Single-arm Study With Bimiralisib in Patients With HNSCC Harboring NOTCH1 Loss of Function Mutations: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Single-arm Study With Bimiralisib in Patients With HNSCC Harboring NOTCH1 Loss of Function Mutations (NCT03740100), a na phase 2 study. The primary outcome is Objective Response Rate (ORR).

2. Clinical Question

The study asks whether patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) harboring NOTCH1 loss-of-function (LOF) mutations achieved a confirmed radiological response while receiving bimiralisib. The primary outcome is Objective Response Rate (ORR), defined in the registry record as the number of participants with a confirmed partial response or confirmed complete response according to RECIST 1.1. Assessments were scheduled at 6 and 12 weeks after treatment began, with a ± 3 days window.

This question is about observed tumor response in a molecularly selected group, not a randomized comparison of treatments. The design can describe outcomes among participants treated in the study, but, without a concurrent control group, it cannot by itself separate treatment effects from other explanations for those outcomes. The endpoint result needed to describe the observed response is not reported in the registry record.

3. Trial Design

This is an open-label, single-arm Phase 2 study sponsored by M.D. Anderson Cancer Center. The official title describes it as a two-stage study, while the registry lists a single group receiving bimiralisib. The recorded allocation is NA and masking is NONE. There is no randomized allocation or blinded comparison described in the registry record.

The study enrolled 8 participants. The registry lists a start date of 2019-01-25, a primary completion date of 2020-08-05, and a status of TERMINATED. The reason for termination and the details of the two-stage design are not reported in the registry record. The title alone does not establish how the stages were implemented, whether a stage-specific decision rule was used, or whether any planned enrollment target was reached.

Participants were described as having recurrent or metastatic HNSCC with NOTCH1 LOF mutations; the brief summary additionally describes disease as refractory and/or metastatic. The intervention was bimiralisib capsules taken orally. Eligibility criteria, dose, administration schedule, permitted concomitant treatment and follow-up beyond the listed primary endpoint timeframe are not reported in the registry record.

The primary endpoint was ORR, assessed using CT or MRI according to a standard protocol and defined using confirmed complete or partial response per RECIST 1.1. Assessments were scheduled at 6 and 12 weeks after treatment started, each with a ± 3 days window. No comparator arm is listed. Accordingly, the posted design is suited to describing outcomes in the treated group, but it does not provide a randomized estimate of how outcomes would differ under another treatment or no study treatment.

The record lists one outcome measure and one analysis, but the primary response count and result are not reported in the registry record. Information about the statistical analysis plan, including any planned decision rules associated with the two-stage description, is also not reported. The status and enrollment figures describe the registry entry; they do not fill in these missing design or outcome details.

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:

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 Objective Response Rate (ORR), measured over At 6 and 12 weeks after the start of therapy (± 3 days).

The primary endpoint is Objective Response Rate (ORR), reported in the registry as a count of participants. A participant qualifies under the endpoint definition if radiological assessment shows a confirmed partial response or confirmed complete response according to RECIST 1.1. Tumor assessments were performed by CT or MRI under a standard protocol. The assessment times were 6 and 12 weeks after the start of therapy, with a ± 3 days window.

In general, response endpoints summarize whether tumors meet prespecified radiological criteria for shrinkage. They turn imaging assessments into a defined outcome that can be counted across participants. A confirmed response requirement is intended to distinguish a response that meets the criteria on confirmation from an unconfirmed observation; the registry record does not provide further details about confirmation procedures.

ORR is used to describe response in a treated group. It is not, by itself, a measure of how long a response lasts, how long participants live, or how outcomes compare with an untreated or alternative-treatment group. Those are distinct questions and are not addressed by the endpoint description.

Although the endpoint definition and assessment schedule are posted, the response count and ORR result are not reported in the registry record. The number enrolled therefore cannot be used as a substitute for the number with a response, or as proof that every enrolled participant had an evaluable assessment.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a single-arm study estimate?

In general, a single-arm study summarizes outcomes observed among participants receiving the study intervention. For a binary endpoint such as response, the basic descriptive result is a count of participants meeting the response definition and a corresponding proportion among the participants included in the analysis. The registry record gives the endpoint definition and enrollment, but does not report the response count, the analysis denominator or the resulting ORR. No response proportion can therefore be stated from this record.

A single-arm estimate answers a descriptive question about the observed group. It does not directly estimate a difference between bimiralisib and another treatment. A randomized comparator can help distinguish treatment-group differences from differences in participant characteristics, time trends and other influences. There is no such comparator in this study design. Historical or external comparisons would require information and assumptions not reported in the registry record.

How should a binary response endpoint be read?

In general, a binary endpoint classifies each participant into outcome categories, such as meeting or not meeting a response definition. Here, the posted definition counts participants with a confirmed complete or partial response per RECIST 1.1. The record says that CT or MRI assessments followed a standard protocol and identifies the 6- and 12-week assessment times. It does not report how a participant with an absent scan, an unevaluable scan, or differing results across visits was classified for the primary analysis.

For a binary estimate, the numerator is the number meeting the definition and the denominator is the number included in the endpoint analysis. Both are needed to interpret the result. Enrollment of 8 supplies neither the response numerator nor proof of the analysis denominator. A confidence interval would express uncertainty around an estimate under a stated method. The registry record does not report an ORR estimate or its confidence interval.

What can a significance test add?

In general, a hypothesis test compares observed data with a specified statistical model and null hypothesis. A p-value describes how unusual data at least as extreme as those observed would be under that model and null hypothesis. It is not the probability that a treatment works, and it does not communicate the size or clinical importance of an effect. The registry record does not report a primary-endpoint p-value, null hypothesis, or inferential test. A test result should not be inferred from the endpoint definition or study phase.

Statistical significance is also distinct from precision. An interval estimate provides information about the uncertainty and range of values compatible with the data under the method used. Neither an interval nor a test can be reconstructed when the response count and analysis denominator are absent. The exact analysis methods for the endpoint are not reported in the registry record.

What does the sample-size section represent?

The sample-size section is a planning illustration, not a record of the study's observed power. Its stated framework uses a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is described as a stated fraction of the observed effect. The framework specifies participants per arm for outcomes other than time-to-event outcomes; time-to-event illustrations use a total number of events. Those are assumptions for hypothetical planning calculations, not evidence that this single-arm study had two arms or was designed with those assumptions.

In general, a planning calculation estimates the sample size needed to detect a chosen effect under specified assumptions. Changing the target effect, significance level, allocation or statistical approximation changes the planning result. Such a calculation does not show whether the study actually had a particular probability of detecting an effect. Observed power is not an appropriate substitute for examining the effect estimate and its uncertainty. Here, the registry record does not report a sample-size justification for the trial, and the calculation framework should not be mistaken for the trial's own design rationale.

Why can over-dispersion matter?

In general, over-dispersion occurs when the variability in observed data is greater than expected under a statistical model. If a model assumes less variability than the data have, its standard errors may be too small and its intervals or tests may appear more certain than warranted. This is a general statistical issue, not a method identified for this trial. The primary outcome is described as a binary participant count, and the statistical model used for the posted analysis is not reported in the registry record.

For event counts, repeated events or differences in underlying event risk can also make a simple model's assumptions inadequate. Whether such features were evaluated in the safety analysis is not reported. The general concept helps explain why model assumptions matter; it does not establish that over-dispersion occurred in this study.

How do the assessment schedule and two-stage title affect interpretation?

The registry identifies assessments at 6 and 12 weeks after therapy began, each with a ± 3 days window. In general, repeated assessment times can raise questions about which visit defines the primary result, how responses across visits are summarized, and whether statistical adjustment is considered when multiple hypotheses are tested. The registry title describes a two-stage study, but the stage procedures, decision thresholds, and any relationship between stages and the assessment times are not reported. No specific interim analysis or stage-based stopping rule can be inferred from the title.

The registry lists one outcome measure and one analysis. It does not give the analysis plan or clarify whether the endpoint was analyzed at both time points, whether either analysis was interim, or how multiplicity was addressed. These omissions prevent a detailed reconstruction of the inferential methods. The most defensible reading is to distinguish the stated endpoint and schedule from statistical procedures that are not described.

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("Open Single Arm")
n      <- c(6)
events <- c(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  Open Single Arm  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 identifies ORR assessments at 6 and 12 weeks after treatment began. It does not clarify whether the response result was intended to be summarized separately at both times, whether one time was designated as the main analysis, or whether the two assessments formed part of a formal testing strategy. A multiplicity adjustment or decision rule is not reported in the registry record.

In general, multiplicity arises when several outcomes, time points, subgroups or statistical tests are examined. If many tests are treated as independent opportunities to declare a finding, the chance of at least one apparently unusual result can increase. Prespecified priorities or suitable statistical adjustments can address this concern, depending on the question and analysis plan. This general explanation does not imply that the study performed multiple hypothesis tests or that any adjustment was required; the plan is not reported.

Missing-data handling is also not reported. The record does not state how participants without an assessment, participants who discontinued before assessment, or scans that could not be classified were handled. Enrollment of 8 does not establish the response-analysis denominator. The registry record does not report a participant flow description or the number with evaluable imaging at either assessment time.

The analysis population is not described beyond the endpoint wording. The record does not say whether the primary analysis included all enrolled participants, only participants who received treatment, or another defined set. It also does not report protocol deviations or exclusions from analysis. These details are important because different analysis populations can yield different summaries, especially when outcomes are unavailable. No particular imputation method, sensitivity analysis or missing-data assumption is reported in the registry record.

These omissions mean that neither multiplicity control nor robustness to missing observations can be evaluated from the posted entry. They do not establish that the trial failed to use such methods; the relevant methods are simply 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: hyperglycemia (25.0%), disease progression (12.5%), skin infection (12.5%), osteomyelitis (12.5%), sepsis (12.5%).

The safety group lists 8 participants at risk for serious adverse events, with 5 affected. For other adverse events, 8 participants are listed at risk and 8 affected. The record also lists 2 deaths. These are counts in the registry record; it does not report whether the deaths were considered related to treatment or provide their causes.

The listed serious adverse event terms and percentages are Hyperglycemia, 25.0%; Disease Progression, 12.5%; Skin Infection, 12.5%; Osteomyelitis, 12.5%; Sepsis, 12.5%; and Alanine aminotransferase increased, 12.5%. These are the terms and percentages as posted. The registry record does not explain the denominator or whether the displayed terms represent unique participants, events, or a selected set of terms.

In general, adverse-event categories can overlap: a participant may experience more than one event, and an event may be counted under a serious-event category as well as in a broader adverse-event summary. Therefore, category counts should not be added as though they represented distinct participants. The definitions, event timing, duration, severity grading and attribution procedures are not reported in the registry record.

These figures describe reported safety information; they do not establish causation. The record does not provide enough detail to determine whether an event arose from treatment, underlying disease or another cause, and the listed deaths should not be interpreted as treatment-related on the basis of the counts alone.

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

This entry documents an open-label, single-arm Phase 2 study of oral bimiralisib in patients with recurrent or metastatic HNSCC harboring NOTCH1 LOF mutations. It specifies a radiological primary endpoint, a response definition based on RECIST 1.1, and assessment times at 6 and 12 weeks after treatment began. It also reports enrollment of 8 and selected safety counts. These are useful descriptions of the study and its registry record.

The entry does not report the primary response count or ORR. It therefore does not show the observed response result, the precision of that result, or whether response differed across the listed assessment times. The missing result must not be read as a zero response count or as evidence that no participant responded. The analysis denominator and handling of unavailable assessments are also not reported.

Even if a response estimate were available, the single-arm design would describe outcomes in the treated group rather than provide a randomized comparison. In general, without a concurrent control group, it is difficult to attribute observed outcomes to the intervention rather than to other factors. The open-label design is another feature to consider when interpreting results, although the endpoint uses radiological criteria and a standard assessment protocol.

The serious adverse event counts and listed terms are descriptive. They do not establish that bimiralisib caused the events or deaths. The record does not report attribution details or enough information to assess event timing and clinical context.

Accordingly, this registry entry supports a cautious account of design and reported counts, not a conclusion about treatment benefit, lack of benefit, or comparative safety. The endpoint outcome and key analysis details are not reported in the registry record, so claims that depend on those results are not supported by this entry.

14. Why This Trial Matters Statistically

Statistically, this study brings together a defined molecular subgroup, a single-arm treatment design and a binary radiological response endpoint. That combination makes the distinction between describing an outcome and estimating a comparative treatment effect especially important. The design can record whether participants in the study met the response definition, but it does not include a concurrent control group to provide a direct comparison.

The enrolled group contains 8 participants. In general, estimates based on a limited number of observations can be imprecise, and a response count alone would not communicate that uncertainty. Interpretable reporting would also require the analysis denominator and an interval or other measure of precision. The registry record does not report the ORR result, its denominator or its precision, so the magnitude and uncertainty of the response cannot be evaluated from this entry.

The scheduled assessments at 6 and 12 weeks also illustrate why endpoint timing and analysis plans matter. A result can depend on how repeated assessments are summarized, which time point is emphasized, and how missing scans are handled. The registry entry does not report those analysis details. Its two-stage title raises a further design question, but the operational details and any stage-based rules are not reported.

Finally, safety counts require careful interpretation. Counts of participants with serious and other adverse events answer a descriptive question, while attribution and event context are needed to assess causality. The record lists counts and selected terms, but does not report those details.

The statistical importance of the entry is therefore not a conclusion about efficacy. It is a reminder that a clearly defined endpoint is only part of an interpretable trial result: the outcome count, analysis population, uncertainty, missing-data approach and design context also matter.

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 registry record reports enrollment of 8 and a TERMINATED status, but does not report the reason for termination or explain whether the planned two-stage structure was completed as intended. The official title identifies a two-stage design; operational details, stage-specific enrollment and decision rules are not reported. These omissions limit assessment of how the registered design was implemented.

The primary endpoint is defined, but its result is not reported. The response count, ORR, analysis denominator and measure of precision are absent. The registry record also does not explain whether responses were summarized separately at 6 and 12 weeks or how participants with missing or unevaluable scans were treated. Enrollment should not be treated as proof that all participants contributed evaluable endpoint data.

The study is open-label and single-arm, with no concurrent comparator. Any observed outcomes would therefore be descriptive of the treated group and would not provide a randomized estimate of a treatment difference. The record does not report details about independent radiology review or blinded assessment.

Further limits include the lack of reported eligibility criteria beyond the disease and mutation description, and the absence of dose, treatment schedule, analysis population, statistical plan and sample-size justification. The endpoint timeframe is reported, but follow-up information for outcomes beyond that schedule is not reported in the registry record. For safety, event definitions, grading, timing and attribution are not provided. These missing details constrain interpretation without establishing that the corresponding procedures or information were absent from the study itself.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Single-arm Study With Bimiralisib in Patients With HNSCC Harboring NOTCH1 Loss of Function Mutations — NCT03740100.
• Registry record last updated 2023-07-14; status last verified 2023-07.
• Results first posted 2022-01-20.
• 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 an open-label, single-arm Phase 2 study of bimiralisib in patients with recurrent or metastatic HNSCC harboring NOTCH1 LOF mutations. The sponsor is M.D. Anderson Cancer Center. The study enrolled 8 participants and is listed as TERMINATED, with a start date of 2019-01-25 and a primary completion date of 2020-08-05.

The primary endpoint is ORR: participants with confirmed complete or partial response per RECIST 1.1, assessed by CT or MRI at 6 and 12 weeks after treatment began, with a ± 3 days window. The registry record does not report the primary response result, the analysis denominator or its precision.

The safety summary lists 5 of 8 participants affected by serious adverse events, 8 of 8 affected by other adverse events, and 2 deaths. The record does not report causality or the reason for termination. It also does not report detailed two-stage procedures, missing-data methods or the primary statistical analysis plan.