Phase I Study of Intravenous Lipotecan® (TLC388 HCl for Injection) in Patients With Advanced Solid Tumors: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase I Study of Intravenous Lipotecan® (TLC388 HCl for Injection) in Patients With Advanced Solid Tumors (NCT00747474), a na phase 1 study. The primary outcome is Maximum Tolerated Dose (MTD) of Lipotecan.

2. Clinical Question

3. Trial Design

This was a Phase I, open-label study of intravenous Lipotecan in patients with advanced solid tumors. The registry identifies the study model as single group and the allocation as not applicable. No randomized control arm is described, so the design is a dose-escalation investigation rather than a like-for-like comparison of treatment groups.

The stated purpose was to identify a safe and tolerable dose. The official study description also refers to safety, tolerability, and pharmacokinetics. The intervention was Lipotecan, identified as TLC388 HCl for Injection. The registry describes the design as sequential dose escalation, but does not report the individual dose levels, the escalation sequence, or participant counts at each level.

The study was listed as Phase I and completed. The registry gives a start date of 2008-09 and a primary completion date of 2011-08. Enrollment was 54. These details describe the registered study, but do not establish how many participants contributed to each endpoint or how many completed all study procedures.

The primary endpoint was maximum tolerated dose, assessed from first treatment to toxicity up to 42 days. The registry describes a 3+3 rule: the selected dose was the highest level meeting the specified dose-limiting toxicity threshold, with a higher dose level required to show the stated toxicity pattern. The endpoint description does not give the observed dose-level results needed to identify which dose met that rule.

Anti-tumor activity was listed as a secondary outcome. The registry record lists 23 outcome measures overall, but does not report the results of the secondary outcome in the information available for this analysis. It also reports zero analyses. That does not establish that no analyses were performed; it means analyses are not recorded in this results listing.

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: Patients will attend the clinic for a screening visit up to 28 days before receiving, if eligible, the first dose of Lipotecan®.

Only the first 6 of 12 groups are shown.

Cohort 1 (1.5 mg/m^2) Period

Cohort 2 (3 mg/m^2) Period

Cohort 3 (6 mg/m^2) Period

Cohort 4 (9 mg/m^2) Period

Analysis population for the primary outcome, as defined in the registry: Patients received at least one dose of Lipotecan.

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 Maximum Tolerated Dose (MTD) of Lipotecan, measured over First treatment to toxicity up to 42 days.

The primary endpoint was the maximum tolerated dose of Lipotecan, expressed in mg/m^2. The registry defines this as the highest dose that did not cause an unacceptable side effect, identified as a dose-limiting toxicity. The assessment timeframe was from first treatment to toxicity up to 42 days, and the endpoint population was patients who received at least one dose.

This endpoint is used in early dose-escalation studies to guide dose selection based on observed toxicity. In the registry’s 3+3 description, a dose level is considered acceptable under the stated rule when 0 of 3 or 1 of 6 patients experience a dose-limiting toxicity; the next higher level is described as having at least 2 of 3 or 2 of 6 patients with such toxicity. The rule specifies how the endpoint is determined, but does not itself give the study’s result.

The registry lists the endpoint type as a number, but the numerical maximum tolerated dose is not reported in the registry record. Nor are the dose-limiting toxicity counts by dose level reported. Consequently, the endpoint’s definition and assessment window can be described, but the selected dose cannot be reconstructed from the posted information.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

How the 3+3 rule works

The registry describes a 3+3 dose-escalation design for determining the maximum tolerated dose. In general, such a rule evaluates toxicity within successive dose levels and uses the observed number of dose-limiting toxicities to guide whether escalation can proceed or whether a dose should be treated as the upper tolerable level. The record’s specific rule defines the maximum tolerated dose as the highest dose level at which 0 of 3 or 1 of 6 patients experience a dose-limiting toxicity, with the next higher dose level having at least 2 of 3 or 2 of 6 patients with one.

This is a rule-based dose-selection procedure, not a randomized comparison between Lipotecan and a control. Its result depends on the observed toxicity pattern at each dose. The registry does not report those dose-level counts, the actual dose levels, or the numerical maximum tolerated dose. The rule can therefore be explained, but cannot be applied independently to recover the study result.

What the endpoint window means

The primary endpoint timeframe is described as first treatment to toxicity up to 42 days. This defines the period relevant to the registry’s endpoint description. It does not provide individual event times or establish how participants with incomplete observation were handled. The record says the endpoint population included patients who received at least one dose, but further details on assessment completeness are not reported in the registry record.

What a confidence interval would convey

As a general statistical point, a confidence interval expresses the uncertainty around an estimated quantity under a specified statistical model. It gives a range of values compatible with the observed data at the stated confidence level; it is not a guarantee that the true value lies within that particular interval. For a dose-finding result, uncertainty may concern how well the selected dose reflects the underlying toxicity pattern. No confidence interval for the maximum tolerated dose is reported in the registry record, and the necessary dose-level results are not available in the listed information.

Why dose-level detail matters

As a general statistical point, an overall enrollment count does not show how much information is available at each dose level. Dose-finding interpretation depends on the number treated at each level and the observed toxicities within those groups. The record reports enrollment of 54, but does not report the dose-by-dose distribution or toxicity counts. The total enrollment alone cannot establish the precision of the dose-selection result.

Over-dispersion and event counts

As a general statistical point, over-dispersion occurs when variability in count data exceeds what a simple statistical model assumes. It can arise when event rates vary across participants or when events cluster within individuals. In safety data, repeated events in some participants can make total event counts more variable than a model that assumes comparable, independent event rates. Participant-level counts of those affected do not reveal this structure. The registry gives affected-participant counts and selected event terms, but does not report event-level distributions or an over-dispersion analysis. No conclusion about over-dispersion in this study can be drawn from those summaries.

Planning calculations are not trial results

As a general statistical point, a sample-size calculation is a planning exercise based on assumptions about the effect to detect, the significance level, allocation, and statistical model. It is not an observed result and does not indicate the probability that a completed study found an effect. The registry’s planning assumptions describe a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the target effect defined as a stated fraction of an observed effect. Those assumptions do not match the registered single-group dose-escalation structure as a like-for-like two-arm comparison. No planning illustration can supply the missing maximum tolerated dose or serve as observed power for this study.

Analyses and inferential claims

The registry lists zero analyses. No statistical analysis plan, model specification, inferential test, or adjustment approach is reported in the registry record. As a general statistical point, a p-value quantifies how unusual data would be under a stated null model and assumptions; it does not measure the size or clinical importance of an effect. A p-value is not reported for the primary endpoint or the secondary anti-tumor activity outcome. Without an estimate and its uncertainty, the recorded safety counts and endpoint definition cannot be turned into a comparative treatment-effect claim.

10. Multiplicity, Missing Data and Analysis Populations

The registry identifies 23 outcome measures and lists anti-tumor activity as a secondary outcome, but does not report an analysis plan for how multiple outcomes or repeated statistical tests were handled. Whether multiplicity adjustments were planned or used is not reported in the registry record. As a general statistical point, when many outcomes or tests are examined, the chance of at least one apparently notable result can increase; interpretation depends on which outcomes were prespecified and how testing was managed. The available record does not allow that assessment.

Missing-data methods are not reported in the registry record. The primary endpoint population is described as participants who received at least one dose, but the record does not state how participants with incomplete toxicity observation, withdrawal, or missing assessments were handled. It also does not report the number contributing to each outcome beyond the overall enrollment and the safety-group counts.

The registry lists zero analyses and does not report a statistical analysis plan, analysis populations beyond the primary endpoint definition, or sensitivity analyses. It is therefore not possible to establish whether the reported safety groups include all enrolled participants under a consistent analysis rule, or whether any outcomes were analyzed in a different subset. These omissions limit assessment of selective reporting, missingness, and robustness. They do not establish that the investigators failed to perform such procedures; those details are simply not reported in the registry record.

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: anaemia (3.7%), cerebrovascular accident (3.7%), hyponatraemia (3.7%), thrombocytopenia (3.7%), urinary tract infection (3.7%).

The registry’s overall safety group lists 54 participants at risk for serious events and 11 affected. For other events, it lists 54 at risk and 54 affected. These are participant counts, not necessarily counts of all individual events. The registry does not provide event-level totals in the information available for this analysis.

The serious-event terms displayed include anaemia, cerebrovascular accident, hyponatraemia, thrombocytopenia, and urinary tract infection, each at 3.7%, and abdominal pain at 1.9%. These percentages are presented as recorded; they should not be interpreted as a complete account of all events or as dose-specific risks. The record does not report the number of participants at each dose level, the timing or duration of events, or event attribution to Lipotecan in the available information.

The death count is not reported in the registry record. This absence should not be interpreted as a count of zero. Similarly, the count of participants with other events does not identify how many events each participant experienced. These safety summaries describe the posted counts but do not establish a causal relationship between treatment and any event.

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

The record describes a completed Phase I study designed to identify a maximum tolerated dose of intravenous Lipotecan in patients with advanced solid tumors. It gives the primary endpoint definition, the assessment timeframe, the 3+3 decision rule, overall enrollment of 54, and summary safety counts. These details show the intended structure of the dose-finding question and the scope of the recorded safety summaries.

The record does not state the numerical maximum tolerated dose, dose-limiting toxicity counts by dose level, or dose-level enrollment. As a result, it does not permit a reader to determine which dose met the specified rule. It also does not report a statistical estimate or confidence interval for the primary outcome. The listed secondary outcome, anti-tumor activity, has no result in the available record.

The safety counts indicate that 11 of 54 participants were recorded as affected in the serious-event category and 54 of 54 in the other-event category. The named serious-event terms and their displayed percentages add descriptive detail, but do not establish causality, comparative risk, or how safety varied with dose. The death count is not reported in the registry record.

Because the study was open label and single group, it does not provide a randomized comparison with a control. Its results, even if fully reported, would need interpretation in light of that design. In the available record, the absence of outcome estimates and dose-level data limits interpretation further. Missing reporting is not evidence that an outcome did not occur, that an analysis was not performed, or that a treatment effect is absent. The defensible conclusion is limited to the design and descriptive information that the registry records.

13. Why This Trial Matters Statistically

This study is statistically relevant because it illustrates a central feature of early-phase dose finding: the primary question is dose selection based on toxicity, not a randomized estimate of comparative efficacy. The registry’s 3+3 description makes the decision rule explicit, while the lack of dose-level results prevents independent evaluation of how that rule was applied in this study.

The distinction between a defined method and a reported result matters. Knowing the rule does not reveal the selected dose; that requires the observed dose-limiting toxicity pattern at each level. Likewise, overall enrollment of 54 does not show how many participants informed each step of escalation. Reporting the dose levels, group counts, toxicity counts, and endpoint result would be necessary to assess the dose-selection evidence and its uncertainty.

The safety summary also illustrates why participant counts and event counts should not be conflated. Counts of participants affected provide one kind of information, while the total number and distribution of events provide another. The registry’s listed figures support a limited descriptive account, but do not show event recurrence, timing, dose relation, or attribution.

Finally, the record demonstrates how registry results can be informative about design while remaining incomplete for outcome interpretation. It identifies the phase, intervention, population, endpoint, assessment window, and safety counts. But the maximum tolerated dose, secondary outcome results, and statistical analyses are not reported. Clear separation between what is specified and what is observed is essential when interpreting an early-phase study.

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 main limitation is that the primary endpoint result is not reported in the registry record. Although the maximum tolerated dose is defined and the 3+3 rule is described, neither the selected dose nor the toxicity counts supporting that selection are available. The dose levels and the number treated at each level are also not reported, preventing reconstruction or evaluation of the dose-escalation outcome.

The registry gives overall enrollment of 54, but does not report how many participants contributed to each outcome or completed the assessment period. The primary endpoint population is defined as those who received at least one dose, yet further analysis-population details and handling of incomplete follow-up are not reported in the registry record. Missing-data methods and sensitivity analyses are also not reported.

The safety information is limited to affected-participant counts and selected event terms with percentages. The record does not provide event-level counts, dose-specific safety summaries, timing, duration, severity grading for the full set of events, or attribution details in the information available for this analysis. The death count is not reported.

The study had no comparator and was open label, so it cannot provide a randomized treatment comparison. The registry names anti-tumor activity as a secondary outcome but does not report its result. It lists zero analyses, and an analysis plan, inferential methods, and multiplicity approach are not reported in the registry record. These limitations constrain conclusions about dose selection, precision, safety patterns, and anti-tumor activity.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Phase I Study of Intravenous Lipotecan® (TLC388 HCl for Injection) in Patients With Advanced Solid Tumors — NCT00747474.
• Registry record last updated 2019-11-18; status last verified 2019-10.
• Results first posted 2012-02-09.
• 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

The registry describes NCT00747474 as a completed Phase I, open-label, single-group study of intravenous Lipotecan in patients with advanced solid tumors. Enrollment was 54. The study’s stated purpose was to identify a safe and tolerable dose, and the primary endpoint was maximum tolerated dose, assessed from first treatment to toxicity up to 42 days using a described 3+3 rule.

The registry lists anti-tumor activity as a secondary outcome and 23 outcome measures overall. It reports 11 of 54 participants affected in the serious-event group and 54 of 54 affected in the other-event group. The numerical maximum tolerated dose, dose-level toxicity results, anti-tumor activity result, and death count are not reported in the registry record. The record lists zero analyses and does not report an analysis plan.