Aflibercept and FOLFOX6 Treatment for Previously Untreated Stage IV Colorectal Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Aflibercept and FOLFOX6 Treatment for Previously Untreated Stage IV Colorectal Cancer (NCT01652196), a na phase 2 study. The primary outcome is Proportion of Patients Alive and Progression-free at 15 Months.

2. Clinical Question

The clinical question is therefore about the observed status of participants receiving the combination, not about a randomized difference between treatments. A single-group study can describe outcomes among people enrolled in that group, but it does not provide a concurrent control group for separating treatment effects from other explanations for those outcomes. The registry lists additional outcomes, including response, surgery, progression-free survival, overall survival, and adverse events. Results for those outcomes are not reported in the registry record.

3. Trial Design

This is a phase II, single-group study of aflibercept with modified FOLFOX6. The registry lists enrollment of 56 participants and identifies the study status as completed. The listed start date is 2012-11-14, and the primary completion date is 2019-08-06. These dates describe the registry record; they do not supply a treatment or follow-up schedule beyond the primary endpoint’s timeframe.

Allocation is listed as not applicable, consistent with the single-group design, and masking is listed as none. There is no randomized control group or other trial arm described for a like-for-like comparison. The intervention list includes aflibercept, oxaliplatin, leucovorin, and fluorouracil, as well as correlative studies and imaging procedures. The arm description identifies the treatment as aflibercept with combination chemotherapy and notes that leucovorin could be omitted if unavailable because of drug shortages.

The registry describes the primary endpoint as the proportion of participants alive and progression-free at 15 months from initiation of therapy. The planned statistical description assumes a binomial distribution of treatment successes and calls for a proportion estimate with an exact 95% confidence interval. The registry does not report the observed count of participants meeting the endpoint, the number included in its analysis, or the resulting estimate and interval.

A single-group phase II design can characterize outcomes and safety in the enrolled group. Without a control group, it cannot establish how those outcomes compare with another treatment or with an untreated course. The registry record does not report a protocol-based sample-size justification, a detailed analysis plan, or interim analyses.

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

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 Proportion of Patients Alive and Progression-free at 15 Months, measured over At 15 months from initiation of therapy.

The primary endpoint is the proportion of participants who are alive and progression-free at 15 months from initiation of therapy. It combines two conditions at a defined time: a participant must be alive and must not have experienced disease progression by that point. A participant who does not meet either condition is not counted as a success under that endpoint definition.

A proportion gives the frequency of participants meeting a specified outcome within the group being analyzed. In general, a fixed-time endpoint can provide an interpretable snapshot at a clinically specified follow-up point, while a time-to-event analysis uses the timing of events and can account for differing follow-up durations in its analysis. The registry lists progression-free survival separately as a secondary outcome, but its analysis details and results are not reported in the registry record.

The registry’s statistical description assumes that the number of participants who are alive and progression-free follows a binomial distribution. It states that a proportion estimate and exact 95% confidence interval will be calculated. In general, a confidence interval expresses the uncertainty around an estimated proportion; its width depends in part on the amount of information available. The registry record does not report the primary endpoint estimate, interval, analysis population, or missing-data handling, so the outcome’s observed frequency and precision cannot be assessed from the record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry’s methods description for the primary endpoint is brief. It says that treatment successes—participants alive and progression-free at 15 months—are assumed to follow a binomial distribution. It also states that a proportion estimate and exact 95% confidence interval will be calculated. It does not report an observed estimate, the confidence interval, or further details of the endpoint analysis.

What does a binomial model mean for this endpoint?

In general, a binomial model represents a set of participants for whom each person is classified into one of two categories for a defined outcome. Here, the stated success category is being alive and progression-free at the specified time. The model is used to estimate the proportion of participants meeting that definition. Its interpretation depends on having a clear outcome definition and an identified analysis population. The registry does not report the number of participants classified as successes, the analysis denominator, or how participants with unknown status were treated.

What does an exact confidence interval communicate?

In general, a confidence interval describes statistical uncertainty around an estimate. An exact interval is calculated using the assumed binomial model rather than relying on a large-sample normal approximation. This is one method for expressing uncertainty in a proportion. The interval is not a guarantee that an individual participant’s outcome is predictable, and it does not address bias from missing data, outcome assessment, or study design. Because the registry record does not include the endpoint estimate or interval, neither the estimated proportion nor its precision can be evaluated.

How does the design shape the interpretation?

The trial is identified as single-group, with allocation listed as not applicable and masking listed as none. In general, single-group results describe outcomes among participants receiving the study intervention; they do not estimate a randomized treatment contrast. Without a concurrent comparator, the primary proportion cannot show how the same participants would have fared under a different treatment. The registry record does not report a comparative statistical analysis.

The primary endpoint is fixed at 15 months after therapy initiation. In general, a fixed-time proportion and a time-to-event measure answer related but distinct questions. A fixed-time measure classifies participants at one specified time, whereas time-to-event methods use the timing of events and may account for censored follow-up under their assumptions. The registry lists progression-free survival as a secondary outcome, but the method used for that outcome is not reported in the registry record. No time-to-event analysis details should be inferred from the primary endpoint description.

What is not documented about the analysis?

The registry records zero analyses, and no analysis population is described for the primary endpoint. The record does not report how progression was defined for analysis, how follow-up status was established, how missing or incomplete outcome data were handled, or whether any participants were excluded from the endpoint analysis. The registry also does not report a protocol-based sample-size justification, an interim-analysis plan, or other detail about the statistical plan. Absence of those details in the registry record does not establish what procedures may have appeared in a separate protocol.

Any sample-size illustration associated with the analysis is a planning illustration based on the observed effect, not the trial’s own documented design justification. In general, such illustrations show how sample size could vary under stated assumptions; they are not a measure of observed power and do not substitute for the trial’s actual design rationale. The stated illustration assumptions include a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. Those hypothetical two-arm assumptions do not describe the enrolled single-group design. No sample-size figure is needed to interpret the endpoint, and no unreported value can be inferred from the assumptions.

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("Aflibercept (Combination Chemotherapy)")
n      <- c(56)
events <- c(0)
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  Aflibercept (Combination Chemotherapy)  56  0  0.0  0.0  6.4  0.0  6.4  0.0  6.3

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary endpoint and several secondary outcomes, including objective response, surgery, progression-free survival, overall survival, severe adverse events or toxicities, dose changes or delays, and stopping treatment because of adverse reactions or reduced willingness to continue. It records eight outcome measures, but does not report results for them. The analysis count is listed as zero.

When a study evaluates multiple outcomes, the chance of at least one apparently unusual result can increase if each is tested separately without accounting for multiplicity. In general, a prespecified strategy can clarify which outcomes are confirmatory and whether adjustments or a hierarchy are used. The registry record does not report a multiplicity strategy, testing hierarchy, or a detailed statistical analysis plan. It is therefore not possible to determine from the record whether or how multiple outcome analyses were controlled.

The primary endpoint description specifies a binomial assumption and an exact 95% confidence interval, but does not identify the analysis population or provide an endpoint result. The record does not report the number with evaluable 15-month status, the handling of participants with incomplete follow-up, or whether any missing observations were imputed or excluded. In general, the handling of missing outcome information can affect both the estimated proportion and the uncertainty around it. No particular missing-data approach should be assumed.

Eligibility and analysis populations are also not described in detail. The registry’s primary population field is blank, and the record does not specify whether the endpoint was assessed among all enrolled participants or a subset. These omissions limit interpretation of any proportion that might be reported elsewhere; the registry record itself does not provide enough information to reconstruct an analysis.

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: thromboembolic event (12.5%), hypertension (7.1%), non-cardiac chest pain (3.6%), abdominal pain (3.6%), dyspnea (3.6%).

The serious adverse-event record lists 56 participants at risk and seven affected by serious adverse events in the aflibercept combination-chemotherapy group. It also lists 56 participants at risk for other adverse events and 56 affected. The record lists one death in the group. These are reported counts and should be read as descriptive safety information, not as proof that an event or death was caused by treatment.

The registry lists thromboembolic event at 12.5%, hypertension at 7.1%, and non-cardiac chest pain, abdominal pain, dyspnea, and fever at 3.6% each among the top serious-event terms. These percentages are reproduced as recorded. The entry does not provide additional context about timing, recurrence, duration, treatment exposure, or event attribution. It also does not offer a control group for comparing event frequencies.

In general, serious adverse events are a regulatory reporting category and are not identical to a simple ranking of symptom intensity. A serious event can be classified by its consequences, while severity describes intensity; these concepts should not be treated as interchangeable. The registry’s listed counts and terms do not establish causality, and the listed death should not be assumed to be treatment-related. The record does not report detailed safety-analysis methods or comparative safety results.

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

The record establishes that this was a completed, single-group phase II study of aflibercept with modified FOLFOX6 in previously untreated metastatic colorectal cancer. It also identifies the primary endpoint: the proportion alive and progression-free at 15 months from therapy initiation. These design and endpoint details define the question the study set out to describe.

The record does not report the primary endpoint estimate or exact 95% confidence interval. It therefore does not establish what proportion of participants met the endpoint or how precisely that proportion was estimated. Enrollment of 56 participants is not a substitute for the endpoint denominator, since the registry does not state how many were evaluable for this outcome.

Because the trial has no comparator arm, an outcome in the treated group would not by itself show a difference versus another treatment. In general, a randomized control group helps distinguish a treatment contrast from other explanations for observed outcomes. The single-group design cannot answer that comparative question. It also does not support a causal conclusion based solely on a reported event or outcome within the treated group.

The registry lists secondary outcomes and adverse-event information, but does not report results for the listed efficacy outcomes. The adverse-event counts and terms provide descriptive safety information; they do not establish treatment attribution or comparative risk. Missing information on endpoint analysis, follow-up, and missing-data handling further limits interpretation. The appropriate reading is that the registry describes the study’s design and intended outcome assessment, while leaving the primary outcome result and its precision unreported.

14. Why This Trial Matters Statistically

This trial is statistically notable for the distinction between a clearly defined endpoint and an unavailable endpoint result. The registry states a specific question—whether participants are alive and progression-free at 15 months—and identifies a binomial proportion with an exact 95% confidence interval as the planned summary. Those details indicate what quantity the analysis was intended to estimate. Without the observed estimate, denominator, or interval, however, the result itself cannot be evaluated.

The single-group design also illustrates why design matters to interpretation. In general, a proportion within one treatment group is descriptive. It is not a randomized contrast, and it cannot establish what would have occurred under another intervention. The registry identifies no comparator, so claims of relative benefit or harm cannot be derived from its design.

The record also highlights the value of transparent reporting beyond a primary endpoint label. Analysis populations, missing-data handling, progression assessment, and multiplicity plans help readers understand how an estimate was produced and what uncertainty it captures. Those details are not reported in the registry record. Their absence means readers cannot independently assess whether the analysis population matched the enrolled group or how incomplete follow-up may have been treated.

Finally, the safety entries show why event counts require context. Serious adverse-event counts and listed terms can describe what was recorded, but without attribution, timing, and a comparator they do not establish causation or relative safety. The statistical lesson is to separate study design, planned methods, observed results, and causal conclusions. In this record, the design and intended primary analysis are described, while the primary outcome result is 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.

The main limitation for interpretation is that the registry record does not report the primary endpoint result. It gives no observed proportion, exact 95% confidence interval, or analysis denominator for participants alive and progression-free at 15 months. Enrollment of 56 does not resolve those omissions, because the number included in the endpoint analysis is not reported.

The single-group design has no concurrent comparator. Thus, even if outcome estimates were available, they would describe the enrolled group rather than provide a randomized comparison. The registry also lists no masking. How outcome assessments were conducted and whether progression assessments were independently reviewed are not reported in the registry record.

The record does not report detailed eligibility criteria beyond its summary description and condition list, or define the primary analysis population. It also does not describe the handling of missing 15-month status, withdrawals, censoring, or exclusions. These details can affect the interpretation of an endpoint estimate, but no particular procedure can be inferred.

The registry lists secondary outcomes and safety events without corresponding efficacy results or detailed analysis methods. A multiplicity plan, interim-analysis plan, and protocol-based sample-size justification are not reported in the registry record. The listed serious-event terms and counts do not include enough context to establish causation, duration, or comparative risk. These limitations concern what the record documents; they do not establish what may have been included in a separate protocol or report.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Aflibercept and FOLFOX6 Treatment for Previously Untreated Stage IV Colorectal Cancer — NCT01652196.
• Registry record last updated 2025-02-05; status last verified 2025-02.
• Results first posted 2025-02-05.
• 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

NCT01652196 is a completed phase II, single-group study of aflibercept with modified FOLFOX6 for previously untreated metastatic colorectal cancer. The registry lists enrollment of 56 participants, no masking, a start date of 2012-11-14, and a primary completion date of 2019-08-06.

The primary endpoint is the proportion alive and progression-free at 15 months from therapy initiation. The registry describes a binomial estimate with an exact 95% confidence interval, but does not report the endpoint result, interval, or analysis population. It lists secondary efficacy and safety outcomes, but their results are not reported in the registry record. The adverse-event record lists seven participants with serious adverse events and one death in the treatment group; these entries do not establish treatment causality.