Obatoclax Mesylate and Topotecan Hydrochloride in Treating Patients With Relapsed or Refractory Small Cell Lung Cancer or Advanced Solid Tumors: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Obatoclax Mesylate and Topotecan Hydrochloride in Treating Patients With Relapsed or Refractory Small Cell Lung Cancer or Advanced Solid Tumors (NCT00521144), a na phase 1, phase 2 study. The primary outcome is Overall Response Rate (Phase II).

2. Clinical Question

The study was intended to examine side effects and dose as well as whether the combination could produce tumor responses. Those aims span distinct questions. Phase I dose-level experience relates to treatment administration and safety, while the Phase II endpoint concerns response among patients meeting the evaluability criteria. The registry identifies the endpoint definition, but does not provide its outcome value or a statistical comparison against a control. Consequently, the record describes what investigators planned to assess, not evidence that establishes the combination’s efficacy.

3. Trial Design

This was a completed Phase I/II study sponsored by the National Cancer Institute (NCI). The registry lists enrollment as 22 and describes a single-group model with no masking and allocation not applicable. The study began in 2007-08, reached primary completion in 2010-08, and is listed as completed. The record’s title includes relapsed or refractory small cell lung cancer and advanced solid tumors; the official title emphasizes the Phase I/II study of obatoclax mesylate plus topotecan in relapsed small cell lung carcinoma.

The treatment description identifies one regimen with phase-specific dose levels. In Phase I, the adverse-event listings distinguish Level 1, Level 2, Level 3, and Level 4. A separate Phase II listing concerns obatoclax mesylate plus topotecan in small cell lung cancer. These listings do not create a randomized comparison. Dose-level groups can differ in enrollment, treatment exposure, and patient characteristics, and the registry does not report a design that would make comparisons among them equivalent to a controlled treatment contrast.

Obatoclax mesylate was given intravenously over 3 hours on day 1 or days 1 and 3, while topotecan hydrochloride was given intravenously over 30 minutes on days 1–5. Courses repeated every 3 weeks in the absence of disease progression or unacceptable toxicity. The record does not provide additional detail on treatment modifications, the number of courses received, or adherence to the regimen.

Response was assessed every 6 weeks, with assessment described as continuing up to 30 days. The response population was restricted to patients who had measurable disease at baseline, received at least one therapy cycle, and had their disease re-evaluated. The registry does not report the count assessed, the count evaluable, or the reasons patients may not have been evaluable. Nor does it report the sample-size justification, the statistical plan, interim analyses, or the planned handling of participants who lacked response assessments. Those omissions limit interpretation of the study’s design and its reported outcome information.

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: Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response.

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 Overall Response Rate (Phase II), measured over Every 6 weeks, assessed up to 30 days.

The Phase II primary endpoint was Overall Response Rate, described in the registry as a number of participants. It used RECIST v1.0 criteria for target lesions, with assessment by MRI. Complete response was defined as disappearance of all target lesions. Partial response was defined as a >30% decrease in the sum of the longest diameters of target lesions. Overall response combined complete and partial responses.

Response endpoints are used to classify whether measurable target lesions meet prespecified criteria for tumor shrinkage. In general, a clearly defined response rule can make assessments more consistent by specifying which changes count as a response. It is distinct from outcomes that measure how long a response lasts, how long participants remain alive, or how symptoms change; none of those endpoints is identified as the primary endpoint in this record.

The registry specified that only patients with measurable disease present at baseline, at least one cycle of therapy, and a disease re-evaluation would be evaluable for response. This restriction matters because a response count is meaningful only in relation to the population assessed. The record does not report the number of participants meeting these criteria, the number with complete or partial response, or the resulting overall response rate. Although the endpoint definition and assessment schedule are registered, the primary response result is not reported in the registry record. Therefore, the endpoint’s clinical and statistical result cannot be reconstructed from the endpoint description alone.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical interpretation depends on matching the method to the study question, outcome, and design. In this record, the primary endpoint is a response classification, while the trial is described as single-group. The registry lists no analyses. As a result, the endpoint definition is available, but the method used to estimate or analyze the primary response result is not reported in the registry record.

What does a response endpoint represent?

A binary response endpoint classifies each evaluable participant according to whether the prespecified response condition is met. In general, a count of participants with an event is a descriptive summary; a proportion relates that count to a stated denominator. For this trial, the endpoint is described as a number of participants, and the registry gives an evaluability rule. The count of evaluable participants and the response count are not reported in the registry record, so neither the proportion nor its precision can be established from the posted endpoint information.

The registered response criteria specify complete response as disappearance of all target lesions and partial response as a >30% decrease in the sum of the longest diameters of target lesions. Combining those categories defines the overall response endpoint. In general, prespecification helps distinguish a response according to a defined rule from other changes that may be clinically or radiologically relevant but do not meet that rule. It does not, by itself, show how many participants met the rule or whether response differences are attributable to treatment.

What does a confidence interval communicate?

In general, a confidence interval expresses the statistical uncertainty around an estimate under the assumptions of the method used. A narrower interval indicates greater precision under those assumptions, while a wider interval indicates greater uncertainty. A confidence interval does not correct for a biased study design, missing outcome information, or an inappropriate analysis population. No confidence interval for the primary response outcome is reported in the registry record, and no interval can be interpreted without the response estimate and its denominator.

For a single-group study, an interval around a response proportion would describe uncertainty about the response proportion in the population represented by the analyzed participants, subject to the method and assumptions. It would not turn the study into a randomized comparison. In general, a causal treatment contrast requires an appropriate comparator and design; neither is described for this study. Comparisons between phase or dose-level entries also require caution because the record does not identify them as randomized, comparable groups.

How should the planning illustration be understood?

The registry describes planning illustrations based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It states that the effect to detect is a stated fraction of the observed effect; for time-to-event outcomes, the illustration gives a total number of events, while other outcomes are expressed as participants per arm. These are planning assumptions, not a report of the trial’s design or an observed treatment effect. The registry does not report a sample-size justification or statistical plan for the trial itself.

In general, a sample-size calculation asks what study size would be needed under specified assumptions to detect a chosen effect with a chosen level of statistical power. It is conditional on the assumed effect, outcome variability, significance threshold, allocation, and analysis method. It does not demonstrate that an effect exists, and it is not observed power. A planning illustration based on a fraction of an observed effect is not an independent confirmation of that effect. In this record, the primary response result is not reported, so the observed response effect underlying any such illustration cannot be evaluated from the registry record.

Why does over-dispersion matter in general?

Over-dispersion is a general statistical issue for count outcomes when the observed variability exceeds what a chosen model assumes. If it is ignored, standard errors can be too small and intervals or tests can appear more certain than warranted. The registered primary endpoint is a participant response count, not a time-to-event endpoint, and the record does not report a model or an over-dispersion adjustment. Thus, over-dispersion is a general concept rather than a documented feature or method of this trial.

More broadly, all statistical summaries depend on clearly defining the analysis population and outcome data. The response endpoint’s evaluability criteria are explicit, but the registry does not report how many participants were evaluable, whether any response assessments were missing, or how missing information was treated. Those details affect the denominator and interpretation of an estimate. Without the outcome counts, denominator, and analysis method, statistical precision and robustness cannot be assessed. The record’s adverse-event entries likewise require descriptive interpretation because there is no reported comparative analysis and no stated model for safety outcomes.

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("Phase I; Level 1: Obatoclax Mesylate + Topetecan", "Phase I; Level 2: Obatoclax Mesylate + Topetecan", "Phase I; Level 3: Obatoclax Mesylate + Topetecan", "Phase II Obatoclax Mesylate + Topotecan in SCLC")
n      <- c(6, 5, 3, 7)
events <- c(0, 0, 0, 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  Phase I; Level 1: Obatoclax Mesylate + Topetecan  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Phase I; Level 2: Obatoclax Mesylate + Topetecan  5  0  0.0  0.0  52.2  0.0  43.4  0.4  45.9
ARM  Phase I; Level 3: Obatoclax Mesylate + Topetecan  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Phase II Obatoclax Mesylate + Topotecan in SCLC  7  0  0.0  0.0  41.0  0.0  35.4  0.3  36.9

11. Multiplicity, Missing Data and Analysis Populations

Multiplicity concerns arise when a study assesses multiple outcomes, comparisons, time points, or subgroups. In general, repeated testing can increase the chance of finding an apparently notable result by chance, and a statistical plan may specify how such testing is handled. The registry identifies one outcome measure and names a Phase II primary response endpoint, but does not report a multiplicity strategy or a broader inferential plan. The number of analyses listed is 0. Whether additional analyses were conducted or planned is not reported in the registry record.

Missing-data interpretation is also limited. The response population excludes participants who did not have measurable disease at baseline, did not receive at least one cycle, or did not have disease re-evaluated. The record does not give counts for those categories, report the number evaluable, describe missing response assessments, or explain how missing outcomes were handled. These omissions prevent an assessment of whether the observed response population could differ systematically from enrolled participants. The registry’s enrollment figure of 22 should not be treated as the response denominator.

The record does not report whether the primary analysis was based on all enrolled participants, only response-evaluable participants, or another analysis population. It does state the criteria for response evaluability, but does not provide an analysis-population definition beyond those criteria. It also does not report interim analyses, prespecified subgroup analyses, or a missing-data sensitivity analysis. These design and analysis details are not reported in the registry record, so conclusions about multiplicity control or missing-data robustness are not possible.

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: depressed level of consciousness (60.0%), euphoria (50.0%), ataxia (incoordination) (40.0%), anemia-hemoglobin decrease (40.0%), alt, sgpt (33.3%).

The adverse-event entries are organized by phase and dose level. For each group, the registry reports a number at risk and a number affected for serious and other adverse events. For Phase I Level 1, the serious-event figures are 6 at risk and 4 affected, and the other-event figures are 6 at risk and 6 affected. For Level 2, the corresponding figures are 5 and 4 for serious events, and 5 and 3 for other events. For Level 3, they are 3 and 2 for serious events, and 3 and 2 for other events. For Level 4, they are 1 and 0 for serious events, and 1 and 0 for other events. For Phase II in small cell lung cancer, they are 7 and 4 for serious events, and 7 and 7 for other events.

The registry also lists serious adverse-event terms with percentages: depressed level of consciousness, 60.0%; euphoria, 50.0%; ataxia (incoordination), 40.0%; anemia-hemoglobin decrease, 40.0%; ALT, SGPT, 33.3%; and alkaline phosphatase, 33.3%. The denominator and overlap among these terms are not reported in the registry record, so the percentages should not be treated as mutually exclusive categories or used to reconstruct participant counts.

These entries are descriptive and are not a randomized safety comparison. Death counts are not reported in the registry record. The listed figures do not establish that an event was caused by either drug, and they do not represent a complete account of all possible safety outcomes.

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

The record documents a Phase I/II investigation of obatoclax mesylate with topotecan hydrochloride, including the treatment schedule, the RECIST-based Phase II response definition, and selected adverse-event summaries. It shows how the primary endpoint was intended to be classified and identifies the criteria for being evaluable for response. Those details are useful for understanding the question the study set out to address.

The record does not report the primary response count or overall response rate. It also does not report the response-evaluable denominator or a confidence interval for the endpoint. Therefore, it does not establish the magnitude or precision of the response outcome. No claim that the combination produced a particular response result can be supported from the registry information.

The study’s single-group design also limits what can be concluded about treatment effects. Without a randomized comparator, outcomes cannot be attributed to the combination through a direct controlled contrast. Differences among the Phase I dose-level listings and the Phase II listing should not be interpreted as if they were comparisons between equivalent randomized arms. The record itself notes that the arms are not a like-for-like control comparison.

The adverse-event counts and serious-event terms offer descriptive information, but they do not quantify a comparative safety effect. The registry does not report attribution, a complete analysis of safety outcomes, or the death counts. Nor does it provide enough information to judge whether the observed safety entries reflect all enrolled participants or a particular analysis population.

In general, a trial record can clarify design and outcome definitions even when it does not provide a complete results analysis. Here, those design details should be separated from evidence about outcomes: the former are reported, while the primary response result and statistical analysis details are not reported in the registry record. The most defensible reading is that the registry describes the study and selected safety data, but leaves the primary efficacy result unresolved.

14. Why This Trial Matters Statistically

This trial illustrates why a registered endpoint definition and an endpoint result are different kinds of information. The record identifies overall response as the Phase II primary endpoint, specifies RECIST v1.0 criteria, and explains which participants could be considered evaluable. Yet it does not report the response count, response denominator, or overall response rate. A precise outcome definition is essential for interpretation, but it cannot substitute for the result itself.

The single-group structure is another important statistical feature. The study can describe responses or adverse events among participants receiving the combination, but the absence of a comparator means the record cannot estimate a controlled treatment contrast. Separating Phase I dose levels from the Phase II group is also important: labels corresponding to different phases and dose levels do not make groups comparable in the way random assignment is intended to do.

The safety summaries demonstrate the need to read denominators and group definitions alongside event counts. The registry reports both at-risk and affected values for serious and other events across its listed groups, and it gives percentages for selected serious-event terms. Without a reported analysis plan, event attribution, and details on denominator definitions for the term percentages, these entries should remain descriptive rather than be interpreted as comparative risks.

Finally, this record highlights how missing analysis details constrain statistical assessment. The registry does not report the trial’s statistical plan, sample-size justification, response analysis population, missing-data handling, or multiplicity approach. Those omissions do not erase the registered study design, but they limit the ability to evaluate precision, bias, and inferential strength. For clinical researchers, the distinction between a registered question, a reported descriptive summary, and a supported comparative conclusion is central to careful evidence interpretation.

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 principal trial-specific limitation in the registry record is the absence of the primary response result. Although the response endpoint is defined and its assessment schedule is listed, the record does not provide the number of participants with complete or partial response, the overall response count, the response denominator, or an uncertainty interval. It is therefore not possible to judge the size or precision of the primary outcome from this information.

The response-evaluation population is narrower than the general enrollment description: patients needed measurable disease at baseline, at least one cycle of therapy, and a disease re-evaluation. The registry does not report how many participants satisfied each requirement or explain what happened to participants who did not. Enrollment is listed as 22, but that does not tell the reader how many were included in a response analysis.

The single-group design does not offer a randomized control comparison. Consequently, response and safety descriptions cannot isolate treatment effects from other causes, and comparisons across phase or dose-level groups are not like-for-like control comparisons. The record also does not report the detailed statistical plan, sample-size justification, interim analyses, multiplicity handling, or missing-data methods. These omissions limit assessment of the intended inference and the robustness of any analysis.

The adverse-event information is also limited to the reported group counts and selected serious-event terms. The record does not report death counts, attribution, the denominator for the term percentages, or a complete comparative safety analysis. These limitations call for descriptive interpretation rather than causal or comparative conclusions.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Obatoclax Mesylate and Topotecan Hydrochloride in Treating Patients With Relapsed or Refractory Small Cell Lung Cancer or Advanced Solid Tumors — NCT00521144.
• Registry record last updated 2015-05-05; status last verified 2013-12.
• Results first posted 2014-07-22.
• 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

NCT00521144 is a completed Phase I/II, single-group study sponsored by the National Cancer Institute (NCI), with enrollment listed as 22. It studied obatoclax mesylate with topotecan hydrochloride in relapsed or refractory small cell lung cancer or advanced solid tumors. The regimen used intravenous obatoclax mesylate on day 1 or days 1 and 3 and intravenous topotecan hydrochloride on days 1–5, with courses repeated every 3 weeks if disease progression or unacceptable toxicity was absent.

The Phase II primary endpoint was overall response according to RECIST v1.0, assessed by MRI. The registry defines complete and partial response and specifies response-evaluability criteria, but does not report the response result or its denominator. It lists adverse-event counts by phase and dose level and selected serious-event terms. A randomized comparator, detailed statistical analysis plan, sample-size justification, response missing-data method, and death counts are not reported in the registry record. The single-group design does not support a like-for-like control comparison.