A Study of Niraparib as Single Agent in Participants With Advanced Solid Tumors: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of Niraparib as Single Agent in Participants With Advanced Solid Tumors (NCT03497429), a non-randomized phase 1 study. The primary outcome is Number of Participants With Dose Limiting Toxicities (DLTs).

2. Clinical Question

In practical terms, the central question was whether participants in these dose cohorts experienced qualifying toxicities during the first treatment cycle, with safety and tolerability as the main focus. This is an early-phase safety question, not a randomized efficacy comparison. The secondary outcomes were pharmacokinetic measures: maximum observed plasma concentration, time to reach that maximum concentration, and the area under the plasma concentration-time curve from time 0 to 24 hours. Their inclusion reflects the study's stated interest in how niraparib behaves in the body as well as how it is tolerated. Results for those secondary outcomes are not reported in the registry record.

3. Trial Design

The registry record describes a completed Phase 1, open-label study of niraparib as a single agent in participants with advanced solid tumors. The study was non-randomized and used a sequential model. Participants and investigators were not masked to treatment. Enrollment is recorded as 9. The record lists Takeda as sponsor, gives a start date of 2018-04-05, and records primary completion on 2020-02-10.

Two cohorts are described: Niraparib 200 mg and Niraparib 300 mg. In both, niraparib was administered once orally on Days 1 through 21 of a 21-day treatment cycle. The record does not report random assignment between these cohorts, so their observed outcomes should not be treated as if they arose from a randomized head-to-head comparison. Sequential allocation does not, by itself, establish the exact rules or timing used to place participants into cohorts; those details are not reported in the registry record.

The primary outcome was a count of participants with DLTs during Cycle 1. The outcome description specifies a DLT definition based on NCI-CTCAE v4.03 criteria, with investigator judgment that the event was related to niraparib. The registry record also lists pharmacokinetic secondary outcomes, including Cmax, Tmax and AUC24. It records 8 outcome measures, but does not provide results for the primary or secondary outcomes in the registry record for this analysis.

This design is suited to describing early safety and pharmacokinetic observations within the studied participants. It does not provide a randomized treatment contrast, and the non-randomized dose cohorts may differ in ways that affect observed outcomes. The registry record does not report the protocol's dose-selection rules, a statistical analysis plan, a sample-size justification, or interim analysis procedures. Those features should not be inferred from the Phase 1 label or from the fact that the study used sequential cohorts.

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: Japanese participants with advanced solid tumors were enrolled in this dose-escalation study to receive niraparib 200 milligram (mg) in Cohort 1 and niraparib 300 mg in Cohort 2.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The DLT-evaluable set included participants who had received at least 80 percent (%) of planned doses of niraparib in Cycle 1 (for at least 17 days out of 21 days) unless interrupted by study drug-related toxicities and had sufficient follow-up data considered by sponsor and investigator to determine whether DLT occurred.

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.

Population: The safety analysis set included participants who received at least 1 dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Dose Limiting Toxicities (DLTs), measured over Baseline up to Day 21 in Cycle 1 (Cycle length=21 days).

The primary endpoint counts participants with dose-limiting toxicities during the first treatment cycle, from baseline up to Day 21. It is a safety endpoint rather than a measure of tumor response or clinical benefit. The registry record defines qualifying events by specified toxicity grades and circumstances, and requires that events be considered related to niraparib by the investigator.

The definition includes any Grade 5 or 4 hematologic toxicity, with an exception for Grade 4 neutropenia lasting less than 7 days; Grade 3 or 4 neutropenia with fever greater than 38.5 degrees Celsius and/or infection requiring antibiotic or antifungal treatment; and any Grade 3, 4, or 5 non-hematologic toxicity, subject to listed exceptions. Those exceptions include certain short-lived gastrointestinal events in the setting of inadequate supportive-care compliance, inadequately treated hypersensitivity reactions, acidosis or alkalosis that improved to less than or equal to Grade 2 within 48 hours, isolated asymptomatic Grade 3 amylase elevation, hypercholesterolemia and hypertriglyceridemia. A treatment-emergent adverse event leading to a niraparib interruption for greater than 14 days also qualifies under the definition.

In general, a DLT endpoint is used in early-phase research to identify clinically important toxicities within a specified period and under a prespecified definition. The registry record's endpoint definition makes the count dependent both on the observed event and on the stated attribution and assessment criteria. The result for this primary endpoint is not reported in the registry record, so its observed count cannot be interpreted from the available record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count represent?

The primary outcome is a count of participants meeting the registry's DLT definition during Cycle 1. A participant count differs from a count of all event episodes: the endpoint is framed around participants with DLTs, and a participant with more than one qualifying toxicity may still contribute as a participant rather than as multiple independent people. The registry record does not report the primary count, so the observed value is unavailable.

In general, binary outcomes classify each person as having or not having a defined event over a specified period. They can be reported as counts, proportions, or model-based contrasts. A count is straightforward to interpret only alongside its eligible population and outcome definition. Here, both the timing window and the qualifying toxicity criteria are specified, but the number meeting the definition is not reported in the registry record.

Why do the analysis population and endpoint window matter?

The DLT-evaluable set is described as including participants who received at least 80 percent of planned doses in Cycle 1, meaning at least 17 days out of 21, unless dosing was interrupted because of study drug-related toxicities, and who had sufficient follow-up as considered by the sponsor and investigator. This matters because an endpoint count based on an evaluable set can differ from a count based on everyone enrolled. Excluding participants with limited exposure or follow-up can change what the result describes, while including interruptions caused by toxicity helps avoid treating toxicity-related interruptions as ordinary non-exposure.

The exact handling of participants who did not meet the evaluability criteria, including their disposition in the primary analysis, is not reported in the registry record. Nor is the complete operational definition of sufficient follow-up stated. A reader should therefore avoid assuming that the DLT denominator equals enrollment or any cohort's at-risk count for adverse event reporting.

How should the sequential, non-randomized design be read?

In general, randomization makes treatment assignment independent of measured and unmeasured baseline characteristics on average, subject to chance. This study was non-randomized, so that protection does not apply. The record describes a sequential model, but does not report the rules governing cohort assignment. Consequently, differences in observed safety counts may reflect differences in participants, timing, exposure, follow-up, or other factors as well as any dose-related pattern. The cohort summaries are descriptive, not a randomized causal contrast.

Open-label means treatment assignment was not masked. For outcomes involving toxicity assessment, knowledge of treatment can be relevant to reporting or clinical decisions, although the registry's DLT definition includes clinical criteria and investigator attribution. The record does not report procedures intended to reduce assessment bias or any independent review process.

What do the planning assumptions mean?

In general, a sample-size calculation describes how many participants would be needed under specified statistical assumptions to target a chosen probability of detecting an effect. The registry-associated planning description uses a two-sided significance level of 0.05, equal allocation between arms, a normal approximation, and an effect expressed as a stated fraction of the observed effect. These assumptions describe a planning illustration, not the actual design justification reported by the sponsor. The trial's own sample-size rationale is not reported in the registry record.

Such illustrations are sensitive to the effect size used, the assumed allocation, the statistical model and the endpoint definition. They do not describe observed power. Observed power is not a substitute for reporting the effect estimate and its uncertainty; a planning calculation should instead be read as a hypothetical design exercise. The registry record does not report a randomized allocation scheme, and the two cohorts should not be presumed to satisfy equal allocation in the trial.

For a binary outcome, the amount of information depends on how many participants are observed and how many experience the event. When events are uncommon or groups are small, estimates are typically imprecise. General statistical methods can quantify that uncertainty, for example with confidence intervals, but the relevant primary endpoint estimate and interval are not reported in the registry record. No calculation should be reconstructed from counts that are absent.

What is not available about the analysis?

The registry record lists 0 analyses. It does not report an inferential method for the DLT endpoint, a model for comparing cohorts, adjustment for baseline characteristics, interim monitoring, or multiplicity control. These features should not be inferred from the endpoint type or study phase. Without the analysis specification and results, the reader cannot determine whether any formal statistical comparison was planned or performed.

The secondary pharmacokinetic outcomes are Cmax, Tmax and AUC24. In general, pharmacokinetic outcomes describe concentration and exposure over time; interpretation depends on collection timing, assay methods, summaries, and analysis populations. Those methodological details and the numerical results are not reported in the registry record. The same caution applies to any unreported outcome: its absence from the record does not mean that the outcome was not measured, only that its result is not available 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("Cohort 1: Niraparib 200 mg", "Cohort 2: Niraparib 300 mg")
n      <- c(3, 6)
events <- c(0, 1)
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  Cohort 1: Niraparib 200 mg  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Cohort 2: Niraparib 300 mg  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 8 outcome measures, including the primary DLT endpoint and secondary pharmacokinetic outcomes for Cmax, Tmax and AUC24. It records 0 analyses. No statistical plan describing how multiple outcomes were handled is reported in the registry record. In general, testing many outcomes can increase the chance of at least one apparently unusual result if each is assessed separately. A multiplicity strategy may be needed when formal confirmatory claims are intended, but the record does not report whether one was planned or used. The existence of several outcomes alone does not establish that formal hypothesis tests were performed.

The DLT-evaluable population has stated exposure and follow-up criteria, but the complete analysis-population definitions are not reported. The handling of participants who were not evaluable, missing toxicity assessments, withdrawals, or incomplete pharmacokinetic samples is not reported in the registry record. It is also not reported whether missing observations were imputed, excluded, or addressed through another method.

These omissions limit interpretation of denominators and analysis choices. The adverse-event counts include at-risk and affected counts for each cohort, while the primary endpoint's evaluable-set count is not reported. Those populations should not be assumed to match. In general, missing data can affect a result when the chance of missingness is related to health status, treatment exposure, or an event itself. Without information about missingness and analysis populations, the direction or magnitude of any such effect cannot be assessed.

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: pyelonephritis (16.7%).

The serious adverse event counts are reported by cohort. In the Niraparib 200 mg cohort, 3 participants were at risk and 0 were affected; in the Niraparib 300 mg cohort, 6 were at risk and 1 was affected. The record reports 0 deaths in each cohort. For other adverse events, 3 of the 3 at-risk participants in the 200 mg cohort and 6 of the 6 at-risk participants in the 300 mg cohort were affected. These are descriptive participant counts and do not establish that one dose caused more events than the other.

The top serious adverse event term is Pyelonephritis, reported as 16.7%. The denominator and calculation basis for that percentage are not reported in the registry record, so it should not be directly compared with the cohort participant counts without further information.

In general, serious adverse events are a defined subset of adverse events and are not interchangeable with all adverse events or with DLTs. The DLT endpoint has its own Cycle 1 window and attribution criteria. The registry record does not provide enough information to assume that every serious adverse event was a DLT, or that every DLT was classified as serious. The small cohort counts and non-randomized design also constrain comparisons. The figures describe what was recorded, rather than providing a precise estimate of comparative safety.

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

The record establishes that this was a completed, open-label, non-randomized Phase 1 study of niraparib in Japanese participants with advanced solid tumors. It describes two dose cohorts and a Cycle 1 DLT endpoint, alongside pharmacokinetic outcomes. The reported serious adverse event counts show 0 affected participants in the 200 mg cohort and 1 in the 300 mg cohort, with 0 deaths reported in both cohorts. Other adverse events were reported among participants in both cohorts.

Those observations do not answer the primary endpoint question because the number of participants with DLTs is not reported in the registry record. The safety counts should not be substituted for the DLT result: the endpoint definitions and potentially the analysis populations differ. The pharmacokinetic outcomes are listed, but numerical results are not reported in the registry record.

The design also does not support a causal comparison between the dose cohorts. Allocation was non-randomized, and the registry record does not describe cohort assignment rules. Any contrast in observed counts may reflect differences in who entered each cohort, in exposure or follow-up, or in other factors. The counts are descriptive and do not establish that either dose caused more or fewer events.

In general, early-phase safety findings can help characterize events observed under a study's conditions, but estimates from limited cohorts are uncertain and may not represent all patients with advanced solid tumors. The record does not provide a confidence interval or formal analysis for the safety counts. It also does not report efficacy outcomes in the registry record for this analysis. No conclusion about tumor response or treatment benefit follows from the safety and pharmacokinetic aims stated in the registry record.

The appropriate interpretation is therefore bounded: the registry record describes the study, its endpoint definitions, and selected adverse-event counts, while leaving the primary DLT result and important analysis details unavailable. Missing registry results should not be interpreted as zero events or as evidence for a treatment effect.

14. Why This Trial Matters Statistically

This study is statistically informative as an example of how a Phase 1 safety question differs from a comparative treatment question. Its primary endpoint is a count of participants meeting a defined toxicity threshold during Cycle 1, rather than an efficacy measure. The endpoint definition specifies grades, timing, exclusions and investigator attribution, all of which determine what qualifies as a DLT and therefore what the resulting count would mean.

The non-randomized, sequential design is central to interpretation. Dose cohorts can be described separately, but their outcomes do not form an unbiased randomized comparison. This distinction matters even when the intervention and endpoint are clearly stated: study design governs the strength of conclusions that can be drawn from observed differences.

The record also illustrates why a listed outcome is not the same as a reported result. Although the DLT endpoint and pharmacokinetic measures are specified, the primary DLT count and pharmacokinetic findings are not reported in the registry record. An endpoint definition allows readers to understand what was intended to be measured; it does not reveal what was observed. Similarly, safety counts for other adverse events cannot fill in the missing primary endpoint result.

Finally, small cohort summaries require attention to denominators, analysis populations, and uncertainty. The serious adverse event counts are informative descriptively, but the record does not provide confidence intervals or enough detail to determine how those counts relate to the DLT-evaluable set. The absence of reported analyses and missing-data procedures further limits inferential interpretation. These distinctions are useful when evaluating early-phase records: separate the design, outcome definition, observed counts, and unreported statistical details rather than treating them as interchangeable evidence.

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 most consequential limitation for interpreting the primary question is that the registry record does not report the number of participants with DLTs. It also does not give a primary endpoint estimate or uncertainty interval. The DLT definition is detailed, but the result needed to apply that definition is absent.

The DLT-evaluable population description is incomplete in the registry record. It states exposure requirements and refers to sufficient follow-up as considered by the sponsor and investigator, but does not report the full operational criteria or the number of participants meeting them. The primary analysis denominator therefore cannot be established in the registry record. Nor is it reported how participants with incomplete dosing or follow-up were handled.

The cohorts were non-randomized, and assignment procedures are not reported. Cohort comparisons are vulnerable to differences between participants and should be treated as descriptive. The open-label design may also affect assessment or reporting, while procedures for independent review are not reported.

Although serious and other adverse-event counts are available, the registry record does not report detailed event timing, duration, recurrence, severity distributions, or the relationship of those events to the DLT endpoint. The basis for the reported 16.7% Pyelonephritis figure is not stated. Pharmacokinetic outcomes are listed without numerical results or the relevant collection and analysis details.

The record does not report a statistical analysis plan, multiplicity handling, missing-data methods, interim analyses, or the study's sample-size justification. These absences prevent assessment of the intended inferential framework and limit the conclusions that can be drawn from the posted summaries.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study of Niraparib as Single Agent in Participants With Advanced Solid Tumors — NCT03497429.
• Registry record last updated 2021-11-09; status last verified 2021-10.
• Results first posted 2021-11-09.
• 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.

19. Record Summary

NCT03497429 is a completed, open-label, non-randomized Phase 1 study of niraparib as a single agent in Japanese participants with advanced solid tumors. The registry record describes sequential cohorts receiving 200 mg or 300 mg orally once daily on Days 1 through 21 of each 21-day cycle. Its primary outcome was the number of participants with DLTs during Cycle 1, defined using NCI-CTCAE v4.03 criteria and investigator judgment of relationship to niraparib.

The record lists pharmacokinetic secondary outcomes, 8 outcome measures and 0 analyses. It reports serious adverse event counts by cohort, including 0 deaths in each, but does not report the primary DLT count or pharmacokinetic results. The non-randomized design and unreported analysis details limit comparisons between cohorts. The registry record supports descriptive interpretation of the reported counts, not a definitive comparative or efficacy conclusion.