A Phase I/II Trial of Crolibulin (EPC2407) Plus Cisplatin in Adults With Solid Tumors With a Focus on Anaplastic Thyroid Cancer (ATC): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Phase I/II Trial of Crolibulin (EPC2407) Plus Cisplatin in Adults With Solid Tumors With a Focus on Anaplastic Thyroid Cancer (ATC) (NCT01240590), a randomized phase 1, phase 2 study. The primary outcome is Progression Free Survival (Phase II).

2. Clinical Question

3. Trial Design

The registry describes NCT01240590 as a randomized, parallel, open-label Phase I/II trial. It lists enrollment of 27 participants and a completed status. The listed start date is 2011-01-26, and the primary completion date is 2015-08-31. The sponsor was the National Cancer Institute (NCI). These design labels describe the registered study; they do not by themselves establish how treatment assignment was carried out or how participants were followed.

The study had dose-seeking and comparative components. In Phase I, the stated primary objective was to assess the safety and tolerability of cisplatin and crolibulin given in a 21-day cycle, assess toxicities and dose-limiting toxicities (DLTs), and determine the maximum tolerated dose (MTD) for the combination. Listed combination cohorts included cisplatin 75mg/m(2) with crolibulin 8 mg/m(2), cisplatin 75mg/m(2) with crolibulin 13 mg/m(2), and cisplatin 100mg/m(2) with crolibulin 13 mg/m(2).

For Phase II, the registry listed cisplatin 100mg/m(2) with crolibulin 20 mg/m(2), and a cisplatin-alone arm at 100mg/m(2). The primary objective was to compare PFS. RECIST-based response rates were described as an important secondary objective. The registry record does not report the number of participants assigned to each arm, the sequence or rules used to move between dose levels, or whether Phase I participants could enter Phase II. It also does not report the allocation ratio, randomization method, or concealment procedures.

Open-label masking means that the study was registered as having no masking. Details about who knew treatment assignments, and whether outcome assessment involved any independent review, are not reported in the registry record. Enrollment, trial completion, and a randomized designation do not supply the missing details needed to reconstruct the conduct of the trial.

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: The phase II portion was not completed because it was impossible to recruit.

Phase I

Reasons for not completing this period:

Phase II

Reasons for not completing this period:

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 Progression Free Survival (Phase II), measured over 6 weeks.

The Phase II primary endpoint was progression-free survival (PFS), with a listed timeframe of 6 weeks. The registry defines PFS as the duration from the start of study treatment to the time of progression. It describes tumor response using RECIST: complete response is disappearance of all target lesions; partial response is at least a 30% decrease in the sum of the longest diameters of target lesions from baseline; progressive disease is at least a 20% increase from the smallest sum recorded since treatment began, or the appearance of one or more new lesions; stable disease is neither enough shrinkage for partial response nor enough increase for progressive disease.

As a general statistical concept, PFS is used to capture the time until disease progression, rather than only whether a tumor response was observed at a particular assessment. It can therefore reflect both progression events and the timing of those events. Its interpretation depends on clear definitions of progression, the timing and completeness of assessments, and how deaths and other events are handled in the analysis. Those analysis details are not reported in the registry record.

The registry states that the outcome was not met because patients died and were not scanned before death. It does not report a PFS estimate, an effect estimate comparing arms, or uncertainty around a comparison. The stated timeframe does not establish that a PFS result was successfully measured or analyzed.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registered design combines a dose-seeking Phase I component with a Phase II comparative objective. These components address different statistical questions. Phase I focuses on safety and dose selection; Phase II aims to compare outcomes between treatment groups. A design label alone does not reveal the analysis methods actually used, so the explanations below distinguish general statistical principles from details reported for this trial.

What does randomization contribute?

As a general principle, random assignment is used to reduce systematic differences between treatment groups at baseline. If implemented successfully, it supports a fair comparison because treatment assignment is not chosen according to a participant’s prognosis. Randomization does not guarantee that groups will be identical, especially in a small study, and it cannot correct missing outcome data or incomplete reporting. For this trial, randomized allocation and a parallel model are recorded, but the method of sequence generation, allocation concealment, allocation ratio, and arm-specific enrollment are not reported in the registry record.

How should the Phase I objective be understood?

The Phase I objective was to assess safety and tolerability, evaluate DLTs, and determine an MTD for cisplatin plus crolibulin. In general, dose-seeking studies use observations of toxicity at candidate doses to guide decisions about further dose evaluation. The particular decision rule matters: it determines how many participants are treated at each level and how observed toxicities affect subsequent dosing. The registry lists combination dose levels, but does not report a dose-escalation algorithm, DLT observation window, DLT definition, or the decision rule used to identify an MTD. Thus, the listed doses do not establish which dose was selected or why.

What would a PFS analysis usually require?

As a general concept, time-to-event analysis uses the time from a defined starting point until a specified event. The registry defines the PFS starting point as the beginning of study treatment and progression according to RECIST as the event. In time-to-event settings, some participants may not have an event recorded during observed follow-up. Statistical methods can account for such incomplete observation when the relevant assumptions and censoring rules are specified. The registry record does not report a censoring definition, follow-up schedule, PFS analysis method, or how deaths without a scan were classified.

The stated reason the endpoint was not met—patients died before being scanned—raises a question about how the disease status and event time were determined. A death may be handled as an event in some PFS definitions, but the registry’s stated PFS definition refers to time to progression and does not describe the handling of death. It would be inappropriate to infer the trial’s operational rule from common practice. The registry record does not report whether death was counted as progression, whether scans were missed for other reasons, or whether any sensitivity analysis addressed incomplete assessments.

What does a confidence interval communicate?

As a general explanation, a confidence interval expresses the statistical uncertainty around an estimated quantity under a specified method. A narrow interval indicates greater precision than a wide interval, while both the estimate and interval are needed to judge the range of effects compatible with the data. No PFS estimate or confidence interval is reported for this trial, so precision of the intended comparison cannot be assessed from the registry record.

Why can over-dispersion matter?

As a general statistical issue, over-dispersion occurs when count data vary more than a model’s assumptions allow. If it is ignored, standard errors can be too small and uncertainty can be understated. This is relevant in some analyses of counts or rates, but the registry record does not provide a count-based efficacy analysis or describe a model for this trial. It therefore does not support a claim that over-dispersion was present or that a particular correction was used.

Were interim analyses or a sample-size rationale reported?

Interim analyses can affect interpretation when data are reviewed before the planned end of a study, particularly if stopping decisions or repeated testing are involved. The registry record does not report whether interim analyses were planned or conducted, or whether any stopping rules were used. It also does not report a protocol sample-size justification or the assumptions used for an original power calculation. These omissions mean that the planned statistical operating characteristics cannot be reconstructed from the registry entry.

A sample-size illustration based on an observed effect, when available, is a planning exercise rather than evidence that a study had adequate power after completion. It is not an observed measure of power. No resulting planning estimates are reported in the registry record, and the PFS effect needed to anchor such an illustration is also not reported. The registry lists enrollment of 27, but that overall count does not establish the number analyzed for any outcome or the number in each comparison arm.

What analysis details are missing?

The registry record contains no listed analysis records. It does not report the statistical model, analysis population, treatment of withdrawals, missing-data methods, handling of protocol deviations, or adjustment for baseline characteristics. It also does not provide an effect estimate, standard error, test statistic, or p-value for PFS. These are not minor details: they determine what population and estimand a reported comparison represents, and how much uncertainty surrounds the result. In their absence, the registered objective can be described, but the planned or completed comparative analysis cannot be reproduced or evaluated.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary Phase II endpoint of PFS and describes RECIST response rates as an important secondary objective. It also lists secondary outcomes concerning medically necessary interventions and tumor growth rate constant. The presence of multiple outcomes creates a general multiplicity issue: when several hypotheses are tested, the chance of at least one apparently positive result can increase unless the testing strategy is specified. Statistical plans may address this through a prespecified hierarchy, adjustment, or another approach. The registry record does not report a multiplicity strategy, hypothesis hierarchy, or adjusted significance threshold.

The record does not provide an efficacy analysis for PFS or response rates. No p-values or confidence intervals are reported for these outcomes, and no adjustment method is reported. As a result, it is not possible to assess whether any inferential claims account for multiple outcomes or analyses. The absence of a reported PFS result should not be interpreted as a nonsignificant finding; no test result is posted in the registry record.

Missing outcome information is particularly important for PFS because the record says patients died without being scanned. The registry does not explain how those deaths were incorporated, whether there were other missed assessments, or whether missingness was addressed through censoring, imputation, a sensitivity analysis, or another method. Each choice could affect interpretation, and no method should be assumed.

The analysis populations are also not described. The record does not say whether analyses were intended to include all randomized participants, only participants who received treatment, or another defined group. It does not report exclusions, withdrawals, or the number of participants contributing to each outcome. Overall enrollment of 27 cannot be treated as the analysis denominator for every endpoint. Without these details, the extent of missing data and the relationship between enrollment, assignment, and analysis remain unclear.

11. 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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: aspiration (100.0%), dysphagia (100.0%), dyspnea (100.0%), atrial fibrillation (16.7%), hypoxia (16.7%).

The serious adverse-event entries are presented by listed treatment group as participants at risk and participants affected. In the Phase I Level 1 cisplatin-and-crolibulin group, 6 participants were at risk and 1 was affected by a serious adverse event. In Phase I Level 2, 3 were at risk and 0 were affected. In Phase II Level 3, 17 were at risk and 5 were affected. In the cisplatin Phase II Level 4 group, 1 was at risk and 1 was affected. The Phase I Level -1 group lists 0 participants at risk and 0 affected.

These counts are descriptive. They do not establish that a treatment caused an event, and they do not by themselves support a reliable comparison between regimens. The groups differ in size and dose, and the registry record does not report an adjusted safety comparison, exposure duration, or the method used to attribute events. A group with a small number at risk can have a count that is difficult to compare with a larger group.

The listed serious adverse-event terms include aspiration, dysphagia, and dyspnea at 100.0% each; atrial fibrillation, hypoxia, and lipase increased are listed at 16.7% each. The registry record does not explain the denominator or calculation basis for these percentages. The percentages should therefore be read as registry-reported figures, not as comparative risk estimates. Serious adverse events should also be distinguished from the separate count of participants affected by other adverse events. No causal interpretation or treatment recommendation follows from these entries.

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

The record establishes that a randomized, open-label Phase I/II study was registered to evaluate crolibulin with cisplatin, with an emphasis on ATC. The Phase I aims addressed safety, tolerability, DLTs, and MTD. The Phase II objective was to compare PFS for the combination against cisplatin alone. The registry identifies dose levels for the combination and the cisplatin comparator, and it reports enrollment of 27 participants.

The key result available for the primary Phase II endpoint is that it was not met because patients died and were not scanned before death. This is not a reported estimate showing longer or shorter PFS in either group. No effect estimate, confidence interval, p-value, or arm-specific PFS result is reported. The record therefore does not establish whether the treatments differed on PFS, nor how precise a comparison might have been.

Likewise, the serious adverse-event counts describe the listed groups but do not show that events were caused by a treatment or establish a comparative safety profile. The record lacks details about exposure, event attribution, and statistical comparison. The displayed percentages for selected serious terms have no described denominator in the registry entry.

These limitations do not mean that no analyses or assessments occurred during the study; they mean that such information is not reported in the registry record. The record does not report the analysis population, missing-data methods, interim analyses, sample-size justification, or multiplicity plan. The trial’s completion status and its registered design cannot fill those gaps.

The defensible reading is narrow: the registry records the intended Phase II PFS comparison and states that the outcome was not met because deaths occurred before scans. It does not provide the numerical efficacy evidence needed to estimate or compare PFS. The entry also provides group-level safety counts that warrant descriptive reading rather than causal or comparative conclusions.

13. Why This Trial Matters Statistically

This trial is statistically informative as an example of the difference between a registered research question and a reported result. The study’s Phase II objective was a treatment comparison based on PFS, but the registry states that the outcome was not met because patients died before being scanned and provides no PFS estimate. This makes clear that an endpoint’s definition and intended timeframe do not guarantee that an interpretable endpoint analysis will be available.

It also highlights how missing assessments can affect a time-to-event outcome. PFS relies on disease evaluations to determine progression, and the registry’s explanation identifies deaths without scans as a barrier to meeting the outcome. The record does not state how those deaths were handled analytically. This illustrates why endpoint rules for death, missed scans, censoring, and follow-up need to be explicit: otherwise, readers cannot determine what event was analyzed or how incomplete observation influenced the result.

The Phase I and Phase II objectives further illustrate distinct roles within an early clinical trial. Dose-seeking and toxicity evaluation ask questions about safety and dose selection; a randomized Phase II comparison asks whether outcomes differ between treatment groups. The registry provides some dose-level and safety information but does not report an MTD determination or a comparative PFS analysis. Readers should not treat dose levels or safety counts as substitutes for evidence on the primary Phase II endpoint.

Finally, the registry’s sparse analysis details show why reporting matters for interpretation. Without arm-specific outcome data, an analysis population, uncertainty estimates, and a description of missing-data handling, neither the magnitude nor the precision of a treatment contrast can be evaluated. The trial’s statistical importance lies in the questions it set out to address and in the limits of what its registry record allows readers to conclude.

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 principal trial-specific limitation in the registry record is the absence of a reported Phase II PFS result. The record states that the outcome was not met because patients died before scans were obtained, but it does not provide an analysis of PFS or explain how death without a scan was classified. Since PFS depends on event definitions and assessment timing, this omission prevents reconstruction of the endpoint analysis.

The registry does not report arm-specific enrollment or the number of participants included in any efficacy analysis. Although overall enrollment is listed as 27, the available information does not show how those participants were distributed across the Phase I dose cohorts and Phase II groups, or how many contributed data to each outcome. The randomization procedure and allocation ratio are also not reported, despite the randomized designation.

There is no reported statistical analysis plan, model, analysis population, follow-up schedule, censoring rule, missing-data method, or sensitivity analysis. The registry also does not report a sample-size justification, interim-analysis plan, or multiplicity strategy. These gaps limit assessment of the intended inferential framework as well as the interpretation of any outcomes.

Safety interpretation is constrained by group sizes that differ and by the absence of details about treatment exposure, event attribution, or the denominator behind the listed serious-event percentages. Phase I dose groups and Phase II treatment groups have different purposes, so their safety counts are not a straightforward randomized comparison of the Phase II regimens. The registry record offers descriptive counts, but not enough information for a causal safety comparison.

Finally, the completed status does not resolve these reporting limitations. It indicates the study’s registered status, not that every planned endpoint was successfully measured or that all analyses are available in the registry record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Phase I/II Trial of Crolibulin (EPC2407) Plus Cisplatin in Adults With Solid Tumors With a Focus on Anaplastic Thyroid Cancer (ATC) — NCT01240590.
• Registry record last updated 2017-04-10; status last verified 2017-02.
• Results first posted 2015-12-31.
• 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

NCT01240590 is listed as a completed, randomized, open-label, parallel Phase I/II study sponsored by the National Cancer Institute (NCI), with enrollment of 27. Its focus was adults with solid tumors, particularly ATC. The Phase I objective addressed safety, tolerability, DLTs, and MTD for crolibulin plus cisplatin. The Phase II objective was to compare PFS for the combination with cisplatin alone in adults with ATC.

The registry lists several dose levels and group-level adverse-event counts. It states that the Phase II PFS outcome was not met because patients died before they were scanned. No PFS estimate, comparative efficacy analysis, or confidence interval is reported. Details of the randomization procedure, analysis population, missing-data handling, and statistical plan are not reported in the registry record.