A Study to Assess the Pharmacokinetics of Ramucirumab (IMC-1121B) in Combination With FOLFIRI: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Assess the Pharmacokinetics of Ramucirumab (IMC-1121B) in Combination With FOLFIRI (NCT01634555), a na phase 2 study. The primary outcome is Pharmacokinetics: Dose-Normalized Area Under the Concentration Versus Time Curve of Irinotecan and Its Metabolite SN-38 From Time Zero to Infinity [AUC(0-∞)] in Cycle 1.

2. Clinical Question

3. Trial Design

This completed Phase 2 study enrolled 29 participants and was registered as a single-group study with allocation recorded as NA and masking recorded as none. It concerned pharmacokinetics of ramucirumab with FOLFIRI in participants with advanced malignant solid tumors. The registry dates the study start to 2012-10 and primary completion to 2013-08.

The treatment description specifies sequential administration. Ramucirumab (IMC-1121B) was given before FOLFIRI, which comprised irinotecan, folinic acid and 5-fluorouracil. FOLFIRI was administered each cycle, while ramucirumab began in Cycle 2; each cycle was 2 weeks. This schedule describes the intended treatment sequence, but does not establish a randomized comparison between treatment conditions.

The primary outcome concerned dose-normalized AUC from time zero to infinity for irinotecan and SN-38 in Cycle 1. The stated analysis population required completion of the specified treatment on Cycle 1, Day 1 and Cycle 2, Day 1, as well as concentration data sufficient to calculate the Cycle 1 AUC. Thus, the population for the primary pharmacokinetic measure was defined by treatment completion and data availability, not simply by enrollment.

The registry lists secondary outcomes for ramucirumab maximum concentration and treatment-emergent anti-drug antibodies. It lists six outcome measures and four analyses, but the available record does not provide a full protocol or statistical analysis plan. The rationale for the enrollment target, randomization procedures, and any planned interim analyses are 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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All participants in DDI population (who completed the required treatment in Cycle 1, Day 1 and Cycle 2, Day 1) and had sufficient concentration data to calculate irinotecan and its metabolite SN-38 AUC(0-∞) in Cycle 1.

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 enrolled participants who received at least 1 dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as Pharmacokinetics: Dose-Normalized Area Under the Concentration Versus Time Curve of Irinotecan and Its Metabolite SN-38 From Time Zero to Infinity [AUC(0-∞)] in Cycle 1, measured over Cycle 1: 0, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 22, 25, 28, 31, 34, 48, 72, 96 and 168 hours post-irinotecan infusion.

The primary endpoint is dose-normalized area under the concentration-versus-time curve from time zero to infinity, abbreviated AUC(0-∞), for irinotecan and its metabolite SN-38 in Cycle 1. AUC represents drug exposure over time, estimated from measured concentrations. Dividing by dose expresses exposure relative to the administered dose, which can assist comparisons when dose levels differ. The registered unit is nanograms*hour/milliliter/milligram.

The registry describes the reported measure as a geometric least-squares mean adjusted for cycle, participant and random error. It specifies concentration sampling after irinotecan infusion at 0, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 22, 25, 28, 31, 34, 48, 72, 96 and 168 hours. Pharmacokinetic measures are used to characterize how drug concentration changes over time and the resulting exposure.

The endpoint is a pharmacokinetic measure, not a direct measure of tumor response or clinical benefit. Although the study purpose concerns the effect of concomitant ramucirumab, the registered primary endpoint is specifically identified as a Cycle 1 measure. Numerical estimates for irinotecan or SN-38 AUC(0-∞), their confidence intervals, and a numerical comparison relevant to the effect of concomitant ramucirumab are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is described as a geometric least-squares mean for dose-normalized AUC(0-∞), with a 90% confidence interval. These terms describe how the concentration data were transformed and summarized; they do not supply the missing numerical results. The endpoint population was defined by required treatment completion and sufficient concentration measurements for the AUC calculation.

What does AUC measure?

General statistical explanation: Area under the concentration-versus-time curve represents cumulative exposure across a period of observation. AUC(0-∞) includes the observed concentration profile from time zero and an extrapolated tail extending beyond the last measured time. The accuracy of that tail depends on the concentration-time data and the assumptions used to model the decline. The registry identifies the AUC(0-∞) measure but does not report details of the calculation or extrapolation method.

The endpoint was dose-normalized, meaning the AUC was divided by dose. General statistical explanation: Dose normalization can make exposure estimates easier to interpret relative to administered amount. It does not adjust for every difference between participants, and it does not turn a single-group study into a randomized comparison. The registry reports the unit as nanograms*hour/milliliter/milligram.

What is a geometric least-squares mean?

General statistical explanation: A geometric mean summarizes values on a multiplicative scale, often after analysis on a logarithmic scale and transformation back to the original scale. A least-squares mean is a model-based adjusted mean, rather than necessarily the simple arithmetic average of the observed values. The registry calls the values geometric least-squares means and says they were adjusted for cycle, participant and random error. It does not report the model equation, estimation procedure, or additional covariates in the registry record.

Adjustment can account for specified features in a statistical model, but the meaning of an adjusted estimate depends on the model and the data supporting it. The record’s brief description does not provide enough detail to reproduce the model or determine how each adjustment was implemented. In particular, it does not report the numerical estimates, standard errors, or confidence limits needed to evaluate the fitted results.

How should a 90% confidence interval be read?

General statistical explanation: A confidence interval represents uncertainty about an estimated quantity under the assumptions of the analysis. It is not a range containing a stated proportion of individual participant measurements, and it is not a guarantee that the true value is within the particular interval. A narrower interval generally indicates greater precision than a wider interval, when the same quantity and method are being considered. Here, the registry names a 90% confidence interval but does not report its limits, so the precision of the primary estimates cannot be evaluated.

What do the concentration sampling times contribute?

The registry lists post-infusion measurements at 0, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 22, 25, 28, 31, 34, 48, 72, 96 and 168 hours for the Cycle 1 endpoint. General statistical explanation: Concentration measurements across time describe the shape of the exposure profile and support estimation of AUC. The timing and completeness of observations matter because missing or sparse measurements can affect estimation, particularly for portions of the curve that are not directly observed. The registry does not report the number of usable concentration measurements, the handling of incomplete profiles, or the AUC estimation algorithm.

The primary analysis population included participants who completed required treatment on Cycle 1, Day 1 and Cycle 2, Day 1 and had sufficient concentration data to calculate the Cycle 1 AUC for irinotecan and SN-38. This is a data- and completion-defined population. General statistical explanation: Restricting an analysis to participants with complete treatment and sufficient measurements may change the composition of the analyzed group relative to everyone enrolled. How that affects interpretation depends on why participants were excluded and whether their results differ from those included. Reasons for exclusions and the missing-data approach are not reported in the registry record.

The study’s sequential schedule and single-group structure also matter for interpretation. General statistical explanation: Repeated measurement or a treatment sequence can provide within-participant information, but a comparison across periods may also reflect time-related changes or sequence effects. A concurrent randomized control can help separate treatment effects from other influences; this study is not reported as having such a control. The registry record does not provide enough detail to evaluate a comparative model or determine whether period effects were assessed.

10. Multiplicity, Missing Data and Analysis Populations

The registry record does not report a multiplicity-adjustment plan. It lists a primary pharmacokinetic outcome and secondary outcomes concerning ramucirumab maximum concentration and treatment-emergent anti-drug antibodies. The record does not specify which hypotheses were confirmatory, how the multiple outcomes or analyses were ordered, or whether statistical testing was adjusted to account for multiple comparisons. Without that information, the nominal interpretation of any unreported tests cannot be assessed.

The primary pharmacokinetic population was defined as participants in the DDI population who completed required treatment in Cycle 1, Day 1 and Cycle 2, Day 1 and had sufficient concentration data to calculate Cycle 1 AUC(0-∞) for irinotecan and SN-38. This differs conceptually from treating enrollment alone as the analysis population. The registry record does not state how many participants met this definition or provide participant flow and reasons for any exclusions.

Handling of missing concentration measurements, incomplete treatment, protocol deviations, or unavailable outcome data is not reported in the registry record. The record also does not describe imputation, sensitivity analyses, or assumptions about missingness. These details matter because pharmacokinetic estimates rely on adequate concentration data over time, and exclusions related to data availability can affect which participants contribute to the reported estimates.

The record does not report the full statistical analysis plan, sample-size justification, or interim-analysis plan. It therefore does not establish whether the study had prespecified methods for multiplicity or missing data beyond the brief endpoint description. The lack of these details in the registry record should be read as a reporting limitation, not proof that no such procedures existed.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pneumonia (10.3%), dehydration (6.9%), pulmonary embolism (6.9%), respiratory failure (6.9%), ascites (3.4%).

The registry reports serious adverse events for the ramucirumab and FOLFIRI group, with 29 participants at risk and 11 affected. For other adverse events, it reports 29 participants at risk and 28 affected. The listed serious-event terms and percentages are pneumonia, 10.3%; dehydration, 6.9%; pulmonary embolism, 6.9%; respiratory failure, 6.9%; ascites, 3.4%; and colonic fistula, 3.4%.

These figures describe events recorded in the treated group. They do not show that the treatment caused an event, and an event’s appearance in a list does not establish its relationship to treatment. Serious adverse events and other adverse events are separate categories in the record; the figures should not be added together, since the registry does not specify whether participants may appear in both categories or how events were counted across terms.

The registry record does not report a death count, and the serious-event listing does not provide event-level timing, duration, outcome, or attribution details. There is no randomized control group for a like-for-like safety comparison. Accordingly, these counts should be read descriptively rather than as estimates of comparative risk.

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

The study addresses a pharmacokinetic question: whether concomitant ramucirumab might affect exposure to irinotecan and SN-38 when given with FOLFIRI. The registry identifies dose-normalized AUC(0-∞) in Cycle 1 as the primary measure and describes adjusted geometric least-squares means with 90% confidence intervals. Those measures are relevant to drug exposure, but the numerical estimates and intervals are not reported in the registry record.

As a result, the posted information does not show the size, direction, or precision of the primary pharmacokinetic findings. The study purpose alone is not evidence that an effect was observed. Nor does the endpoint directly measure tumor control, survival, or another clinical outcome. No such result can be inferred from a pharmacokinetic endpoint.

The record describes a single-group, sequential treatment schedule rather than a randomized comparison with a separate control group. It therefore does not report a randomized estimate of the difference attributable to ramucirumab. Even if concentration data were collected at different treatment times, a treatment sequence alone cannot establish that an observed change was caused by the added treatment rather than other time-related or participant-related influences.

The safety counts document that serious and other adverse events were recorded among participants receiving the regimen. They do not establish causation or comparative safety. The registry record does not report deaths, detailed attribution, or an independent control-group rate. The adverse-event percentages attached to selected serious-event terms should be understood as registry descriptions, not as estimates of a treatment effect.

In short, the registry record describes the intended pharmacokinetic question, treatment sequence, endpoint definition, and safety reporting. It does not include enough numerical primary-outcome information to assess whether exposure differed or how precisely it was estimated. This absence limits interpretation of the posted record; it does not establish that the study produced no results or that no further analyses exist.

13. Why This Trial Matters Statistically

This study is statistically notable because it focuses on pharmacokinetics rather than a direct clinical outcome. The primary measure, dose-normalized AUC(0-∞), summarizes drug exposure over time for irinotecan and SN-38. Understanding the intended measure helps distinguish an exposure question from questions about tumor response, survival, or comparative clinical benefit.

The design also illustrates why treatment sequence and control structure matter. Ramucirumab began in Cycle 2, while the primary endpoint is identified as a Cycle 1 measure. The registry record does not explain how that Cycle 1 endpoint was used to estimate the effect of concomitant ramucirumab, and it reports no numerical comparison. A clearly specified comparison and its estimates are important for connecting a pharmacokinetic objective to evidence about a treatment effect.

Another statistical issue is the defined analysis population. The primary endpoint required completion of treatment on specified days and sufficient concentration data. Pharmacokinetic results can depend on which participants have profiles adequate for exposure estimation, so participant flow and missing-data methods are useful for judging how representative the analyzed population may be. Those details are not reported in the registry record.

Finally, the record distinguishes a named endpoint and analysis description from the results needed to judge magnitude and uncertainty. A geometric least-squares mean and confidence interval are useful only when their numerical values and methods are available. The posted record supplies an outline of the statistical question, but not the numerical primary outcome findings needed to evaluate its answer.

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 does not report numerical results for the primary endpoint. It names dose-normalized AUC(0-∞) for irinotecan and SN-38 in Cycle 1 and describes adjusted geometric least-squares means with 90% confidence intervals, but provides no estimates or interval limits. Therefore, the magnitude and precision of the pharmacokinetic findings cannot be assessed from the posted record.

The study is listed as single-group, with allocation recorded as NA and masking as none. There is no reported randomized control group for a like-for-like comparison. The treatment was sequential, with ramucirumab starting in Cycle 2, while the primary endpoint title specifies Cycle 1. How the primary measure addresses the stated concomitant-treatment question is not explained in the registry record.

The primary endpoint population required completion of specified treatment and sufficient concentration data. The record does not report how many participants met those criteria, reasons for any exclusions, or how incomplete concentration profiles and missing data were handled. It also does not provide the AUC estimation method, full model specification, or a complete analysis plan. The adjustment description names cycle, participant and random error, but gives no further modeling detail.

The registry record does not report a sample-size justification, multiplicity plan, interim-analysis plan, detailed protocol, or numerical results for the listed secondary outcomes. Safety information is descriptive and does not include a death count or a randomized comparison. These limitations concern the information available in the record and do not establish that additional methods or results were never reported elsewhere.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study to Assess the Pharmacokinetics of Ramucirumab (IMC-1121B) in Combination With FOLFIRI — NCT01634555.
• Registry record last updated 2019-02-26; status last verified 2018-02.
• Results first posted 2014-07-14.
• 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

This completed Phase 2 study enrolled 29 participants with advanced malignant solid tumors. Its purpose was to assess ramucirumab’s effect on irinotecan and SN-38 pharmacokinetics when administered with folinic acid and 5-fluorouracil. Ramucirumab was administered before FOLFIRI and began in Cycle 2; the treatment cycle was 2 weeks.

The primary endpoint was dose-normalized AUC(0-∞) for irinotecan and SN-38 in Cycle 1, described as adjusted geometric least-squares means with 90% confidence intervals. Numerical primary endpoint results are not reported in the registry record. The listed safety information includes 11 participants affected by serious adverse events and 28 affected by other adverse events, each among 29 at risk; a death count is not reported.

The study had a single-group design and no randomized control comparison. The record does not provide a full statistical analysis plan, missing-data methods, or numerical estimates needed to evaluate the primary pharmacokinetic result.