Study Using IMC-A12 (Cixutumumab) With or Without Cetuximab in Participants With Metastatic Colorectal Cancer Who Have Failed a Treatment Regimen That Consisted of a Prior Anti-EGFR Therapy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study Using IMC-A12 (Cixutumumab) With or Without Cetuximab in Participants With Metastatic Colorectal Cancer Who Have Failed a Treatment Regimen That Consisted of a Prior Anti-EGFR Therapy (NCT00503685), a randomized phase 2 study. The primary outcome is Percentage of Participants With Complete Response (CR) or Partial Response [PR, Objective Response Rate (ORR)].

2. Clinical Question

3. Trial Design

This was a randomized, Phase 2, parallel-group trial with no masking. The registry lists an enrollment of 65 and a completed study. The recorded start was 2007-06, and primary completion was 2009-03. The listed condition was colorectal cancer; the study description focused on metastatic colorectal cancer after progression on a prior anti-EGFR regimen.

The registry lists three treatment groups: IMC-A12, IMC-A12 plus cetuximab, and IMC-A12 plus cetuximab in participants with K-ras wild-type disease. The recorded group sizes for the primary outcome were 23, 21, and 20, respectively. Each arm description states administration every 2 weeks. The K-ras wild-type arm has a specific eligibility description: participants had previously experienced a confirmed partial response or stable disease lasting at least 24 weeks on anti-EGFR-containing therapy, followed by disease progression.

The primary outcome was the percentage of participants with a confirmed complete or partial response. The registry also lists progression-free survival, overall survival, duration of stable disease, duration of overall response, treatment-emergent adverse events, severe treatment-emergent adverse events, and pharmacokinetic measures. It lists 13 outcome measures and 12 posted secondary outcomes. The statistical analysis plan, allocation ratio, details of randomization procedures, and whether any interim analyses were planned are not reported in the registry record. The absence of masking is relevant when interpreting an investigator-classified response outcome: the registry does not describe masking of investigators or participants.

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: Participants with progressive disease (PD) or death are considered having completed study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All randomized/enrolled participants who received at least 1 dose of 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: All randomized/enrolled participants who received at least 1 dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Complete Response (CR) or Partial Response [PR, Objective Response Rate (ORR)], measured over Start of randomization/treatment to date of objective progressive disease (PD) up to 28.3 weeks.

The primary endpoint is the percentage of participants with an investigator-classified, confirmed complete response or partial response. A complete response means disappearance of all target and non-target lesions. A partial response means a decrease of at least 30% in the sum of the longest diameters of target lesions, without a new lesion or progression of non-target lesions. These classifications followed RECIST version 1.0.

The registry defines the percentage as the number of treated participants with a complete or partial response from treatment start until disease progression or recurrence, divided by the total number treated, then multiplied by 100. The stated analysis population is all randomized or enrolled participants who received at least one dose of study drug. The timeframe runs from the start of randomization or treatment to objective progressive disease, up to 28.3 weeks.

As a general statistical concept, an objective response endpoint records whether a participant meets a predefined tumor-change category during a specified period. Combining complete and partial responses into an overall response rate provides a binary summary for each participant: a qualifying response or no qualifying response. It does not describe how long a response lasts, whether disease remains stable, or survival. Those are separate outcomes in the registry. Because the endpoint depends on investigator classification, the absence of masking is relevant context, while the registry’s use of stated RECIST criteria provides a defined basis for classification.

7. Results Posted in the Registry

• IMC-A12 + Cetuximab: 4.8% (1/21) versus 0.0% (0/23) on control; risk difference 4.8 percentage points (95% CI -4.3 to 13.9); unadjusted two-proportion z-test p = 0.290.
• IMC-A12 + Cetuximab (K-ras Wild-type): 0.0% (0/20) versus 0.0% (0/23) on control; risk difference 0.0 percentage points (95% CI 0.0 to 0.0); unadjusted two-proportion z-test p = n/a.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary at the participant level: a participant either had a confirmed complete or partial response under the registry’s definition, or did not. The registry reports the percentage in each group and a 95% confidence interval. It also posts risk-difference comparisons against the IMC-A12 group. These summaries answer related but distinct questions: the group percentages describe each arm, while a risk difference describes the contrast between two arm proportions.

What does a percentage with a confidence interval describe?

In general, a percentage estimates the fraction of participants in a group who experienced the event of interest. A confidence interval expresses the uncertainty around that estimate under the statistical method used. It is not a range containing a known fixed proportion with a stated probability after the data have been observed. Rather, it indicates the range of estimates compatible with the data and method at the stated confidence level. Wider intervals indicate less precision than narrower intervals, all else equal.

Here, the recorded rates are 0%, 4.8%, and 0%, with 95% confidence intervals of 0.0% to 14.8%, 0.1% to 23.8%, and 0.0% to 16.8%, respectively. A zero observed rate does not mean that the underlying response probability is known to be zero. The upper limits of the intervals show that the estimates remain uncertain. Likewise, the interval around the 4.8% estimate is broad, so the point estimate alone should not be treated as a precise characterization of the response probability.

What does the risk difference mean?

In general, a risk difference is the proportion with an event in one group minus the proportion in the comparator group. It is expressed on the proportion scale, where zero represents equal observed proportions. A positive estimate means the event proportion was higher in the named treatment group than in the comparator; a negative estimate means it was lower. The registry’s comparison of IMC-A12 plus cetuximab with IMC-A12 alone has an estimate of 0.048, with a 95% confidence interval from -0.043 to 0.139. Because this interval spans zero, it does not rule out no difference under the reported interval calculation.

The unadjusted p-value for that comparison is 0.29. In general, a p-value describes how unusual data at least as incompatible with a null hypothesis would be if that null hypothesis and the test assumptions held. It is not the probability that the null hypothesis is true, nor a measure of the size or clinical importance of an effect. The p-value is labelled unadjusted; a multiplicity adjustment is not reported in the registry record. No p-value is listed for the K-ras wild-type comparison.

Why are subgroup comparisons different?

The third arm is described for participants with K-ras wild-type disease and a specified prior history of response or stable disease lasting at least 24 weeks, followed by progression. That eligibility description makes this group distinct in its clinical selection from the broadly described population. In general, comparisons across groups with different eligibility criteria need cautious interpretation: an observed contrast can reflect both treatment assignment and differences in who qualifies for each group. The registry does not report an adjusted analysis addressing such differences.

What do the planning illustrations represent?

In general, a sample-size planning illustration uses assumptions about a future study, including an effect to detect, a significance level, allocation, and a statistical approximation. The registry record describes illustrations based on the observed effect, two-sided significance level 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is stated as a fraction of the observed effect. Such figures are planning illustrations, not observed power and not evidence that the trial had a particular probability of detecting an effect. The trial’s own sample-size justification and design assumptions are not reported in the registry record. No numerical planning values are included in the registry record for this explanation.

The registry lists no posted analyses. It does not report the confidence-interval construction method, a full statistical analysis plan, covariate adjustment, or a procedure for handling multiple comparisons. Accordingly, interpretation should remain anchored to the posted summaries rather than assuming an unreported model or analysis procedure.

10. Confidence Intervals and Precision

The confidence intervals provide important context for the observed response percentages. The IMC-A12 estimate was 0%, with a 95% confidence interval from 0.0% to 14.8%. The IMC-A12 plus cetuximab estimate was 4.8%, with an interval from 0.1% to 23.8%. The K-ras wild-type combination estimate was 0%, with an interval from 0.0% to 16.8%. These intervals are wide relative to the point estimates, indicating limited precision in the response-rate estimates.

For the combination-versus-monotherapy comparison, the risk-difference estimate was 0.048 and the 95% confidence interval ran from -0.043 to 0.139. It includes zero and extends in both directions. Thus, the posted estimate does not distinguish clearly between no difference and a range of possible differences. The K-ras wild-type comparison has a reported estimate and interval of 0.0 and 0.0 to 0.0, with observed rates of 0% in both groups; no p-value is listed for it.

In general, confidence intervals tend to be less precise when the amount of information available for an estimate is limited. Here, the recorded group sizes were 23, 21, and 20, and the number of observed responses was low. These features are relevant when reading the breadth of the intervals, but the registry does not report the method used to calculate them. An interval should not be interpreted as proof that values outside it are impossible, or as a direct measure of clinical importance. It describes statistical uncertainty under the method used.

The posted percentages are rounded, while the comparison estimate is reported on a proportion scale. Small apparent inconsistencies between rounded arm percentages and the comparison estimate can arise from presentation precision; the comparison should be read using its posted estimate and interval rather than recalculating a contrast from rounded percentages.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 13 outcome measures and 12 posted secondary outcomes, including progression-free survival, overall survival, response duration, stable-disease duration, adverse events, and pharmacokinetic measures. The primary response outcome is one among several outcomes recorded for the trial. When multiple outcomes or comparisons are examined, the chance of obtaining an apparently unusual result can increase. As a general statistical principle, a prespecified approach to multiplicity can help explain how a set of tests should be interpreted. The registry record does not report whether such an approach was planned or used.

The posted p-value for IMC-A12 plus cetuximab versus IMC-A12 alone is explicitly unadjusted. No multiplicity-adjusted p-value or testing hierarchy is reported. No p-value is listed for the K-ras wild-type comparison. The registry lists no posted analyses, so the full set of analyses and any decisions about which comparisons were confirmatory cannot be determined from the record.

The primary outcome population is described as all randomized or enrolled participants who received at least one dose of study drug. This definition excludes participants who did not receive a dose, but the record does not provide further detail about how participants were counted if response status could not be assessed, if they discontinued early, or if data were missing. The missing-data approach, handling of participants without an evaluable response, and any sensitivity analyses are not reported in the registry record.

The record also does not describe whether the primary analysis followed intention-to-treat principles, how protocol deviations were handled, or whether analyses were adjusted for baseline characteristics. Those details matter because the reported analysis population is not described simply as all randomized participants; it specifies receipt of at least one dose. Without a fuller analysis plan and participant accounting, the posted summaries should be interpreted as applying to the stated treated population, rather than assumed to represent another analysis population.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: abdominal pain (8.7%), asthenia (8.7%), disease progression (8.7%), thrombocytopenia (5.0%), constipation (5.0%).

The registry reports serious adverse event counts for each group: 7 participants in the IMC-A12 group, 6 in the IMC-A12 plus cetuximab group, and 4 in the K-ras wild-type combination group. The corresponding numbers at risk were 23, 21, and 20. These are counts of participants reported with serious adverse events, not counts of individual events, and they should be read alongside the group sizes.

For other treatment-emergent adverse events, the recorded participant counts were 18, 19, and 20, respectively, with the same group-specific numbers at risk. The registry also lists serious-event terms and their percentages: abdominal pain, asthenia, and disease progression at 8.7% each; thrombocytopenia, constipation, and small intestinal obstruction at 5.0% each. These term percentages are registry entries and are not necessarily interchangeable with the overall participant counts, because a participant may experience more than one event. The record does not provide event-level detail in the registry record for this explanation.

Deaths are listed as null for each group, so death counts are not reported in the registry record. The serious adverse event counts alone do not establish a comparative safety profile. In general, interpretation of adverse-event differences also depends on definitions, duration of observation, severity, attribution, and completeness of reporting; those details are not reported in the registry record.

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

The primary result describes the proportion of treated participants with a confirmed complete or partial response during the registry’s specified assessment period. The observed response rates were 0% for IMC-A12, 4.8% for IMC-A12 plus cetuximab, and 0% for the K-ras wild-type combination group. The comparison of the first combination group with IMC-A12 alone had a risk-difference estimate of 0.048 and a 95% confidence interval from -0.043 to 0.139. These results describe the posted data; they do not establish that one treatment is superior or equivalent to another.

A confidence interval spanning zero for the risk difference indicates that the estimate remains compatible with no difference under the reported interval method, as well as differences in either direction within the interval. It does not prove that the groups are the same. Conversely, the point estimate by itself does not establish a meaningful difference. The posted unadjusted p-value of 0.29 is another summary of the comparison, not a probability that the treatments are equal or a measure of clinical benefit.

The trial’s third group has a specific K-ras wild-type and prior-response eligibility description. Its findings should not be treated as a direct substitute for findings in the other groups or generalized automatically to participants who would not meet those criteria. The trial is randomized and parallel-group, but it was unmasked, and the primary endpoint depended on investigator classification. The registry does not report details that would clarify how response assessments were protected from potential assessment bias.

The primary endpoint does not answer questions about duration of response, stable disease, progression-free survival, overall survival, or adverse-event balance. Those outcomes are listed in the registry, but their numerical results are not included in the registry record for this explanation. Nor do these data establish effects in populations or treatment settings not described by the registry. The appropriate interpretation is limited to the recorded response proportions, their uncertainty, and the population and timeframe specified for that outcome.

14. Why This Trial Matters Statistically

This trial illustrates why a response percentage should not be read in isolation. The primary result is presented for three groups, but the third group has a specific K-ras wild-type eligibility description and a particular prior treatment history. Keeping that distinction visible helps avoid treating all three groups as if they represented identical populations.

The trial also illustrates the importance of precision. The response estimates are based on group sizes of 23, 21, and 20, and the reported confidence intervals extend substantially beyond the point estimates. A percentage can appear straightforward while remaining uncertain, especially when relatively few participants meet the event definition. Reporting the interval alongside the estimate makes that uncertainty explicit.

The comparison measure adds another useful perspective. The registry’s risk-difference estimate for IMC-A12 plus cetuximab versus IMC-A12 alone is accompanied by an interval spanning zero. The estimate and interval are more informative together than either the p-value or the arm percentages alone. The unadjusted p-value should be interpreted in context, particularly because the record lists multiple outcomes and does not report a multiplicity procedure.

Finally, the registry record identifies key limits to what can be inferred: no posted analyses, no reported analysis plan, and no described approach to missing response data. These are not reasons to discard the observed results. They are reasons to state clearly which population and endpoint the results describe, and to avoid extending them to outcomes or analyses that are not reported.

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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The registry record does not report a full statistical analysis plan, the confidence-interval method, allocation ratio, randomization procedures, or any interim-analysis plan. It lists no posted analyses. Consequently, the exact analysis procedures behind the primary summaries cannot be established from the record alone.

The primary analysis population is defined as participants who were randomized or enrolled and received at least one dose. The record does not explain how participants with missing or unevaluable response assessments were handled, whether any participants were excluded from the endpoint analysis, or whether sensitivity analyses were performed. It also does not report an intention-to-treat analysis.

The study was unmasked, and response was classified by investigators. The registry gives RECIST version 1.0 criteria but does not report whether response assessment was independently reviewed or otherwise protected from knowledge of treatment assignment. The record also does not report baseline characteristics or adjusted comparisons, so the extent to which the groups were similar on other factors cannot be evaluated from these registry entries.

The third group has a distinct eligibility description based on K-ras wild-type status and prior response or stable disease lasting at least 24 weeks before progression. Its comparison with the broader monotherapy group therefore needs particular caution. The posted results do not include numerical findings for the listed secondary outcomes. In addition, deaths are not reported in the registry record. These gaps limit conclusions about survival, response durability, comparative safety, and the completeness of outcome reporting.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study Using IMC-A12 (Cixutumumab) With or Without Cetuximab in Participants With Metastatic Colorectal Cancer Who Have Failed a Treatment Regimen That Consisted of a Prior Anti-EGFR Therapy — NCT00503685.
• Registry record last updated 2018-06-06; status last verified 2018-05.
• Results first posted 2018-06-06.
• 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

NCT00503685 is a completed randomized Phase 2 parallel-group trial of IMC-A12 alone or with cetuximab in metastatic colorectal cancer after progression on prior anti-EGFR therapy. The study was unmasked. The primary endpoint was the percentage of treated participants with confirmed complete or partial response by investigator assessment using RECIST version 1.0, through objective progressive disease and up to 28.3 weeks.

The posted response rates were 0% for IMC-A12, 4.8% for IMC-A12 plus cetuximab, and 0% for the K-ras wild-type combination group. The first combination-versus-monotherapy risk difference was 0.048, with a 95% confidence interval from -0.043 to 0.139 and an unadjusted p-value of 0.29. The record lists 13 outcome measures, 12 posted secondary outcomes, and no posted analyses. Analysis details and handling of missing response data are not reported in the registry record.