A Pilot Trial of GI-4000 Plus Bevacizumab and Either FOLFOX or FOLFIRI: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Pilot Trial of GI-4000 Plus Bevacizumab and Either FOLFOX or FOLFIRI (NCT01322815), a non-randomized phase 2 study. The primary outcome is Number of Participants Alive and Free of Progression at 4 Months (Patients Who Have Undergone Prior Therapy) and 10 Months (Untreated Patients).

2. Clinical Question

3. Trial Design

This was a phase 2 pilot trial with parallel treatment groups, non-randomized allocation, and no masking. The registry lists enrollment as 11 and the study status as terminated. The study start is recorded as 2010-10 and primary completion as 2014-09. The reason for termination is not reported in the registry record.

The trial concerned patients with RAS mutant positive metastatic colorectal cancer. The registry describes newly diagnosed patients and patients who had completed first-line therapy. The treatment descriptions reflect these differing clinical contexts: one arm received GI-4000 alongside chemotherapy and bevacizumab, while the maintenance arm received GI-4000 and bevacizumab after first-line chemotherapy. The record does not describe these arms as randomized alternatives for the same treatment decision.

In the chemotherapy arm, GI-4000 was described as 40 yeast units before chemotherapy and then between cycles, 7 days after each chemotherapy cycle, for up to 8 cycles. The description then specifies maintenance injections of GI-4000 and bevacizumab every 2 weeks. For the other arm, the record describes maintenance with GI-4000 and bevacizumab for patients who completed first-line chemotherapy.

The study purpose included assessing safety, effects against cancer over time, and immune response to GI-4000. These aims do not establish what was observed. The registry lists 1 outcome measure and 0 analysis results. A detailed statistical analysis plan, including planned comparisons and analysis populations, 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.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Patients with RAS mutant positive metastatic colorectal cancer (CRC), either newly diagnosed, or having completed first line therapy with an oxaliplatin or irinotecan plus fluoropyrimidine and bevacizumab containing regimen.

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: Patients with RAS mutant positive metastatic colorectal cancer (CRC), either having received prior 1st-line therapy with an oxaliplatin or irinotecan plus fluoropyrimidine and bevacizumab containing regimen, or no prior therapy.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants Alive and Free of Progression at 4 Months (Patients Who Have Undergone Prior Therapy) and 10 Months (Untreated Patients), measured over 4 Months for patients who had undergone prior 1st-line therapy, and 10 months for previously untreated patients.

The primary endpoint is a count of participants who were alive and free of progression at a specified assessment time. The time point differs by treatment history: 4 months for patients who had undergone prior therapy and 10 months for previously untreated patients. Both assessments are described as measured from the first GI-4000 treatment. Although the endpoint title refers to a number of participants, its description calls the clinical benefit rate a proportion. The registry does not provide a reported count or proportion for either group.

This kind of endpoint combines survival status and disease progression status at a defined time. It can give a fixed-time description of clinical status without requiring a time-to-event summary. That can be useful when the intended question concerns whether participants remain alive and free of progression at a clinically specified landmark. It does not, by itself, describe when progression occurred between assessments or how long participants remained in each state.

The registry’s progression description lists complete response, partial response, progressive disease, and stable disease, with size-change criteria for some categories. It defines complete response as disappearance of all target lesions, partial response as a 30% decrease in the sum of the longest diameter of target lesions, and progressive disease as a 20% increase in that sum. Stable disease is described as small changes that do not meet the stated criteria. The record does not clarify how these response categories were translated into the primary alive-and-free-of-progression count, nor does it report the assessment procedures or endpoint data.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The record identifies the primary measure as a binary-status endpoint summarized as a number of participants. In general, a binary endpoint classifies each participant according to whether a defined condition is met at the assessment time. Here, the condition combines being alive and free of progression. A count describes how many participants met that condition; a proportion additionally requires a clearly defined denominator. The registry describes a clinical benefit rate but does not report the count, denominator, or calculated rate.

What does a fixed-time endpoint capture?

A fixed-time endpoint describes status at a chosen landmark. It is different from a time-to-event analysis, which uses the time until an event and can account for differing follow-up durations under its assumptions. A landmark result may be straightforward to communicate, but it does not show the full timing of progression or death. Participants who experience an event before the landmark and participants who remain event-free through it are distinguished by their status at that time; the endpoint alone does not explain the clinical course between those points.

The registry specifies 4 months for patients who had undergone prior therapy and 10 months for previously untreated patients. These separate time points should be interpreted in their own populations. Direct comparison across them would combine differences in assessment timing with differences in treatment history and treatment context. The record does not describe a common-landmark comparison or a statistical method for comparing these groups.

What do uncertainty estimates mean?

In general, a confidence interval expresses statistical uncertainty around an estimated effect or rate under the assumptions of the analysis. A narrow interval indicates greater precision than a wide interval, but interval width also depends on the amount and distribution of information. An interval does not account automatically for bias from non-random allocation, unclear outcome classification, or incomplete follow-up. No confidence interval for the primary endpoint is reported in the registry record.

A p-value, when used, assesses how compatible the data are with a specified null hypothesis under a statistical model. It does not measure the probability that a treatment works, and it does not convey the magnitude or clinical importance of an effect. The registry lists 0 analysis results for the outcome, so a primary endpoint p-value or modeled comparison is not reported. The statistical plan and any planned hypothesis tests are also not reported in the registry record.

Why does allocation matter?

Random allocation can help balance measured and unmeasured prognostic factors between groups on average. This study is listed as non-randomized, so that protection is not established. General sources of confounding can include prior treatment, disease severity, patient eligibility, and clinical decisions about treatment. The arm descriptions themselves identify different treatment circumstances, which makes a direct arm contrast particularly difficult to interpret as an effect of one regimen versus another. The registry does not report an adjustment strategy or enough baseline information to evaluate comparability.

Unmasking is also relevant to some outcomes. The study is listed as having no masking. In general, knowledge of treatment can influence outcome assessment or reporting, especially where assessment involves judgment. The record does not explain whether progression assessments were centrally reviewed, conducted using blinded assessment, or otherwise protected from knowledge of treatment.

How should planning calculations be read?

Sample-size calculations based on an observed effect are planning illustrations, not evidence that the trial had a particular level of power after completion. They describe how a future study might be planned under stated assumptions. The record’s illustration assumptions include a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the detectable effect expressed as a fraction of the observed effect. Those assumptions do not establish the original study’s design rationale or statistical plan. The sample-size justification for this pilot is not reported in the registry record.

Over-dispersion is a general issue when count outcomes vary more than a simple model expects; it can make standard errors too small if the model does not allow for that extra variability. It is not identified as a feature of this endpoint, which is described as a participant count at a fixed time, and no model or dispersion estimate is reported. Statistical methods should match the outcome structure and the way participants are followed, but the record does not specify such methods for the primary outcome.

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("Chemotherapy and GI-4000", "GI-4000 and Bevacizumab")
n      <- c(7, 4)
events <- c(4, 2)
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  Chemotherapy and GI-4000  7  4  57.1  18.4  90.1  25.0  84.2  24.5  84.3
ARM  GI-4000 and Bevacizumab  4  2  50.0  6.8  93.2  15.0  85.0  14.7  85.3

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 1 outcome measure and 0 analysis results. It does not report a multiplicity strategy, such as how testing across outcomes, time points, or treatment groups would be handled. Without a stated analysis plan, it is not possible to determine whether the listed endpoint was the sole planned primary analysis or how any additional analyses were treated.

Missing data are an important consideration for a fixed-time endpoint. In general, a participant without an evaluable status at the landmark cannot automatically be treated as alive and progression-free, nor can that participant automatically be treated as having an event. The approach depends on the prespecified endpoint definition and analysis plan. The registry does not report the number of participants with missing endpoint assessments, reasons for missingness, follow-up completeness, or any method for handling missing status.

The analysis population is also not reported in the registry record. It is therefore unclear whether the primary outcome was intended to include all enrolled participants, only those who began treatment, or another defined population. The record does not specify exclusions, protocol deviations, or how participants who discontinued treatment or withdrew would be handled in the endpoint analysis.

These omissions limit assessment of bias and reproducibility. They do not establish that missing data or multiplicity problems occurred; they mean the registry record does not document how these issues were addressed. Any interpretation should distinguish absence of reported methods from evidence about what the investigators did.

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: thrombosis (14.3%), low neutrophil count (14.3%).

The registry reports serious adverse events by treatment group using the number of participants at risk and the number affected. In the chemotherapy and GI-4000 group, 2 participants were affected by serious adverse events, with 7 at risk. In the GI-4000 and bevacizumab group, 0 participants were affected, with 4 at risk. The record lists thrombosis and low neutrophil count among the top serious terms, each at 14.3%.

These figures are descriptive. The groups were not randomized, and the arm descriptions reflect different treatment contexts. The counts therefore do not establish that one treatment caused more or fewer serious events than the other. Small group sizes also mean that a change in the status of a participant could materially alter the descriptive pattern, without providing a stable estimate of comparative safety.

The registry also reports other adverse events: 7 participants affected among 7 at risk in the chemotherapy and GI-4000 group, and 4 affected among 4 at risk in the GI-4000 and bevacizumab group. The record does not supply event-level detail for these entries in the information. Death counts are not reported in the registry record. The figures do not describe event timing, duration, recurrence, or attribution, and should not be read as a complete account of safety.

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

The registry record establishes that a pilot study was conducted to assess GI-4000 in combination with bevacizumab and either chemotherapy or maintenance treatment in patients with RAS mutant positive metastatic colorectal cancer. It also documents a primary endpoint based on being alive and free of progression at different fixed times for previously treated and untreated patients. These details clarify the intended question and treatment settings.

The record does not report the primary endpoint counts, rates, or analysis results. It therefore does not show the size or precision of any clinical benefit estimate. It also cannot establish whether outcomes differed between the treatment arms or whether any difference was caused by treatment. The non-randomized allocation and distinct treatment contexts would require particular care even if comparative outcomes were reported.

General statistical interpretation distinguishes a descriptive observation from a causal treatment effect. A count of participants meeting an endpoint would describe what was observed in the analyzed group. To estimate a treatment effect, the analysis would need a defensible comparison and clear assumptions about group comparability, outcome measurement, and follow-up. Those details are not reported for the primary outcome.

The safety entries report serious and other adverse-event counts, but these are also descriptive rather than comparative causal estimates. The registry’s serious-event terms and counts should be understood within the small, non-randomized study and alongside the lack of detail on timing and attribution.

Accordingly, the registry record supports a description of the study design, endpoint definition, and reported safety counts. It does not support conclusions about treatment efficacy, comparative effectiveness, or a complete safety profile. The reason for study termination and the investigators’ full statistical analysis are not reported in the registry record.

14. Why This Trial Matters Statistically

This trial is statistically instructive because its primary outcome sounds simple but combines several elements: a defined patient status, a progression assessment, and a time-specific evaluation. Clear interpretation depends on knowing the population, the landmark, the denominator, and the rules for classifying progression. The registry identifies the assessment times and describes response categories, but it does not report the endpoint results or the detailed analysis rules.

The study also illustrates why design features shape what an outcome can support. Non-randomized allocation does not establish that treatment groups are comparable, and the arm descriptions correspond to different treatment contexts. A direct contrast would therefore be vulnerable to confounding and could not be read as a randomized treatment effect. This is a general limitation of observational comparisons, not a finding that a particular bias occurred in this trial.

Different time points for previously treated and untreated patients raise a further interpretive issue: the endpoint does not represent the same landmark question across both groups. Knowing that distinction helps prevent an apparent contrast from being mistaken for a common-time comparison.

Finally, the record distinguishes between a study’s intended purpose and the results needed to answer it. The stated aims include safety, effects over time, and immune response, while the available record lists no analysis results for the primary outcome. A sound statistical reading treats that gap as missing evidence in the registry record, rather than inferring a result from the study’s status or its stated aims.

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 registry record contains limited information for assessing the primary endpoint. It reports the endpoint definition and assessment times but does not report the observed outcome count, denominator, proportion, confidence interval, or analysis result. The detailed statistical plan, analysis population, and method for handling missing assessments are not reported in the registry record.

The non-randomized design limits causal interpretation of any comparison between treatment groups. The arm descriptions also reflect different treatment circumstances, including chemotherapy alongside GI-4000 and bevacizumab versus maintenance treatment after first-line chemotherapy. The record does not report baseline characteristics or an adjustment strategy that would allow readers to assess comparability.

Outcome assessment details are incomplete. The record lists response categories and some lesion-size criteria, but does not describe assessment frequency, independent review, or how those categories informed the primary alive-and-free-of-progression endpoint. Masking is listed as none. The record does not report whether any safeguards were used to limit bias in assessment.

Safety reporting is limited to counts and selected serious-event terms. The death count is not reported in the registry record, and event timing, duration, severity detail, and attribution are not provided. The registry lists the study as terminated, but does not report the reason. These gaps restrict interpretation; they should not be treated as evidence that an unreported event or procedure did or did not occur.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Pilot Trial of GI-4000 Plus Bevacizumab and Either FOLFOX or FOLFIRI — NCT01322815.
• Registry record last updated 2016-08-15; status last verified 2016-02.
• Results first posted 2016-08-15.
• 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

NCT01322815 is a phase 2, non-randomized, unmasked, parallel pilot trial sponsored by Georgetown University. The registry records enrollment of 11, status as terminated, a start date of 2010-10, and primary completion in 2014-09. The reason for termination is not reported in the registry record.

The study concerned patients with RAS mutant positive metastatic colorectal cancer and evaluated GI-4000 alongside bevacizumab and chemotherapy, or GI-4000 with bevacizumab as maintenance. The primary endpoint was the number of participants alive and free of progression at 4 months for patients with prior therapy and 10 months for previously untreated patients. The registry lists 1 outcome measure and 0 analysis results.

Serious adverse-event counts are reported for both treatment groups, along with thrombosis and low neutrophil count as top serious terms. Because allocation was non-randomized and treatment contexts differed, the adverse-event counts are descriptive rather than causal comparisons. Primary endpoint results, analysis methods, and the reason for termination are not reported in the registry record.