Individualized Temozolomide in Treating Patients With Stage IV Melanoma That Cannot Be Removed By Surgery: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Individualized Temozolomide in Treating Patients With Stage IV Melanoma That Cannot Be Removed By Surgery (NCT01328535), a na phase 2 study. The primary outcome is Progression-Free Survival at 4 Months.

2. Clinical Question

The clinical question was whether an individualized timing approach to TMZ could be studied in patients with metastatic melanoma, using progression-free survival at 4 months as the primary endpoint. The registry describes the timing as based on the phase, or biorhythm, of the immune response against the tumor. This description explains the rationale for timing treatment; it is not evidence that the timing altered the immune response or clinical outcomes.

Because the study had a single treatment group, its observations do not provide a concurrent untreated or differently treated group for estimating a comparative treatment effect. The clinical question is therefore descriptive: what progression-free survival and safety outcomes were recorded among participants receiving the study regimen? The registry record does not report a numerical answer for the primary endpoint.

3. Trial Design

This was a phase 2, single-group trial sponsored by Mayo Clinic. The registry lists enrollment of 25 and a completed status. The study start is recorded as 2011-01, and primary completion as 2013-06-22. Allocation is listed as not applicable, and masking as none. These design features mean the record does not describe random assignment or blinding, and it does not include a separate control arm.

The treatment was TMZ by mouth. For patients with an established biorhythm, the record describes dosing on the recommended day for 5 days, with treatment repeating every 21-42 days until disease progression or unacceptable toxicity. For patients without an established biorhythm, the record describes dosing on days 1-5, with courses repeating every 28 days. The text for this latter stopping rule ends after “disease progression or”; the other stopping condition is not reported in the registry record. The intervention list also includes flow cytometry, a staining method, biopsy, and laboratory biomarker analysis. Their detailed timing and analytic roles are not reported in the registry record.

The primary endpoint was progression-free survival at 4 months. The registry describes the time origin as registration and the event timing as the earliest documentation of progression. The endpoint population included only patients evaluable for the primary endpoint, but its size and the evaluability criteria beyond that statement are not reported in the registry record.

Progression-free survival and overall survival are listed as secondary outcomes, along with toxicity assessed using NCI CTCAE Version 4.0. The record lists 6 outcome measures, but does not report outcome-analysis results. The statistical analysis plan, sample-size justification, planned interim analyses, and detailed rules for handling deviations from the treatment schedules are not reported in the registry record.

Any planning illustration associated with the posted results should be distinguished from the actual design. Its stated assumptions are a two-sided significance level of 0.05, equal allocation between two hypothetical arms, and a normal approximation, with the effect to detect expressed as a fraction of the observed effect. Time-to-event illustrations concern total events; other illustrations concern participants per arm. These are planning assumptions, not the design of this single-group trial and not observed power. The trial's own sample-size justification 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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Only patients who were evaluable for the primary endpoint were included in the analysis.

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 at 4 Months, measured over Time from registration to the earliest date of documentation of disease progression, assessed at 4 months.

The primary endpoint is progression-free survival at 4 months, expressed as a percentage of patients. It asks what proportion of the defined analysis population had not experienced documented disease progression by that time after registration. The registry specifies that only patients evaluable for the primary endpoint were included in the analysis. It does not state how many patients met that criterion, nor does it report the endpoint estimate or its 95% confidence interval.

The record defines progression using radiographic or lesion-based criteria. Progression includes at least one new malignant lesion, including a lymph node that was normal at baseline—less than 1.0 cm short axis—and increased to at least 1.0 cm short axis during follow-up. It also includes at least a 20% increase in the sum of the longest diameters of target lesions plus the short axes of target lymph nodes, using the minimum sum of diameters (MSD) as the reference. That increase must also be an absolute increase of at least 0.5 cm from the MSD.

In general, a progression-free survival endpoint captures the time until progression, rather than only whether a patient ever progresses during follow-up. A fixed-time rate such as the four-month rate can communicate the estimated share remaining progression-free at a clinically defined time point. It is useful only when the event definition, time origin, analysis population, and uncertainty around the estimate are clear. Here, the registry names Kaplan-Meier estimation and a 95% confidence interval, but the numerical estimate and interval are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What Kaplan-Meier estimation describes

The registry states that the distribution of time to progression would be estimated using the Kaplan-Meier method and that a progression-free rate at 4 months would be provided. In general, Kaplan-Meier estimation is a way to describe time-to-event data when participants may have different lengths of observation. It uses the timing of observed events and accounts for participants whose event status is not known through the full period of interest by treating their follow-up as censored at the last time their status is known. Censoring is not the same as having experienced an event; it means the event time is not observed within the recorded follow-up.

The method relies on knowing event times and censoring information sufficiently well to construct the estimate. The registry defines progression and the time origin, but does not report the individual follow-up information, the number of events, or the censoring pattern. It also does not report whether any additional analysis rules were used. Therefore, the stated method can be described, but the actual estimate cannot be independently evaluated from the registry record.

What the 4-month rate and confidence interval mean

The four-month progression-free rate is a time-specific summary of the estimated proportion of the analysis population remaining free of documented progression at that time. In general, a confidence interval expresses statistical uncertainty around an estimate: narrower intervals indicate greater precision, while wider intervals indicate less precision. The registry specifies a 95% confidence interval for the primary endpoint, but neither the estimated rate nor the interval limits are reported in the registry record. Without those values, the magnitude and precision of the endpoint are unknown.

A confidence interval is not a guarantee that the true value lies within the interval, and it does not address every source of uncertainty. It reflects uncertainty under the statistical method and assumptions used. In this study, important aspects of the analysis population, follow-up, event counts, and missing outcome handling are not reported in the registry record, so the extent to which the interval would capture all relevant uncertainty cannot be assessed.

How progression was defined

The registry definition combines new lesions with specified increases in measured disease burden. A new malignant lesion meets the progression definition; the record also specifies when a lymph node considered normal at baseline qualifies as enlarged during follow-up. The alternative increase-based criterion uses the sum of the longest diameters of target lesions plus the short axes of target lymph nodes, with the minimum sum of diameters as the reference. It requires both a relative increase of at least 20% and an absolute increase of at least 0.5 cm from that reference.

In general, prespecified event criteria make outcome classification more consistent by clarifying what counts as progression. Their application still depends on how assessments were scheduled, measured, and reviewed. Assessment frequency, central review, and procedures for resolving uncertain classifications are not reported in the registry record. No assumptions about these procedures can be made from the endpoint definition alone.

What the single-group design permits

In general, a single-group study estimates outcomes among participants receiving a treatment strategy, but lacks a concurrent comparison group. It can describe the observed experience and may inform future research questions, but it does not directly estimate how outcomes would have differed under another treatment or no study treatment. Differences between this group's outcomes and an external benchmark could reflect differences in eligibility, disease status, follow-up, or other factors, in addition to any treatment effect.

This trial is listed as single-group, with allocation not applicable and no masking. The registry record does not describe randomization, blinding, or a comparative statistical analysis. The primary outcome should therefore be read as a planned within-group description, not as a randomized treatment-versus-control effect.

How to distinguish planning illustrations from trial findings

The stated sample-size assumptions describe a planning illustration rather than the study's own design justification. The illustration uses a two-sided significance level of 0.05, equal allocation between two hypothetical arms, and a normal approximation. It expresses the effect to detect as a fraction of the observed effect. For time-to-event outcomes, the illustration concerns total events; for other outcomes, it concerns participants per arm.

In general, sample-size planning estimates how much information a future study might need under selected assumptions. Such an illustration is not an observed result, does not show the probability that this completed trial found an effect, and cannot substitute for a reported effect estimate with uncertainty. In this case, the registry record does not report a numerical primary endpoint result or the trial's own sample-size justification. Any planning calculation should therefore be treated only as an illustration, not as observed power or as evidence about the trial outcome.

The posted record contains no detailed analysis results for the outcomes. The methods stated for the primary endpoint are not enough to reconstruct estimates without outcome and follow-up data. The registry does not report a statistical analysis plan, interim analyses, adjustments for covariates, or procedures for multiplicity. Those items should be regarded as unreported, rather than inferred from standard practice.

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("Treatment (Timed Individualized Chemotherapy)")
n      <- c(18)
events <- c(4)
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  Treatment (Timed Individualized Chemotherapy)  18  4  22.2  6.4  47.6  9.0  45.2  9.1  45.6

11. Multiplicity, Missing Data and Analysis Populations

The registry lists progression-free survival at 4 months as the primary endpoint and identifies progression-free survival, overall survival, and toxicity among the secondary outcomes. It also lists 6 outcome measures. The detailed results and analysis procedures for these outcomes are not reported in the registry record. The record does not specify how many hypotheses were tested, whether outcomes were analyzed at multiple time points, or whether any adjustment for multiple comparisons was planned. A multiplicity strategy is therefore not reported in the registry record.

In general, testing several outcomes or making repeated comparisons can increase the chance of observing an apparently unusual result by chance. Methods for addressing that issue depend on the study's prespecified questions and analysis plan. No particular approach should be attributed to this trial because the registry record does not report one.

The primary endpoint population is described as only those patients evaluable for that endpoint. The number evaluable is not reported, and the registry does not describe how missing assessments, incomplete follow-up, or other unevaluable cases were handled. It does not report imputation, sensitivity analyses, or an intention-to-treat analysis population. These methods cannot be assumed.

In general, missing outcome information can affect both the estimated event rate and its uncertainty, especially if the likelihood of missingness is related to health status or outcome. Censoring in time-to-event analysis has a specific role and is not automatically equivalent to missing data; interpretation depends on why follow-up ends and whether censoring is informative. The registry record does not provide enough information to assess these issues for this trial.

Accordingly, the primary endpoint's analysis population is described in broad terms, but its size and missing-data handling remain unclear. The absence of a reported multiplicity plan and detailed analysis population does not prove that no procedures were used; it means they are not reported in the registry record.

12. 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: anemia (4.2%), febrile neutropenia (4.2%), abdominal pain (4.2%), constipation (4.2%), fatigue (4.2%).

The registry reports safety information for the Treatment (Individualized Chemotherapy) group, with 24 participants at risk. It records 3 participants with serious adverse events, 20 with other adverse events, and 0 deaths in the adverse-event listing. The six top serious adverse event terms are anemia, febrile neutropenia, abdominal pain, constipation, fatigue, and abdominal infection; each is listed as 4.2%.

These figures describe the registry's reported safety counts. They should not be treated as a comparison with another regimen or with no treatment: the trial has a single group and no control arm. The registry record does not report the timing, duration, severity grading, or causal attribution for each listed event in the summary information used. It also does not indicate whether the same participant could contribute to more than one serious-event term. Therefore, the listed terms should not be added together or interpreted as distinct individuals.

In general, adverse-event counts are most interpretable when the population at risk, event definitions, follow-up period, severity, and relationship to treatment are clear. Here, the at-risk count and event counts are available, but other details needed for a fuller safety assessment are not reported in the registry record. The absence of recorded deaths in this listing does not establish that the treatment is free of risk.

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

The record establishes that a completed phase 2, single-group study evaluated individualized TMZ administration in patients with metastatic melanoma, with progression-free survival at 4 months designated as the primary endpoint. It describes the progression criteria, the Kaplan-Meier method, and some adverse-event counts. Those details clarify what the study intended to measure and what safety information was posted.

The record does not report the four-month progression-free survival estimate or its 95% confidence interval. It therefore does not show the magnitude or precision of the primary endpoint result. Although enrollment is listed as 25, the primary analysis included only patients evaluable for that endpoint, and the number evaluable is not reported. The enrolled population cannot be assumed to be identical to the endpoint analysis population.

Even with a reported endpoint estimate, the single-group design would describe outcomes in the treatment group rather than establish how those outcomes compare with an alternative. There is no concurrent control group, no randomized comparison, and no masking listed. The data as described cannot isolate the effect of the treatment schedule from other explanations for observed outcomes. The registry's rationale about timing TMZ according to immune biorhythm is a description of the intervention concept, not proof that the approach changed immune function or tumor outcomes.

The safety counts likewise describe reported events in one treatment group. They do not provide a comparative estimate of risk. The record lists 3 serious adverse events among 24 at risk, 20 participants with other adverse events among 24 at risk, and 0 deaths in the adverse-event listing. The serious-event terms and their listed percentages provide additional descriptive detail, but the summary does not establish causality or comparative safety.

In general, a trial result should be interpreted in light of its estimate, uncertainty, analysis population, design, and completeness of follow-up. Because key endpoint results and analysis details are not reported in the registry record, the evidence cannot support a conclusion about the direction, size, or precision of the primary outcome. The record also does not establish that individualized timing is superior, equivalent, or inferior to another approach.

14. Why This Trial Matters Statistically

This trial is statistically notable for the way its treatment schedule is tied to an individualized biological timing concept while its primary outcome is a time-to-event measure. The record distinguishes patients with an established biorhythm from those without one and describes different TMZ schedules for the two groups. That makes clarity about treatment assignment, endpoint definitions, and analysis populations especially important when interpreting the study.

The primary endpoint combines a time origin at registration with a defined progression event and a fixed-time summary at 4 months. In general, a time-to-event method can incorporate follow-up of different lengths, while a fixed-time rate gives a clinically legible summary at a particular point. The registry names Kaplan-Meier estimation and a 95% confidence interval, but does not report the resulting estimate or interval. This demonstrates an important distinction: knowing the planned method does not reveal the result or how precisely it was estimated.

The single-group design also illustrates the difference between describing outcomes and estimating comparative effects. A within-group observation may be useful for characterizing experience, but it does not answer what would have happened under a different schedule or comparator. The absence of randomization and a control group limits causal interpretation, regardless of the sophistication of an outcome method.

Finally, the record provides a reminder that enrollment is not necessarily the same as the endpoint analysis population. The primary endpoint was restricted to evaluable patients, while the number evaluable and the handling of missing information are not reported. These details affect how readers assess the denominator, uncertainty, and potential for bias. The trial's statistical contribution can therefore be understood through its design and measurement plan, while its outcome findings remain unavailable in the registry record.

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.

Several trial-specific limitations constrain interpretation. The registry lists a single treatment group, with allocation not applicable and no masking. There is no concurrent comparator, so treatment outcomes cannot be contrasted within the trial against another regimen or a control condition. The record does not report a randomized comparison or an analysis designed to estimate a comparative treatment effect.

The principal endpoint result is not reported in the registry record. Neither the four-month progression-free estimate nor its 95% confidence interval is available, and the number of patients evaluable for the primary endpoint is also not reported. Enrollment of 25 does not resolve that uncertainty because the registry states that only evaluable patients were included in the primary endpoint analysis.

The treatment description separates patients according to whether a biorhythm was established, but the registry record does not report the number treated under each schedule or outcomes for those subgroups. Consequently, the relative experience of the schedules cannot be assessed. The description of the schedule for patients without an established biorhythm also ends after the stated disease-progression stopping condition; any additional stopping condition is not reported in the registry record.

Assessment frequency, censoring details, missing-data procedures, and the handling of incomplete or unevaluable cases are not reported. Nor are the statistical analysis plan, multiplicity procedures, interim analyses, or the trial's own sample-size justification reported. These omissions prevent assessment of whether the planned analysis was fully implemented and how robust any potential result would be to alternative assumptions.

The safety summary gives counts for the group at risk and lists serious adverse-event terms, but does not provide enough information to assess attribution, event timing, or whether terms overlap within participants. These limits do not demonstrate that the trial lacked relevant procedures or data; they identify what is not reported in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Individualized Temozolomide in Treating Patients With Stage IV Melanoma That Cannot Be Removed By Surgery — NCT01328535.
• Registry record last updated 2020-10-22; status last verified 2019-02.
• Results first posted 2018-11-07.
• 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

The registry describes NCT01328535 as a completed phase 2, single-group study sponsored by Mayo Clinic, with enrollment of 25. It studied individualized TMZ administration in patients with stage IV melanoma that could not be removed by surgery. Treatment timing depended on whether a patient's biorhythm was established, and the primary endpoint was progression-free survival at 4 months.

The endpoint description specifies Kaplan-Meier estimation, a 95% confidence interval, and lesion-based criteria for progression. However, the primary endpoint estimate, its interval, and the number evaluable are not reported in the registry record. Secondary outcomes include progression-free survival, overall survival, and toxicity assessed using NCI CTCAE Version 4.0.

For the treatment group, the safety listing records 3 participants with serious adverse events, 20 with other adverse events, and 0 deaths among 24 at risk. The record does not include a concurrent comparator, and detailed analysis and missing-data procedures are not reported.