A Study of NOX66 and External Beam Radiotherapy in Patients With Metastatic Castration-resistant Prostate Cancer and Other Solid Tumors: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of NOX66 and External Beam Radiotherapy in Patients With Metastatic Castration-resistant Prostate Cancer and Other Solid Tumors (NCT04957290), a non-randomized phase 1, phase 2 study. The primary outcome is Part 1 (Dose Escalation): Number of Dose-limiting Toxicities (DLTs).

2. Clinical Question

3. Trial Design

This was a Phase 1b/2a, multicenter study of NOX66 and external beam radiotherapy in people with metastatic castration-resistant prostate cancer and other solid tumors. The registry describes the study as open-label, non-randomized, and sequential. Enrollment was 21, and the recorded status is terminated. The study started on 2021-10-25, with primary completion on 2023-05-10.

The study had two parts. Part 1 was a dose-escalation component for patients with any solid tumor. Its named NOX66 cohorts were 800 mg, 1200 mg, 1600 mg, and 2400 mg. The primary endpoint was the number of participants with dose-limiting toxicities in Cycle 1. Part 2 was intended to use the recommended Phase 2 dose in one group of patients with metastatic castration-resistant prostate cancer and another group with breast cancer or non-small-cell lung cancer. Participants in the study were considered in relation to low-dose external beam radiotherapy for a lesion meeting the eligibility description.

Because allocation was non-randomized and the design was sequential, the cohorts should not be read as randomized treatment groups. Differences in their posted counts cannot establish that one dose caused more or fewer events than another. The registry record does not describe a concurrent control group, blinding, or a randomized assignment procedure. It also does not report the actual enrollment by cancer type or the number of participants assigned to every planned cohort.

The registry lists six intervention entries: five for NOX66 and one for external beam radiotherapy. Part 1 and Part 2 have different roles in the study, and the registry’s brief description identifies safety, tolerability, dose selection, efficacy, pharmacokinetics, and pharmacodynamics as study aims. Results for these aims beyond the posted safety information are not reported in the registry record. A reason for termination is not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All patients that completed cycle 1.

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: Study terminated early during part 1- cohort 3.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Part 1 (Dose Escalation): Number of Dose-limiting Toxicities (DLTs), measured over Cycle 1 (Day 1 to Day 21).

The primary endpoint is the count of participants in Part 1 who experienced a dose-limiting toxicity during Cycle 1, defined as Day 1 to Day 21. It is a participant count, not a measure of symptom severity averaged across the group. The registry defines the primary endpoint population as all patients who completed Cycle 1.

The endpoint is used in dose escalation to assess whether a dose level has an unacceptable pattern of toxicity during the specified observation period. The registry defines the maximum tolerated dose as the dose level at which no more than 1 patient out of 6 has a dose-limiting toxicity at the end of Cycle 1. The recommended Phase 2 dose is defined using the same toxicity condition at the highest dose, with the additional requirement that the dosage form is acceptable to patients.

The definition includes adverse events during Cycle 1 that are unrelated to disease, intercurrent illness, or concomitant medications and are possibly to definitely related to NOX66 alone or together with external beam radiotherapy. Listed criteria include severe non-hematological toxicity; febrile neutropenia; specified thrombocytopenia; specified liver enzyme and bilirubin changes; marked AST or ALT elevation; and an adverse event causing a treatment delay longer than 14 days. The registry record does not report the observed count of participants meeting this definition, whether a maximum tolerated dose was determined, or the selected recommended Phase 2 dose.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The study’s statistical structure is best understood as an early-phase, sequential dose evaluation rather than a randomized efficacy comparison. The study record identifies Part 1 as dose escalation and defines dose selection through the number of participants with DLTs in Cycle 1. The study is open-label and non-randomized. These design features matter because the posted data are descriptive: dose cohorts were not assigned through a randomized comparison designed to balance prognostic factors.

What does a participant count tell the reader?

A count reports how many participants met an event definition. For this primary endpoint, the event is a DLT during the specified Cycle 1 period, and the intended population is patients who completed that cycle. Counts are direct and interpretable, but their meaning depends on the number assessed and on a consistent application of the endpoint definition. The registry does not report the primary DLT counts, the number completing Cycle 1, or a breakdown by cohort. Consequently, the primary endpoint cannot be evaluated from the record.

The safety listings use counts of participants at risk and affected. Those figures describe the recorded occurrence of serious and other adverse events in each named cohort. They are not the same outcome as the protocol-defined DLT endpoint: serious adverse events and other adverse events are broader safety groupings, while a DLT has a specific timing, attribution, and clinical-criteria definition. The record does not provide enough detail to determine which, if any, listed adverse events qualified as DLTs.

Why does the sequential design matter?

In a sequential dose-escalation study, the evaluation of a dose level is connected to the stage of the study and the dose decisions made as it proceeds. A cohort at one dose may differ from a cohort at another for reasons beyond dose, including its place in the enrollment sequence and the participants who entered it. Without random assignment and a suitable concurrent control, observed differences between cohort counts cannot be treated as an unbiased estimate of a dose effect. The registry record does not provide the escalation algorithm or the decisions made during enrollment, so those operational details are not reported in the registry record.

The registry’s dose-selection rule refers to no more than 1 patient out of 6 having a DLT at the end of Cycle 1. This is a rule stated for identifying the maximum tolerated dose and recommended Phase 2 dose; it is not itself a reported result. Applying the rule would require the relevant DLT outcomes and assessment denominators, along with the protocol’s handling of participants who did not complete the observation period. Those details and the resulting dose decision are not reported in the registry record.

How should uncertainty be understood?

General statistical explanation: a confidence interval describes a range of values compatible with the data and the assumptions of the method. With small early-phase cohorts, estimates of event frequency can be imprecise, even when the observed count is available. A count alone does not show the range of plausible underlying event frequencies. No confidence intervals or other uncertainty estimates for the primary endpoint or safety counts are reported in the registry record.

General statistical explanation: statistical tests and model-based estimates depend on assumptions about the design, outcome distribution, and analysis population. A non-randomized sequential study does not have the protection against baseline imbalance that random assignment provides. Any comparison across its dose cohorts would therefore need careful interpretation and would not, by itself, isolate a causal dose effect. No adjusted or model-based analyses are reported in the registry record.

The record also does not describe a formal efficacy analysis, despite listing efficacy among the study aims. There are zero analyses listed, and no inferential results are reported. General statistical explanation: when many outcomes, subgroups, or repeated comparisons are examined, multiplicity can increase the chance of finding an apparently notable result by chance. A prespecified multiplicity strategy can clarify how multiple questions are handled. The registry record does not report whether any such strategy was planned or used.

Sample-size planning illustrations, where available, are not observed trial results and are not a measure of the study’s achieved power. General statistical explanation: a planning calculation depends on assumptions about the target effect, variability or event frequency, significance level, allocation, and analysis method. The record does not report the trial’s own sample-size justification or the assumptions underlying its enrollment target. It also does not report a prespecified analysis plan, interim analyses, missing-data methods, or analysis populations beyond the primary endpoint population description. These omissions limit how fully the study’s statistical conduct can be reconstructed from 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("Part 1: Dose Cohort 1: NOX66 800 mg", "Part 1: Dose Cohort 2: NOX66 1200 mg", "Part 1: Dose Cohort 3: NOX66 1600 mg")
n      <- c(4, 7, 10)
events <- c(0, 0, 0)
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  Part 1: Dose Cohort 1: NOX66 800 mg  4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2
ARM  Part 1: Dose Cohort 2: NOX66 1200 mg  7  0  0.0  0.0  41.0  0.0  35.4  0.3  36.9
ARM  Part 1: Dose Cohort 3: NOX66 1600 mg  10  0  0.0  0.0  30.8  0.0  27.8  0.2  28.5

11. Multiplicity, Missing Data and Analysis Populations

The registry lists three outcome measures and zero analyses. It names the Part 1 DLT count as the primary outcome and lists secondary outcomes concerning adverse events for NOX66 and treatment-emergent adverse events by relationship to external beam radiotherapy. The actual results for those secondary outcomes, beyond the posted safety counts, are not reported in the registry record.

Multiplicity concerns how evidence is interpreted when several outcomes, comparisons, time points, or subgroups are examined. General statistical explanation: evaluating multiple questions can increase the chance that at least one result appears notable even when there is no corresponding underlying effect. Prespecified methods can address that issue, but the multiplicity strategy, if any, is not reported in the registry record. The record does not describe a statistical analysis plan or state how primary and secondary outcomes would be prioritized in formal inference.

The primary endpoint is defined for patients who completed Cycle 1, but the number completing Cycle 1 and the handling of participants without a complete assessment are not reported in the registry record. Missing-data methods, reasons for missing endpoint observations, and any rules for including or excluding participants from analyses are not reported in the registry record. The record does not describe analysis populations for Part 2 or for the safety outcomes.

These are limitations in the information available for evaluating the analysis; they do not establish that a particular procedure was or was not used. Without reported denominators, analysis populations, and methods for missing observations, readers cannot determine how the planned endpoint population relates to the overall enrollment or assess whether incomplete follow-up could affect the results.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: anemia (25.0%), non-cardiac chest pain (25.0%), angina pectoris (20.0%), acute respiratory failure (14.3%), encephalopathy (14.3%).

The registry reports serious and other adverse event counts for three Part 1 cohorts. In the 800 mg cohort, serious adverse events are listed for 1 of 4 participants at risk and other adverse events for 4 of 4; deaths are listed as 0. In the 1200 mg cohort, the corresponding counts are 3 of 7, 6 of 7, and 2 deaths. In the 1600 mg cohort, they are 5 of 10, 9 of 10, and 1 death. These figures describe the listed cohorts; they are not randomized comparisons.

The serious adverse event terms include anemia and non-cardiac chest pain at 25.0% each, angina pectoris at 20.0%, and acute respiratory failure, encephalopathy, and pleural effusion at 14.3% each. The registry does not report the denominator or event-count basis for these term percentages. A percentage for a reported term should therefore not be treated as a directly comparable participant risk without that context.

Seriousness does not by itself establish that an event was caused by study treatment. The record does not report causal attribution for these cohort totals. It also does not identify whether any listed serious event met the primary DLT definition. Because the design was non-randomized and sequential, differences in counts across cohorts cannot establish a dose-related safety effect. The posted safety information is descriptive and should be read separately from the defined Cycle 1 DLT endpoint.

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

The registry record documents an early-phase study designed to examine NOX66 with low-dose external beam radiotherapy, including dose escalation and evaluation of safety, tolerability, dose selection, efficacy, pharmacokinetics, and pharmacodynamics. It reports an overall enrollment of 21 and gives selected safety counts for three Part 1 dose cohorts. Those details describe the study and some posted safety observations, but they do not answer every study aim.

The primary question was whether the Part 1 dose levels met the stated DLT criterion during Cycle 1 and which dose could be selected as the maximum tolerated and recommended Phase 2 dose. The observed DLT count and dose decision are not reported in the registry record. The presence of adverse event counts does not allow that result to be reconstructed, because the DLT definition is narrower and depends on timing, clinical criteria, and attribution. The registry record also does not report efficacy results or the outcomes for the planned Part 2 groups.

These data do not establish that NOX66 or radiotherapy caused the reported events, nor do they establish a treatment benefit or lack of benefit. The non-randomized sequential design does not provide a randomized control comparison. Cohort counts can describe what was recorded in those groups, but cannot isolate an effect of dose or treatment from other differences between participants and study stages.

The record’s termination status is a study status, not an explanation of why the study ended or a result about safety or efficacy. The reason for termination is not reported in the registry record. Likewise, zero listed analyses should not be interpreted as evidence that no analyses were performed outside the registry entry; it means that analyses are not reported in the registry record. Conclusions should therefore remain limited to the design and the safety counts that are actually posted.

14. Why This Trial Matters Statistically

This study raises statistical questions that are characteristic of early-phase dose evaluation. The main Part 1 endpoint is not a comparative efficacy measure; it is a DLT count used in a dose-selection framework. Understanding that distinction prevents a safety endpoint from being mistaken for evidence about clinical benefit. It also makes the assessment window and the definition of the event central to interpretation.

The sequential, non-randomized structure is important because it shapes what comparisons can support. Dose cohorts are not randomized arms, so their observed counts are descriptive rather than a controlled estimate of what would happen if otherwise similar participants received different doses. A careful reading recognizes both the intended role of dose escalation and the limits of cohort-to-cohort comparisons.

The study also illustrates why a registry entry’s endpoint definitions and its posted results need to be read together. The record provides a detailed DLT definition and a criterion for dose selection, yet does not report the DLT outcomes or selected dose. The difference between a prespecified rule and a reported finding is fundamental: a rule explains how a result could be used, while an observed result is needed to determine whether the rule was met.

Finally, safety counts require attention to denominators, event definitions, and attribution. Counts by cohort can be useful descriptive information, but they do not alone establish causality or comparative risk. The absence of reported analyses, missing-data procedures, and multiplicity methods further constrains statistical interpretation. This trial is therefore informative as a study-design record and a limited safety account, while leaving its primary dose-selection result and broader efficacy questions unresolved in the registry record.

15. Limitations

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

The primary limitation is that the registry record does not report the primary DLT result, although it defines the endpoint, observation period, and dose-selection criteria. It also does not report whether the maximum tolerated dose or recommended Phase 2 dose was determined. Without the number of participants completing Cycle 1 and the DLT count within the endpoint population, readers cannot assess the primary outcome.

The overall enrollment was 21, but cohort-level enrollment is not given for all planned cohorts. Safety counts are posted for the 800 mg, 1200 mg, and 1600 mg cohorts; a safety group for the planned 2400 mg cohort is not included in the listed groups. The registry record does not explain whether that cohort enrolled, whether it was omitted from these safety listings, or why. Part 2 outcome results are also not reported in the registry record.

The non-randomized sequential design limits causal interpretation of comparisons among dose cohorts. The record does not report a concurrent control group, and the posted safety totals do not show that events were caused by study treatment. Serious adverse event term percentages are listed without a reported denominator basis, and the relationship between these events and the DLT definition is not given.

Further limitations include the absence of reported statistical analyses, confidence intervals, analysis populations beyond the primary endpoint population description, missing-data methods, multiplicity procedures, and a sample-size justification. A reason for termination is not reported in the registry record. These information gaps prevent a complete assessment of the study’s conduct and results; they should not be treated as proof that a particular method or analysis was not performed.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study of NOX66 and External Beam Radiotherapy in Patients With Metastatic Castration-resistant Prostate Cancer and Other Solid Tumors — NCT04957290.
• Registry record last updated 2024-06-18; status last verified 2024-05.
• Results first posted 2024-06-18.
• 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

This is a non-randomized, open-label, sequential Phase 1b/2a multicenter study of NOX66 with low-dose external beam radiotherapy in patients with solid tumors. Part 1 evaluated dose cohorts, with the primary endpoint defined as the number of participants with DLTs during Cycle 1. Part 2 was intended to include disease groups receiving the recommended Phase 2 dose. Enrollment was 21, and the registry status is terminated.

Safety counts are listed for three Part 1 cohorts, along with several serious adverse event terms. The registry record does not report the primary DLT result, a selected dose, efficacy outcomes, or statistical analyses. It also does not report the reason for termination. The posted information therefore supports a description of the study design and selected safety observations, but not a conclusion about dose selection, comparative effects, or efficacy.