Alisertib and Pembrolizumab for the Treatment of Patients With Rb-deficient Head and Neck Squamous Cell Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Alisertib and Pembrolizumab for the Treatment of Patients With Rb-deficient Head and Neck Squamous Cell Cancer (NCT04555837), a na phase 1, phase 2 study. The primary outcome is Phase I: The Recommended Phase II Dose Determenation. Phase II: Overall Response Rate (ORR) and Progression Free Survival (PFS).

2. Clinical Question

3. Trial Design

This is an open-label phase I-II study of alisertib combined with pembrolizumab in patients with Rb-deficient head and neck squamous cell cancer. The registry lists a single-group model, no masking, and allocation as not applicable. As a result, there is no randomized control group for estimating a treatment contrast. The phase I and phase II labels describe the study phases; they should not be read as two competing treatment groups.

The treatment description specifies alisertib by mouth twice daily on days 1–7 and pembrolizumab by intravenous infusion over 30 minutes on day 1. Cycles repeat every 21 days unless disease progresses or toxicity is unacceptable. The registry identifies M.D. Anderson Cancer Center as the sponsor. It lists the study as completed, with a start date of 2020-09-15 and primary completion date of 2025-04-08. The record lists enrollment of 24.

Phase I is described as dose determination, while the primary-outcome title names overall response rate and progression-free survival for phase II. The endpoint details recorded in the registry emphasize dose determination and give the unit as mg. Further protocol details, including the exact dose-escalation procedure, phase-specific enrollment targets, and the operational definitions of the phase II outcomes, are not reported in the registry record.

The registry lists eight outcome measures and zero analyses. That means the posted record does not provide statistical analysis results for the primary outcomes. It also does not report a randomized treatment comparison, and the safety figures by phase should not be treated as comparative evidence about treatment effects. The design supports describing the regimen studied and the outcomes listed, but the available record does not permit estimation of how outcomes would differ under an alternative treatment.

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

Analysis population for the primary outcome, as defined in the registry: Phase I: To determine the recommend phase II dose of the combination of alisertib and pembrolizumab

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 Phase I: The Recommended Phase II Dose Determenation. Phase II: Overall Response Rate (ORR) and Progression Free Survival (PFS), measured over Approximately 33 months.

The primary-outcome title combines two distinct purposes: phase I determination of the recommended phase II dose, and phase II assessment of overall response rate (ORR) and progression-free survival (PFS). Dose determination is a safety and tolerability-oriented task: the investigators seek a dose or regimen judged suitable for later study. ORR is generally a measure of the proportion of participants whose tumors meet specified response criteria, while PFS generally measures time until disease progression or death. These are general descriptions; the specific criteria and analysis definitions for this study are not reported in the registry record.

The registry’s endpoint detail is narrower than its title. It lists the phase I dose objective, uses mg as the unit, and gives a timeframe of approximately 33 months. It does not provide an observed recommended dose, an ORR estimate, a PFS estimate, or uncertainty intervals for these outcomes. Thus, the stated phase II questions are identifiable, but their numerical answers cannot be read from the registry record.

These measures address different questions. Dose determination concerns the regimen selected for further evaluation, whereas ORR and PFS describe tumor response and time-to-event outcomes. Without definitions, results, and analysis details, the listed endpoint names alone do not establish the magnitude or precision of any clinical outcome.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a single-group design allow?

A single-group study follows participants receiving the study regimen without a separate control group. Its observations can describe outcomes and safety among participants treated in the study, subject to the completeness of follow-up and outcome reporting. It does not, by itself, distinguish outcomes attributable to treatment from outcomes that might also occur because of disease course, participant characteristics, or other influences. That distinction is especially important when interpreting response or survival outcomes: without a concurrent comparator, a difference from an external expectation is not a randomized treatment effect.

Here, allocation is listed as not applicable and the model is single-group. The phase I and phase II groups in the safety record correspond to study phases, not randomized alternatives. Comparing their counts as though they were treatment arms would ignore that the phases have different purposes and may include participants selected under different procedures. The registry record does not report details that would support a direct phase-to-phase comparison.

What is the role of phase I dose determination?

Phase I dose determination aims to identify a regimen for further evaluation while monitoring tolerability. In general, dose-finding studies use rules to guide dose selection based on observed safety and other protocol-defined considerations. The specific dose-escalation rules, dose levels, decision criteria, and final recommended dose for this study are not reported in the registry record. The listed unit, mg, indicates that the endpoint is expressed as a dose, but does not supply the selected dose itself.

The phase I objective should not be confused with a test of whether the regimen improves outcomes. Dose selection and efficacy estimation are separate statistical questions. The phase II title names ORR and PFS, but no corresponding estimates or analysis details are posted in the registry record. A dose objective cannot substitute for those efficacy results.

How should ORR and PFS be understood?

In general, ORR summarizes tumor response according to prespecified criteria, and PFS is a time-to-event outcome that measures time until progression or death under a defined analysis rule. The interpretation of either measure depends on operational details: response criteria, assessment timing, confirmation rules, censoring, and the population included in the analysis. These study-specific details are not reported in the registry record. No numerical ORR or PFS result, confidence interval, or other estimate is included in the registry record for this record.

A confidence interval is a range of values compatible with the observed data under a specified statistical model and procedure. It conveys uncertainty around an estimate; it does not guarantee that the true value lies within the particular interval. Because no efficacy estimates or confidence intervals are reported in the registry record, precision cannot be assessed for ORR or PFS.

What do the posted safety counts tell us?

Counts of participants with serious or other adverse events are descriptive. They summarize how many participants were recorded in each category, but their interpretation depends on definitions, observation time, event attribution, and completeness of reporting. The record lists the numbers at risk and affected by phase, as well as deaths. It does not report whether events were considered related to treatment, how long participants were observed, whether participants could contribute more than one event, or the detailed event-level data. Counts should not be converted into a causal claim about the regimen.

Serious adverse events are a classification distinct from simply being an adverse event. The listed serious-event terms and percentages provide a snapshot of the registry’s reported categories. They do not, on their own, show the full frequency of all events, their timing, or their clinical course. In general, a percentage is most interpretable when its denominator and observation window are clear; those details should not be assumed beyond the at-risk counts and figures the registry lists.

How do planning illustrations differ from trial results?

The planning illustrations are based on an observed effect and are described as hypothetical sample-size calculations, not as the trial’s own design or results. The stated assumptions include a two-sided significance level of 0.05, equal allocation between two hypothetical arms, and a normal approximation; the effect to detect is a stated fraction of the observed effect. For time-to-event outcomes, the illustrations concern total events, while other outcomes use participants per arm. These are planning concepts, not evidence that the study was designed or conducted as a two-arm comparison.

In general, a sample-size calculation asks how much information a hypothetical design might need to detect an assumed effect under stated assumptions. Its output depends on the assumed effect, variability, allocation, analysis method, and target power. It is not a measure of the probability that a completed study’s findings are correct. Such calculations must not be described as observed power. Because this trial is single-group and no efficacy estimate is posted, planning illustrations should not be interpreted as a randomized comparison or as an estimate of treatment benefit.

Over-dispersion is a general concern for count outcomes when variability exceeds what a simpler statistical model expects; ignoring it can make uncertainty appear too small. It is not reported as a feature of this trial’s analysis, and no specific count model is reported in the registry record. Likewise, the statistical analysis plan, multiplicity strategy, interim analyses, and model choices are not reported in the registry record. No claim about their use can be made from the posted information.

10. Multiplicity, Missing Data and Analysis Populations

The registry names several outcome domains: phase I dose determination, phase II ORR and PFS in the primary-outcome title, and secondary outcomes covering safety, overall survival, pharmacokinetic and pharmacodynamic relationships, baseline immune and tumor biomarkers, HPV-reactive T cells, tumor-infiltrating lymphocyte function, and T-cell repertoire. When a study evaluates multiple outcomes or many associations, the chance of a nominally notable result arising by chance can increase. Statistical approaches to address this issue vary, and the appropriate approach depends on the objectives and analysis plan.

A multiplicity adjustment or testing hierarchy is not reported in the registry record. The record also does not report whether any interim analyses were planned or conducted, what analysis populations were used, or which outcome was designated primary for each phase beyond the wording in the endpoint title. These omissions prevent assessment of how the investigators handled multiple endpoints or repeated looks at accumulating data.

Missing-data procedures are not reported in the registry record. For ORR, missing response assessments can affect the numerator, denominator, and interpretation, depending on prespecified rules. For PFS and overall survival, incomplete follow-up and censoring rules affect how time-to-event outcomes are estimated. These are general statistical issues; the study-specific definitions and sensitivity analyses are not reported.

The record lists eight outcome measures and zero analyses. It therefore does not supply posted statistical results that would clarify the analysis populations, handling of missing observations, or control of multiplicity. Without those details, the outcome names should be treated as planned or registered questions rather than evidence of a particular result.

11. 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: diarrhea (10.0%), febrile neutropenia (10.0%), mucositis oral (10.0%), nausea (10.0%), rash acneiform (10.0%).

The registry reports safety counts separately for phase I and phase II. For serious adverse events, phase I lists 10 participants at risk and 2 affected; phase II lists 14 at risk and 2 affected. For other adverse events, the corresponding counts are 10 at risk and 10 affected in phase I, and 14 at risk and 13 affected in phase II. Deaths are listed as 2 in phase I and 0 in phase II. These are registry-reported counts; they should not be combined into a treatment comparison because the phases are not randomized arms.

The serious-event terms shown are diarrhea, febrile neutropenia, mucositis oral, nausea, and rash acneiform, each reported as 10.0%, and anemia at 7.1%. The registry record does not provide event-level counts, timing, duration, recurrence, attribution to treatment, or a common observation window. The listed percentages therefore should not be read as complete risk estimates over a specified period.

A serious adverse event is a reporting category, and the counts do not establish that treatment caused an event. The deaths are also listed without an attribution statement in the registry record for this record. No causal conclusion about the regimen can be drawn from these figures alone.

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

The registry record establishes that a phase I-II, open-label, single-group study evaluated alisertib with pembrolizumab in Rb-deficient head and neck squamous cell cancer. It describes the dosing schedule, identifies phase I dose determination as an objective, and names ORR and PFS as phase II outcomes. It also lists safety counts by phase and a set of secondary outcome domains. These details characterize the study’s questions and the information posted about it.

The record does not provide numerical phase II ORR or PFS results, an observed recommended phase II dose, or estimates with confidence intervals. It therefore does not show the magnitude or precision of efficacy outcomes. The absence of posted analyses also means the registry record cannot establish how the outcome data were analyzed or how missing assessments were handled. The study’s completed status does not itself supply those results.

The design has no concurrent randomized comparator. Any outcomes observed in a single group would describe that group under the study conditions, but would not by themselves show what would have happened under another treatment. The safety counts are likewise descriptive and do not establish treatment causation. The phase I and phase II figures should not be treated as a controlled comparison.

The record also does not establish whether results generalize beyond the participants who entered the study. Participant characteristics, detailed eligibility criteria, and the analysis populations are not reported in the registry record. The listed enrollment of 24 provides a study-level enrollment figure, but does not replace outcome-specific denominators or clarify how many participants contributed to each efficacy analysis.

Accordingly, the evidence available from the registry record supports a description of the trial’s design, aims, treatment schedule, and posted safety counts. It does not support a conclusion about the size of any treatment effect, comparative benefit, or causal harm. Those questions require complete outcome results, clear analysis definitions, and appropriate uncertainty information.

13. Why This Trial Matters Statistically

This trial illustrates the distinction between a registered clinical question and a statistically interpretable result. The record identifies a phase I dose objective and phase II efficacy outcomes, but numerical efficacy estimates are not reported in the registry record. Listing an outcome does not show its observed value, its uncertainty, or the rules used to calculate it. Statistical interpretation depends on those elements as well as on the design.

The single-group structure is important. A study can describe outcomes among participants receiving a regimen, but without a concurrent comparator it cannot directly estimate a randomized contrast. This distinction remains true even when a record includes multiple phases or detailed safety counts: phase labels are not control groups, and descriptive counts are not causal effects.

The record also demonstrates why endpoint definition and analysis transparency matter. ORR and PFS are recognizable outcome concepts, but their study-specific meaning depends on criteria, assessment procedures, censoring rules, analysis populations, and missing-data methods. Those details are not reported in the registry record. Without them, readers cannot assess whether an estimate is precise, comparable to another study, or sensitive to analytic choices.

Finally, the safety information shows the value and limits of registry reporting. Counts and selected adverse-event terms can identify what was posted, while absent information about attribution, timing, and follow-up constrains interpretation. The statistical lesson is not a claim about the regimen’s clinical effect. It is that design, endpoint specification, complete results, and transparent analysis procedures are all necessary to evaluate evidence responsibly.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The principal limitation is that efficacy results are not reported in the registry record. Although the primary-outcome title names phase II ORR and PFS, the endpoint detail describes phase I dose determination and provides no numerical efficacy estimates, confidence intervals, or analysis populations. The record therefore does not permit assessment of outcome magnitude or precision.

The study is single-group, open-label, and has no randomized comparator. This limits the ability to distinguish outcomes associated with the regimen from outcomes that might occur under another treatment or through the course of disease. Phase I and phase II are not like-for-like control groups. The record does not report details that would support a direct comparison between them.

Further limitations include the absence of reported eligibility details, participant characteristics, endpoint definitions for ORR and PFS, missing-data methods, censoring rules, multiplicity procedures, and statistical analysis plan. The registry lists eight outcome measures and zero analyses, so the posted record does not resolve these questions. It also does not report an observed recommended phase II dose or describe the dose-finding rules.

Safety information is limited to selected counts and adverse-event terms. The registry does not report event timing, duration, recurrence, treatment attribution, or a common observation window. Death counts are listed without causal attribution in the registry record for this record. These constraints prevent stronger interpretation of safety patterns.

The enrollment figure is listed as 24, but outcome-specific denominators are not available for efficacy endpoints. The listed sample-size assumptions describe planning illustrations rather than the trial’s own design; they do not remedy the absence of efficacy results or create a comparator. Together, these limitations mean the registry record is informative about study structure and selected safety reporting, but insufficient for estimating a comparative treatment effect.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Alisertib and Pembrolizumab for the Treatment of Patients With Rb-deficient Head and Neck Squamous Cell Cancer — NCT04555837.
• Registry record last updated 2025-05-20; status last verified 2025-04.
• Results first posted 2024-12-16.
• 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.

18. Record Summary

NCT04555837 is a completed, open-label phase I-II, single-group study sponsored by M.D. Anderson Cancer Center. It evaluates alisertib with pembrolizumab in patients with Rb-deficient head and neck squamous cell cancer. The registry lists enrollment of 24, a start date of 2020-09-15, and primary completion on 2025-04-08.

The phase I objective is recommended phase II dose determination. The primary-outcome title also names phase II ORR and PFS, but numerical efficacy results and statistical analyses are not reported in the registry record. Safety counts are listed by phase, with serious adverse events affecting 2 of 10 participants at risk in phase I and 2 of 14 in phase II. These descriptive figures are not a randomized comparison and do not establish treatment causation.