancer Institute. The registry record lists an enrollment of 48 and identifies the study as beginning on 2008-10-31, with primary completion on 2013-09-09. It lists no masking and no randomized allocation. The design therefore combines an early dose-finding component with a later phase II component, without a concurrent control group.

In phase I, the study assessed dose-limiting toxicities during the first course and defined a recommended dose level for phase II testing using a rule based on toxicity counts at adjacent dose levels. Participants in the phase II portion received the combination at a dose selected for testing, although the selected dose is not reported in the registry record. The available record also does not state how many participants were assigned to each dose level or explain the dose-escalation procedure beyond the endpoint definition.

The treatment description specifies temsirolimus and cixutumumab administered intravenously on days 1, 8, 15, and 22. Cixutumumab was given on days 8, 15, and 22 of the first course only. Courses repeated every 28 days in the absence of disease progression or unacceptable toxicity. The registry lists laboratory biomarker analysis and pharmacological study among the interventions, as well as the two study drugs.

The registry lists 7 outcome measures and 0 analyses. The record names phase II outcomes that include adverse events, duration of response, progression-free survival, progression-free survival rate, and survival time. Numerical outcome results, the detailed statistical analysis plan, and the rationale for the planned enrollment are not reported in the registry record. The overall enrollment should not be treated as the analysis population for every endpoint.

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

Analysis population for the primary outcome, as defined in the registry: Patients registered to the Phase I portion of the protocol were analyzed for this endpoint. One patient in Dose Level -1, one patient in Dose Level -2, and two patients in Dose Level -2B discontinued study treatment during Cycle 1 for reasons unrelated to toxicity and were excluded from this endpoint.

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.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Recommended Dose Level for Phase II Testing (RPTD) (Phase I), measured over During first course.

The primary endpoint was the recommended dose level for phase II testing, measured in the phase I portion during the first course of treatment. It is a dose-finding endpoint rather than a measure of tumor response or survival. The registry defines the recommended dose as the highest dose level at which at most one of 6 patients develops a dose-limiting toxicity, provided the next highest dose level has 2 or more dose-limiting toxicities. The endpoint description says the number of patients in each cohort reporting a dose-limiting toxicity is reported.

Dose-limiting toxicity was defined by treatment-related adverse events with an attribution of possible, probable, or definite, and by specified severity or clinical criteria. These included any grade 4 hematologic toxicity, hyperglycemia that could not be stably controlled with diabetic medication, and any grade 3 or 4 non-hematologic toxicity, with exceptions for certain asymptomatic, medically manageable laboratory abnormalities.

This type of endpoint is used to guide dose selection: it relates observed early toxicity at tested dose levels to a prespecified rule for choosing a dose for later testing. It does not by itself establish clinical benefit, characterize all later toxicities, or compare the regimen with an alternative. The registry record provides the endpoint definition but does not report the dose-level toxicity counts or the resulting recommended dose.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies a phase I/II, single-group design and lists 0 analyses. The detailed statistical analysis plan is not reported in the registry record. The endpoint definition and descriptive outcome listings therefore provide the main information available about the intended statistical approach; they do not establish which analyses were ultimately performed.

How does the phase I dose rule work?

The primary endpoint uses a toxicity-based rule to identify a dose level for phase II testing. It defines the recommended dose as the highest dose level where at most one of 6 patients develops a dose-limiting toxicity, while the next highest dose level has 2 or more such toxicities. In general, rules of this kind use observed early toxicity to balance the aim of testing a dose with the need to limit dose-limiting events. The rule is a decision criterion, not a treatment-effect estimate. The registry record gives the criterion but not the observed dose-level counts or the decision reached.

The endpoint’s toxicity definition is also important to interpretation. It restricts dose-limiting toxicities to adverse events related to the study agent with possible, probable, or definite attribution, and applies specified severity or clinical conditions. It excludes certain asymptomatic, medically manageable laboratory abnormalities from the stated category. Thus, the primary endpoint is not simply a count of every adverse event recorded during treatment. Broader adverse-event reporting and dose-limiting-toxicity classification answer different questions.

What can a single-group design estimate?

A single-group study can report outcomes observed among participants who received the regimen. Without a randomized control group, it does not estimate a treatment contrast against an alternative group. General statistical interpretation: a between-group comparison can help distinguish a treatment-related difference from changes or outcomes that might also occur under another condition; a single-group record does not supply that comparison. Masking is listed as none, but the registry record does not describe additional procedures for limiting bias in outcome assessment.

The enrollment of 48 is the overall registry enrollment, not automatically the denominator for every outcome. The primary endpoint applies to participants registered to phase I, and its population description notes exclusions after Cycle 1 discontinuation for reasons unrelated to toxicity. The adverse-event information uses separate at-risk counts within dose-level and phase groups. For any outcome, the denominator and analysis population matter because participants may not contribute information in the same way to every endpoint.

How should uncertainty be considered?

General statistical explanation: a confidence interval describes the range of estimates compatible with the data and the method used, and its width reflects precision as well as the amount and variability of information. The registry record does not report confidence intervals for the listed outcomes. Without numerical estimates and uncertainty intervals, the precision of phase II outcome results cannot be assessed from this record.

General statistical explanation: count outcomes can vary more than a simple model assumes, a condition often described as over-dispersion. When it is present, methods that allow extra variability can give more appropriate uncertainty estimates than methods that assume a fixed mean-variance relationship. The registry record does not identify a count model or report an over-dispersion assessment, so no claim can be made about whether such methods were used or needed.

What do planning illustrations mean?

General statistical explanation: a sample-size calculation is a planning exercise tied to assumptions about the effect to detect, the significance level, allocation, and statistical method. It is not an observed outcome and does not establish that a study had a particular probability of detecting an effect after the fact. The planning assumptions described for this trial use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the target effect expressed as a fraction of the observed effect. The record does not report that these assumptions formed the trial’s original design justification; the sample-size rationale is not reported in the registry record.

The planning description specifies that time-to-event illustrations count total events, whereas other illustrations count participants per arm. These are planning conventions, not trial findings. They do not change the study’s single-group design or create a control comparison. The registry record does not report interim analyses, multiplicity procedures, or a prespecified analysis plan for the listed outcomes.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 7 outcome measures, including the phase I recommended dose endpoint and phase II outcomes such as adverse events, duration of response, progression-free survival, progression-free survival rate, and survival time. The record lists 0 analyses. It does not report how the outcomes were prioritized for inferential testing, whether any formal hypothesis tests were planned, or whether adjustments for multiple comparisons were made. Without a stated multiplicity strategy, the interpretation of any unreported collection of outcome tests cannot be assessed.

Missing-data methods are not reported in the registry record. The primary endpoint population description does note that one patient in Dose Level -1, one patient in Dose Level -2, and two patients in Dose Level -2B discontinued study treatment during Cycle 1 for reasons unrelated to toxicity and were excluded from that endpoint. This is a specific endpoint-population detail, not a complete account of missing data across all outcomes. The record does not describe how incomplete follow-up, missing measurements, or other discontinuations were handled.

The phase I endpoint applies to patients registered to that portion of the protocol. The adverse-event record separately gives numbers at risk and affected within each dose group and the Phase II group. The analysis population for the phase II efficacy outcomes is not reported in the registry record. Overall enrollment of 48 should therefore not be read as the denominator for every outcome, and the available record does not support assuming that all enrolled participants were included in each analysis.

11. 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: mucositis oral (50.0%), fatigue (50.0%), pain (50.0%), creatinine increased (50.0%), anorexia (50.0%).

The adverse-event record separates participants by dose level and Phase II, and gives the number at risk and the number affected for serious adverse events and other adverse events. For serious adverse events, the reported counts are 0 of 3 at Dose Level 1, 1 of 2 at Dose Level -1, 1 of 7 at Dose Level -2, 3 of 6 at Dose Level -2A, 3 of 8 at Dose Level -2B, and 7 of 22 in Phase II. These are group-specific descriptive counts, not a randomized comparison.

The other-adverse-event counts list all participants at risk in each group as affected: 3 of 3, 2 of 2, 7 of 7, 6 of 6, 8 of 8, and 22 of 22, respectively. The record lists mucositis oral, fatigue, pain, creatinine increased, anorexia, and dyspnea among serious-event terms, each with a reported value of 50.0%. The registry record does not provide enough detail alongside those term values to infer a comparison or a common denominator from them.

Deaths are not reported in the registry record. These counts describe reported adverse events in the trial groups; they do not establish comparative safety against another regimen.

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

The record establishes that this completed phase I/II study enrolled 48 participants and evaluated cixutumumab with temsirolimus in a single-group design. It provides a definition for the phase I dose-limiting-toxicity endpoint and descriptive adverse-event counts by dose group. Those details explain what the study set out to assess and how the primary dose-selection criterion was defined.

The record does not report the primary endpoint result, including the dose-level toxicity counts or the recommended phase II dose. It also does not report numerical phase II results for duration of response, progression-free survival, progression-free survival rate, or survival time. Accordingly, the available registry information cannot establish the magnitude or precision of these clinical outcomes.

Even with complete outcome estimates, the single-group design would not provide a randomized comparison with another treatment. The study could describe outcomes among people who received the regimen, but differences from an external expectation would not substitute for a concurrent control group. The posted data therefore do not establish a causal treatment effect or a comparative benefit.

The adverse-event counts show that participants in the listed groups had serious and other adverse events recorded. They do not show how those counts compare with another regimen, and the serious-event term values should not be interpreted as comparative risks. The primary dose-finding endpoint also has a narrower purpose than overall safety: it applies a rule to specific toxicities during the first course, rather than summarizing every possible later adverse event.

These limitations are about what can be concluded from the registry record, not evidence that the regimen succeeded or failed. Missing numerical results and uncertainty estimates prevent a quantitative assessment of the listed phase II outcomes. The record supports describing the design, endpoint definition, and posted safety counts, while leaving treatment-effect conclusions unresolved.

13. Why This Trial Matters Statistically

This trial illustrates why a phase I dose-finding endpoint should be distinguished from a phase II outcome. The phase I rule uses dose-limiting toxicities during the first course to select a dose for further testing. It answers a dose-selection question under a stated criterion; it does not directly measure response, progression-free survival, or overall survival. Keeping those questions separate prevents a dose-selection rule from being mistaken for evidence of clinical benefit.

The record also shows why design structure matters when interpreting outcome data. A single-group study can describe what happened among treated participants, but it cannot supply the randomized comparison that helps estimate differences between treatment strategies. Adverse-event counts by dose group remain descriptive, even when the groups have different sizes. They should not be treated as evidence that one dose is safer than another without an appropriate comparative analysis.

Endpoint-specific populations matter as well. The overall enrollment is 48, while the primary endpoint description identifies phase I participants and notes exclusions related to Cycle 1 discontinuation. Safety counts are reported within separate groups. These distinctions are essential when deciding which denominator applies and when considering whether findings generalize across phases.

Finally, the record illustrates the importance of complete results reporting. An endpoint definition explains what was intended to be measured, but without its observed counts or estimates it does not reveal the trial’s finding. Numerical results and measures of uncertainty are needed to assess the size and precision of outcomes. Where those are absent, statistical interpretation should remain limited to the design, definitions, and descriptive data actually reported.

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 registry record identifies the trial as single-group, with no masking and no randomized allocation. This limits comparative interpretation: outcomes in the treated groups cannot be directly contrasted with a randomized control group. Dose-level groups also arise within a dose-finding design, so their descriptive counts should not be read as if they were randomized arms.

The primary endpoint is defined, but its numerical result is not reported. The record does not provide the number of dose-limiting toxicities by cohort or the resulting recommended dose. It also does not report numerical results for the listed phase II outcomes, confidence intervals, or p-values. The absence of these results prevents assessment of outcome magnitude and precision.

The primary endpoint population description notes exclusions after treatment discontinuation during Cycle 1, but the record does not provide a complete account of missing data or analysis populations across all outcomes. The phase II analysis population is not reported in the registry record. The overall enrollment therefore cannot be assumed to be the denominator for every endpoint.

The registry lists 7 outcome measures and 0 analyses, while the detailed statistical analysis plan, multiplicity procedures, interim analyses, and enrollment rationale are not reported. The adverse-event counts are descriptive, and the serious-event term values are not accompanied by enough information to support comparative interpretation. These record-specific limitations leave both the planned analysis details and the principal clinical outcome findings uncertain.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Cixutumumab and Temsirolimus in Treating Patients With Locally Recurrent or Metastatic Breast Cancer — NCT00699491.
• Registry record last updated 2018-06-13; status last verified 2018-05.
• Results first posted 2015-05-21.
• 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

The registry record describes NCT00699491, a completed phase I/II, single-group study of cixutumumab with temsirolimus in patients with locally recurrent or metastatic breast cancer. Enrollment was 48. The primary phase I endpoint was the recommended dose level for phase II testing, defined using dose-limiting toxicities during the first course.

The record describes the treatment schedule and lists phase II outcomes that include adverse events, duration of response, progression-free survival, progression-free survival rate, and survival time. It provides adverse-event counts by dose group and a phase II group. However, the primary endpoint result and numerical phase II outcome results are not reported in the registry record. The listed design has no randomized comparator, and the detailed statistical analysis plan, missing-data methods, and multiplicity approach are not reported.