Talazoparib and Temozolomide in Treating Younger Patients With Refractory or Recurrent Malignancies: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Talazoparib and Temozolomide in Treating Younger Patients With Refractory or Recurrent Malignancies (NCT02116777), a randomized phase 1, phase 2 study. The primary outcome is The Number of Participants With Dose Limiting Toxicities to Determine the Maximum Tolerated Dose of Temozolomide and Talazoparib Combination Therapy.

2. Clinical Question

3. Trial Design

This was a phase 1/2 study of talazoparib and temozolomide in younger patients with refractory or recurrent malignancies. The registry classifies the study as randomized, unmasked, and sequential, with an enrollment of 40. The sponsor was the National Cancer Institute (NCI). The recorded status is completed. The study start date is 2014-05-16, and the primary completion date is 2018-12-31.

The phase 1 portion examined successive dose combinations. Its regimen description specifies oral talazoparib once daily or twice daily on days 1–6, with oral temozolomide once daily on days 2–6. Each course repeated every 28 days, for up to 24 courses in the absence of disease progression or unacceptable toxicity. The phase 2 description concerns patients with relapsed or refractory Ewing sarcoma or peripheral primitive neuroectodermal tumor, who received the maximum tolerated dose from phase 1. It also describes repeating treatment every 28 days for up to 24 courses subject to progression or unacceptable toxicity.

The posted dose groups show combinations with different talazoparib schedules and temozolomide doses. Participant counts and dose-limiting toxicity counts are reported by group. The registry also reports a maximum tolerated dose level of 4, but does not identify in that analysis the corresponding regimen in a way that links the reported level to a specific posted dose-group label.

Randomized allocation is recorded, but the sequence of dose levels and the reason for randomization are not described in sufficient detail to clarify how these features operated together. The allocation procedure, randomization ratio, and protocol-level dose-escalation rules are not reported in the registry record. No separate comparator arm is listed.

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 receive talazoparib PO QD or BID on days 1-6 and temozolomide PO QD on days 2-6. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Only the first 6 of 7 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Patients with toxicity grade 3 or above.

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.

Only the first 6 of 8 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as The Number of Participants With Dose Limiting Toxicities to Determine the Maximum Tolerated Dose of Temozolomide and Talazoparib Combination Therapy, measured over 28 days.

The primary endpoint counts participants with dose-limiting toxicities for the purpose of determining the maximum tolerated dose of the talazoparib and temozolomide combination. The registry gives a 28-day timeframe. Its description defines the maximum tolerated dose as the highest talazoparib dose, combined with a temozolomide dose, that did not cause Grade 3 or higher toxicity in children with refractory or recurrent solid tumors.

A count is a direct summary of how many participants met the endpoint within a dose group. It is not, by itself, a measure of the severity or duration of every adverse event, nor does it describe how frequently each type of toxicity occurred over longer follow-up. The registry's endpoint population wording refers to patients with toxicity grade 3 or above, while its explanatory definition concerns the dose that did not cause Grade 3 or higher toxicity. The detailed endpoint adjudication rules and the method used to classify a dose-limiting toxicity are not reported in the registry record.

In general, a toxicity endpoint is used in early-phase dose-finding because selecting a tolerable dose requires information about harms observed during treatment. The posted group counts describe the endpoint observations at the listed doses; the separate reported maximum tolerated dose level is the registry's summary of dose selection. Neither result alone establishes comparative efficacy.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count tell the reader?

The primary outcome is expressed as a count of participants with dose-limiting toxicities. A count makes the observed number of participants meeting the endpoint visible for each dose group. It does not automatically give a stable estimate of how often the event would occur in a larger population. In general, the precision of an event proportion depends in part on the number of participants observed, and estimates based on small groups can be uncertain even when the count is zero. A zero count means that no qualifying event was recorded in that group during the specified endpoint timeframe; it does not prove that the underlying risk is absent.

The registry reports participant counts and event counts for the posted regimens, but no confidence intervals for these counts or rates. Without those intervals, the record does not quantify the statistical uncertainty around each group’s observed toxicity experience. The description also does not provide a more detailed endpoint definition, including how toxicity attribution, timing, and dose interruptions were handled.

How should the sequential dose groups be understood?

In general, sequential dose-finding studies examine dose levels in an ordered process to inform the choice of a dose for further study. The relevant evidence is not simply a ranking of group counts: interpretation depends on the dose-escalation rules, the decision criteria, the timing of observations, and which participants contribute to dose selection. Those protocol details are not reported in the registry record. The record labels the study sequential and randomized, but does not explain the relationship between the two design features.

The study includes several regimens with different talazoparib schedules or temozolomide doses. Group-specific counts should therefore be interpreted in the context of each regimen, rather than as if all groups received the same exposure. The registry does not provide a formal statistical comparison among the groups, and no p-value or confidence interval is reported for the maximum tolerated dose result.

What is the role of the reported maximum tolerated dose?

The registry reports a maximum tolerated dose level of 4. This is a dose-selection summary, not a treatment-effect estimate. A dose level identifies the result of the study’s dose-finding process as recorded, but the posted analysis does not state a statistical method or give a precision interval. The record also does not explicitly connect level 4 to one of the regimen labels shown among the groups. Thus the reported level can be described, but its exact regimen mapping cannot be established from the registry analysis alone.

In general, a maximum tolerated dose is used to summarize a tolerability-based dose decision. It does not by itself establish that a dose is effective, that it is optimal for every participant, or that its toxicity profile is fully characterized. A toxicity endpoint observed during the stated timeframe also does not necessarily capture toxicities occurring later in treatment.

Why are confidence intervals and p-values relevant?

In general, a confidence interval describes the range of values reasonably compatible with the observed data under a specified statistical model. It communicates precision, which a point estimate or count cannot show by itself. A p-value addresses compatibility with a particular null hypothesis under a model; it does not measure the size or clinical importance of an effect. The registry does not report either measure for the maximum tolerated dose analysis. Because the study does not list a separate comparator arm for the primary endpoint, a conventional two-arm comparison is not available from the posted results.

For binary outcomes, a comparative analysis ordinarily needs clearly defined groups and an effect measure, such as a difference or ratio of event probabilities. No such recalculated contrast is reported for this study. General statistical explanations of contrasts do not imply that a contrast can be estimated from these results. The appropriate description remains the observed counts by listed regimen and the registry’s reported dose-level conclusion.

What do planning sample sizes mean?

In general, a sample-size calculation is a planning exercise based on assumptions about the target effect, significance level, allocation, and statistical model. It is not a measure of what the completed study actually achieved, and it is not observed power. The planning assumptions associated with the posted illustration specify a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the target effect expressed as a fraction of the observed effect. However, the registry record does not report a numerical planning result for this trial. Those assumptions do not substitute for the study’s own design justification, which is not reported in the registry record.

In general, over-dispersion matters when variability in observed counts is greater than a statistical model assumes. Accounting for it can affect estimated uncertainty and inference. The registry does not report an over-dispersion analysis for this endpoint, and the posted primary result is a count-based dose-finding summary rather than a model-based comparison of event rates. Statistical methods, model specifications, and assumptions beyond the reported analysis are not reported in the registry record.

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("400 mcg/m²/Dose BMN 673 QD+20mg/m²/Dose TEM,Max 80", "400 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 8", "600 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 1", "600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM, Max ", "600 mcg/m²/Dose BMN 673 BID+40mg/m²/Dose TEM, Max ", "600 mcg/m²/doseBMN 673 BID+55mg/m²/Dose TEM, Max 1")
n      <- c(3, 3, 3, 7, 6, 3)
events <- c(0, 0, 1, 2, 2, 2)
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  400 mcg/m²/Dose BMN 673 QD+20mg/m²/Dose TEM,Max 80  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  400 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 8  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  600 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 1  3  1  33.3  0.8  90.6  6.1  79.2  6.8  80.6
ARM  600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM, Max   7  2  28.6  3.7  71.0  8.2  64.1  8.5  65.1
ARM  600 mcg/m²/Dose BMN 673 BID+40mg/m²/Dose TEM, Max   6  2  33.3  4.3  77.7  9.7  70.0  9.9  71.0
ARM  600 mcg/m²/doseBMN 673 BID+55mg/m²/Dose TEM, Max 1  3  2  66.7  9.4  99.2  20.8  93.9  19.4  93.2

11. Analyses Reported by the Sponsor

The registry’s reported analysis gives a maximum tolerated dose level of 4. It does not include a confidence interval, p-value, or named statistical method for that conclusion, and it does not explicitly link the level to a particular regimen label among the posted groups. The reported value should therefore be described as the sponsor’s recorded dose-level result, without adding an unreported statistical interpretation.

No recalculated two-arm estimate is available for comparison with the reported result. The endpoint is binary, but the posted groups do not constitute a clearly defined separate control-versus-treatment contrast for recalculation. The registry record also does not report the information needed to reconstruct the dose-selection procedure in full. Because no discrepancy is flagged, there is no competing recalculated estimate to set against the sponsor’s analysis. The sponsor’s own reported analysis remains the relevant source for the stated maximum tolerated dose level.

This distinction matters because descriptive counts and a dose-selection conclusion answer related but different questions. The counts show recorded dose-limiting toxicities by group; the level summarizes the trial’s dose-finding conclusion. The registry does not report sufficient detail to independently reproduce the decision rule that connects the counts to level 4.

12. Multiplicity, Missing Data and Analysis Populations

The registry lists 19 outcome measures and one secondary outcome: the number of solid tumor patients with complete response or partial response. The primary endpoint concerns dose-limiting toxicities and maximum tolerated dose. The record does not report a multiplicity adjustment, a hierarchy for interpreting multiple outcomes, or a prespecified strategy for controlling the chance of false-positive findings across analyses. The number of outcome measures alone does not show how many were formally tested or how their results were intended to be interpreted.

The registry reports one analysis for the primary result, but does not provide the statistical method for that analysis. It also does not report whether any analyses were interim, whether the analysis plan changed, or whether dose-group findings were selected after examining the results. These details are not reported in the registry record and should not be inferred from the sequential design label.

Missing-data handling and analysis populations are not reported in the registry record. The record does not explain whether all enrolled participants were included in each endpoint analysis, how participants who did not complete the 28-day timeframe were treated, or how missing toxicity assessments were handled. It also does not state whether the analysis population was defined by enrollment, treatment received, or another rule.

In general, these decisions matter because excluding participants or treating incomplete outcome information in different ways can change an endpoint summary. They are particularly relevant when group sizes are small. The registry’s participant counts and event counts can be described as posted, but they do not reveal the full analysis-set rules. The record also does not report the handling of missing response data for the secondary outcome or a method for addressing multiplicity in that outcome.

13. 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: neutrophil count decreased (100.0%), anemia (66.7%), lymphocyte count decreased (66.7%), platelet count decreased (66.7%), white blood cell decreased (66.7%).

The registry reports serious adverse events and other adverse events by dose group, including the number at risk and the number affected. Serious adverse event counts include 2 of 3 participants in each of the first two groups, 2 of 3 in the third group, 11 of 13 in one 600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM group, 6 of 6 in the 40mg/m²/Dose TEM group, 3 of 3 in the 55mg/m²/Dose TEM group, and 8 of 9 in the other listed 30 mg/m²/Dose TEM group. The registry also records deaths by group; the reported counts are 0, 0, 0, 2, 1, 0, and 0 in the listed order.

These are descriptive safety counts. They do not establish that the combination caused every event, and they do not indicate that every serious event was a dose-limiting toxicity. The registry lists neutrophil count decreased at 100.0% among the top serious adverse event terms, and anemia, lymphocyte count decreased, platelet count decreased, and white blood cell decreased at 66.7% each. Anorexia is listed at 33.3%. The registry record does not specify the denominator used for these term percentages in the information reported.

Serious adverse event reporting and the primary dose-limiting-toxicity endpoint answer different questions. The posted safety summaries should be interpreted as recorded events in this study, not as comparative estimates against another treatment.

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

The central result is a registry-reported maximum tolerated dose level of 4, alongside dose-group counts of participants with dose-limiting toxicities. These results describe the study’s dose-finding and toxicity observations for talazoparib combined with temozolomide in younger patients with refractory or recurrent malignancies. The recorded counts are relevant to tolerability during the primary endpoint timeframe, while the reported dose level is the registry’s dose-selection summary.

The results do not establish comparative efficacy because no separate control treatment is listed. Although a secondary outcome concerns complete or partial response, the registry information does not include its response counts or a treatment comparison. The stated rationale in the study summary that the combination may work better is not itself evidence of an observed comparative benefit.

The findings also do not determine the frequency of toxicity in a broader population with precision. The posted groups are small, no confidence intervals are reported for the primary outcome, and the registry does not report enough detail to reproduce the dose-selection rules. The maximum tolerated dose level is not explicitly linked to a particular regimen label in the analysis record. The 28-day primary timeframe does not, by itself, describe the full course of adverse events over repeated treatment.

In general, an early-phase dose-finding result is intended to inform dose selection for further research. It should not be interpreted as a guarantee that the same tolerability pattern will occur in other patients, settings, or treatment schedules. Nor does a maximum tolerated dose identify a dose that is necessarily optimal when efficacy, long-term safety, and other clinical considerations are considered. The registry record does not report an analysis establishing such an optimum.

The most defensible reading is therefore descriptive: the registry records a dose-level conclusion and counts of dose-limiting toxicities across the listed regimens, with serious adverse events also reported. The information does not support a causal comparison between regimens or a broad claim about treatment benefit.

15. Why This Trial Matters Statistically

This trial is statistically informative because it illustrates how early-phase dose-finding results differ from a conventional comparison of treatments. The main question is dose selection based on toxicity observations, not an estimate of how much one treatment improves an outcome relative to a control. That distinction affects which summaries are meaningful: group counts and a maximum tolerated dose level are central, while a two-arm treatment-effect estimate is not available from the posted design information.

The record also shows why the process behind a dose-level conclusion matters. A maximum tolerated dose is not determined by the count alone; in general, its interpretation depends on the protocol’s dose-escalation rules and toxicity definitions. Those rules are not reported in the registry record, so readers can describe the recorded level but cannot reconstruct the decision process in detail. The gap between a reported dose level and its explicit mapping to a regimen also limits clinical and statistical interpretation.

The small numbers within the listed dose groups make precision especially important. Counts communicate what was observed, but without confidence intervals they do not show the uncertainty around an event rate. In general, a zero count in a small group does not demonstrate that an event cannot occur. The safety summaries offer additional context, but serious adverse events should not be conflated with the specifically defined primary endpoint.

Finally, the record identifies missing information that would help readers assess robustness: analysis populations, missing-data rules, multiplicity handling, and a detailed statistical method are not reported. These omissions do not invalidate the posted descriptive results, but they limit how far the findings can be generalized or independently checked. The study is therefore useful as a registry-recorded dose-finding example, while its reported summaries should be interpreted within the scope of the data and methodological detail available.

16. 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 records randomized allocation and a sequential model but does not explain how randomization was used in the dose-finding process. It does not identify a separate comparator treatment, describe the allocation procedure, or report the planned allocation ratio. As a result, the listed groups should not be treated as a conventional randomized comparison of the combination against an alternative.

The primary endpoint definition is not fully detailed. The registry states a 28-day timeframe and describes Grade 3 or higher toxicity in its definition of the maximum tolerated dose, but it does not report the full criteria for a dose-limiting toxicity, how events were attributed, or how incomplete observation was handled. The population wording for the endpoint refers to patients with toxicity grade 3 or above, while the dose definition refers to a dose that did not cause Grade 3 or higher toxicity. Further operational clarification is not reported in the registry record.

The analysis record reports a maximum tolerated dose level of 4 without a method, confidence interval, p-value, or explicit mapping of that level to one of the listed regimen labels. Dose-group counts are small, and the registry does not provide uncertainty intervals for them. The record does not report the analysis population, missing-data handling, multiplicity procedures, or a sample-size justification. It also does not report whether interim analyses were conducted or whether the statistical plan changed.

The safety summaries provide counts and selected serious adverse event terms, but the registry information does not give the denominator for the term percentages or establish that serious adverse events meet the primary endpoint definition. The secondary response outcome is identified, but response results are not reported in the information available for this analysis. These gaps limit assessment of efficacy, precision, and the reproducibility of the dose-selection conclusion.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Talazoparib and Temozolomide in Treating Younger Patients With Refractory or Recurrent Malignancies — NCT02116777.
• Registry record last updated 2021-03-26; status last verified 2021-03.
• Results first posted 2021-03-26.
• 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.

20. Record Summary

NCT02116777 is a completed phase 1/2 study of talazoparib plus temozolomide in younger patients with refractory or recurrent malignancies. The registry records randomized allocation, no masking, a sequential model, and enrollment of 40. The study examined multiple dose regimens, with the primary outcome counting participants with dose-limiting toxicities during a 28-day timeframe to inform the maximum tolerated dose.

The registry reports a maximum tolerated dose level of 4 and posts dose-group counts for the primary endpoint. It also lists serious adverse events and identifies a secondary response outcome. A separate comparator arm is not listed, and the maximum tolerated dose analysis does not include a method, confidence interval, or p-value.

Interpretation is limited by the absence of reported dose-selection rules, analysis-population definitions, missing-data procedures, and multiplicity methods. The results are descriptive dose-finding observations and do not establish comparative efficacy.