Phase I/II Eval Safety & Prelim Activity Nivolumab Comb W/Vorolanib Pts W/Refractory Thoracic Tumors: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase I/II Eval Safety & Prelim Activity Nivolumab Comb W/Vorolanib Pts W/Refractory Thoracic Tumors (NCT03583086), a non-randomized phase 1, phase 2 study. The primary outcome is Objective Response Rate in Phase II..

2. Clinical Question

The study's broad clinical question is whether the combination can be administered and whether antitumor activity can be observed across selected refractory thoracic tumor groups. The Phase I component is described as assessing safety, including the maximum tolerated dose, while the Phase II component is described as assessing efficacy. Those purposes are distinct: dose escalation informs tolerability across dose levels, whereas the Phase II objective response rate is a measure of tumor response in a defined population.

The listed groups differ in tumor type and treatment history. In particular, the non-small-cell lung cancer expansion includes participants described as checkpoint-inhibitor naïve, with acquired resistance, or primary refractory; the small-cell lung cancer group had progressed on platinum-based chemotherapy. These cohorts therefore address separate clinical contexts. Their results should not be treated as estimates from one uniform population or as direct comparisons between disease groups.

The registry record identifies 88 participants as the enrollment and marks the study completed. That total does not, by itself, identify how many participants contributed to the Phase II endpoint or to each expansion group. The endpoint population is restricted to those treated with the specified combination and available for response measurement, but its size is not reported in the registry record.

3. Trial Design

This was a Phase I/II, open-label, non-randomized, parallel study of vorolanib plus nivolumab. The registry describes dose escalation followed by dose expansion. Escalation included two listed dose levels: vorolanib 200 with nivolumab 240mg, and vorolanib 300 with nivolumab 240mg. Expansion cohorts were organized by tumor type and treatment history rather than by randomized assignment to competing treatments.

Across the described cohorts, vorolanib was taken orally once daily on days 1-56, and nivolumab was administered intravenously over 30 minutes every two weeks during the first two treatment cycles. The record says that after those cycles the schedule could change to every four weeks. This regimen description establishes the treatment schedule recorded for the study; it does not establish how consistently participants received treatment or how long each participant remained on it.

The trial began on 2018-07-10, had a primary completion date of 2024-02-21, and is marked completed. Enrollment is recorded as 88. The registry does not report the number enrolled in each cohort in the registry record for this analysis, nor does the total enrollment establish the analysis population for every outcome.

Because allocation was non-randomized and masking was absent, treatment assignment was not concealed through random allocation and participants and investigators were not blinded. There is no randomized, concurrent control group described. The dose levels and disease-specific cohorts serve different study purposes, and differences between them may reflect their different populations, treatment histories, or doses. They cannot be interpreted as an unbiased comparison of treatment effects.

The record describes Phase I as intended to assess safety and maximum tolerated dose and Phase II as intended to assess efficacy. It specifies objective response rate as the Phase II primary outcome, with response evaluated by RECIST. Other protocol details, including the full statistical analysis plan, sample-size justification, interim analysis procedures and rules for selecting a dose, are 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.

Only the first 6 of 7 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: 8 patients with NSCLC and 2 patients with TC who received vorolanib orally daily and 240mg nivolumab every 2 weeks, and had assessable results.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Only the first 6 of 8 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Objective Response Rate in Phase II., measured over Up to 1 year..

The primary Phase II endpoint is objective response rate, expressed as the percentage of participants who had a complete response or partial response. Best response is classified as complete response, partial response, stable disease or progressive disease based on RECIST. Stable disease and progressive disease are included in the best-response categories but do not count as objective responses under the endpoint definition.

Objective response rate is used to describe the proportion of a defined treatment group with a measurable tumor response during the specified assessment period. It is a binary outcome at the participant level: each participant either meets the complete-or-partial-response definition or does not. Reporting the estimate with a confidence interval would communicate both the observed proportion and its statistical precision.

The registry specifies a timeframe of up to 1 year. The endpoint population is patients who received 200mg vorolanib daily with 240mg nivolumab every two weeks and were available for tumor-response measurement. The registry record does not report the number of participants in that analysis population, the number with a complete or partial response, the objective response rate, or the 95% confidence interval. Therefore, the endpoint definition and intended population can be described, but the magnitude and precision of the primary Phase II result cannot be assessed from the posted record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary at the participant level. A participant is counted as having an objective response if the best response is complete response or partial response under RECIST. The endpoint is then expressed as a percentage of the applicable analysis population. This is a general description of how a binary response rate is interpreted; it does not supply the unreported rate for this study.

What does a confidence interval convey?

In general, a confidence interval describes the statistical uncertainty around an estimate. For an objective response rate, it would place a range around the observed percentage, reflecting that the result is based on a finite group of participants. A narrower interval indicates greater precision, while a wider interval indicates more uncertainty. The registry specifies a 95% confidence interval for the primary endpoint, but the estimate and interval are not reported in the registry record. Without them, neither the observed response proportion nor its precision can be described.

Why is the analysis population important?

A response percentage depends on both the number of responders and the denominator used. The record defines the endpoint population as those who received 200mg vorolanib daily with 240mg nivolumab every two weeks and were available for tumor-response measurement. It does not report how many participants met that definition or how missing response assessments were handled. The overall enrollment of 88 is not a substitute for the endpoint denominator. In general, excluding participants without an assessment can affect interpretation if their availability for measurement is related to their outcomes.

What can this design estimate?

In general, a non-randomized single-treatment study can describe outcomes among participants who received the regimen. It cannot, on its own, separate treatment effects from other explanations for the outcomes, such as differences in participants' disease histories or other characteristics. Random allocation is used in comparative trials to balance prognostic factors across groups on average. Here, the registry identifies dose levels and disease-specific expansion cohorts, but does not describe random assignment. Those groups are not like-for-like control arms, so comparisons across them should not be interpreted as randomized treatment contrasts.

How should Phase I and Phase II be distinguished?

The record states that the Phase I cohort is intended to assess safety, including maximum tolerated dose, while the Phase II cohort is intended to assess efficacy. These are different aims and can involve different analysis populations and outcomes. The record explicitly notes that outcome measures are distinct by arm, with the relevant Phase I or Phase II cohort included according to the outcome. Accordingly, the safety counts across dose levels and expansion groups should not be combined informally with the Phase II response endpoint or treated as if they used an identical denominator.

What does over-dispersion mean in general?

For binary data, a simple statistical model may assume that observations follow a specified probability structure. Over-dispersion is a general term for more variability in the observed data than that model expects. When present, it can make standard errors too small and confidence intervals too narrow if the analysis does not account for the extra variability. This is a general statistical concept; the registry does not report an over-dispersion assessment or a model for the primary endpoint.

What can planning calculations say?

In general, sample-size calculations are planning exercises that depend on assumptions about the effect to detect, significance level, allocation, and statistical method. They do not describe how many participants were actually analyzed, and they are not observed power. The planning illustration associated with this study is described as using the observed effect, a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the target effect set as a stated fraction of the observed effect. Those assumptions describe an illustration, not the study's own design or its original sample-size justification. The registry record does not report the protocol's sample-size justification. No planning result should be read as evidence that the trial achieved a particular power or that the observed endpoint was statistically significant.

The registry notes no posted analyses in the registry record for this analysis. No adjusted or unadjusted efficacy estimate is therefore available to interpret. A statistical analysis plan, including any model choice, covariate adjustment, multiplicity procedure, or prespecified handling of missing response assessments, is not reported in the registry record.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Dose Expansion - Non Small-Cell-Lung Cancer Acquir", "Dose Expansion - Non Small-Cell-Lung Cancer Naive", "Dose Expansion - Non Small-Cell-Lung Cancer Primar", "Dose Expansion - Small Cell Lung Cancer - Progress", "Dose Expansion - Thymic Carcinoma")
n      <- c(18, 15, 17, 18, 9)
events <- c(2, 5, 1, 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  Dose Expansion - Non Small-Cell-Lung Cancer Acquir  18  2  11.1  1.4  34.7  3.1  32.8  3.4  33.1
ARM  Dose Expansion - Non Small-Cell-Lung Cancer Naive  15  5  33.3  11.8  61.6  15.2  58.3  15.2  58.7
ARM  Dose Expansion - Non Small-Cell-Lung Cancer Primar  17  1  5.9  0.1  28.7  1.0  27.0  1.4  27.3
ARM  Dose Expansion - Small Cell Lung Cancer - Progress  18  0  0.0  0.0  18.5  -0.0  17.6  0.1  17.6
ARM  Dose Expansion - Thymic Carcinoma  9  1  11.1  0.3  48.2  2.0  43.5  2.5  44.5

11. Multiplicity, Missing Data and Analysis Populations

The study includes multiple Phase I dose levels and Phase II expansion cohorts spanning different tumor types and treatment histories. When multiple endpoints, groups, or time points are examined, the chance of finding an apparently notable result by chance can increase. In general, multiplicity procedures can control that risk or distinguish a primary confirmatory question from exploratory analyses. The registry record does not report a multiplicity adjustment or a detailed plan for handling multiple comparisons. No inference about whether such procedures were used in the full study analysis can be made from the posted record.

The primary endpoint is defined for participants treated with 200mg vorolanib daily and 240mg nivolumab every two weeks who were available for tumor-response measurement. The number meeting this definition and the number with missing or unevaluable response assessments are not reported in the registry record. Nor is the method for handling unavailable assessments reported. In general, missing outcome data can affect an estimated response proportion, particularly if the chance of being assessed is associated with disease status or treatment experience. The potential direction and size of any effect cannot be determined without the missingness information and analysis method.

The record distinguishes Phase I safety analyses from Phase II efficacy analyses and states that the relevant cohort is used for each outcome. That distinction is important: the 88 participants enrolled overall should not be assumed to be the denominator for the primary response analysis or for each safety group. The registry does not report a full participant flow or endpoint-specific analysis population counts in the registry record for this analysis.

These gaps limit assessment of how the primary endpoint was analyzed and how representative the analyzed population was. A detailed statistical plan, the prespecified treatment of missing response assessments, and the rationale for any multiplicity approach are 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: lung infection (66.7%), edema (33.3%), cellulitis (33.3%), hypoxia (33.3%), respiratory failure (33.3%).

The registry lists serious adverse event and other adverse event counts by dose-escalation or dose-expansion group. For each group, it gives the number at risk and the number recorded as affected, and it separately lists deaths. These are group-specific counts, not a randomized comparison of treatment strategies. The record also lists serious-event terms with percentages: lung infection at 66.7%, and edema, cellulitis, hypoxia, respiratory failure, and wound infection each at 33.3%.

The percentage denominator and the precise method used to produce those term percentages are not reported in the registry record. They should therefore be read as registry-listed percentages, not as rates that can be independently compared across cohorts. The cohort counts also differ in size, and the groups differ in tumor type, treatment history, or dose; comparing their counts directly would be misleading.

These figures describe events reported in the safety record, but do not establish that an event was caused by vorolanib or nivolumab. The available information does not specify event timing, duration, severity grading beyond the serious-event designation, exposure duration, or attribution to study treatment. Death counts are listed by group, but the cause and relationship to treatment are not reported in the registry record. The counts should be interpreted as descriptive safety information, not as proof of causation or as a comparative estimate of risk.

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

The record documents a completed Phase I/II study of vorolanib with nivolumab in refractory thoracic tumors. It describes a non-randomized, open-label dose-escalation and dose-expansion design, an overall enrollment of 88, and an intended Phase II assessment of objective response rate. It also provides cohort-level safety counts and a list of serious-event terms and percentages. These details help define the study's setting and the outcomes the registry records.

However, the primary endpoint's numerical result is not reported in the registry record. There is no posted response percentage or 95% confidence interval in the registry record for this analysis. Therefore, the frequency of complete or partial responses and the precision of that frequency cannot be determined from the record. This absence is not evidence that no participant responded.

The study design also limits what can be concluded from any observed outcomes. Without random assignment to a comparable control group, the study cannot establish how outcomes would have differed under another treatment or no study treatment. The dose and disease-specific cohorts are not randomized comparators, and variation between their results would not by itself show that one dose or group had a better treatment effect.

Objective response rate is a tumor-response measure, not a complete account of treatment experience or long-term outcomes. The record's stated timeframe is up to 1 year, and details of response follow-up, missing assessments, and endpoint analysis are not reported in the registry record. The listed safety figures likewise do not establish treatment causality or provide a controlled comparison of adverse-event risk.

In statistical terms, the posted information supports a description of the trial's design, endpoint definition, and reported safety counts. It does not support a quantitative conclusion about the primary efficacy result or a causal treatment-effect conclusion. Those distinctions are essential when interpreting a registry record without the corresponding numerical endpoint findings and analysis details.

14. Why This Trial Matters Statistically

This study illustrates why a clinical question must be interpreted alongside the design and the population used to answer it. The trial included several thoracic tumor groups and distinct treatment histories, with dose escalation and later expansion. That structure allows the study to address different safety and activity questions, but it also means that a single overall result would need a clearly defined population and denominator to be interpretable.

The record separates the Phase I safety purpose from the Phase II efficacy purpose. This distinction matters statistically because safety counts and objective response rate answer different questions and may use different analysis populations. Overall enrollment is not necessarily the number contributing to the primary endpoint, and the endpoint is expressly restricted to participants treated at a stated regimen and available for response measurement.

The non-randomized design is another important feature. It can provide descriptive evidence about outcomes observed among enrolled participants, but it does not create a like-for-like control comparison. Recognizing this prevents descriptive response or safety data from being mistaken for a causal estimate of treatment benefit or harm.

Finally, the registry record demonstrates the difference between defining an endpoint and reporting its result. Objective response rate is clearly described, including the response categories and assessment timeframe, yet the numerical estimate and confidence interval are not reported. Statistical interpretation requires both the estimand and the data needed to quantify it. Without the result, endpoint denominator, and analysis details, conclusions about response frequency and precision remain unavailable.

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.

Several limitations specific to this trial follow from the posted design and results information. First, the study was non-randomized and open-label, with no like-for-like control comparison described. Outcomes observed among participants therefore cannot be used as a randomized estimate of treatment effect. Differences between dose levels or disease-specific cohorts may reflect differences in dose, tumor type, prior treatment, or other population characteristics.

Second, the overall enrollment of 88 does not identify the number included in the primary endpoint analysis. The endpoint population is limited to participants receiving the specified regimen and available for tumor-response measurement, but its size and participant flow are not reported in the registry record. The treatment of missing or unevaluable tumor assessments is also not reported, limiting assessment of the endpoint denominator and potential selection effects.

Third, the registry record does not report the numerical Phase II objective response rate or its 95% confidence interval. This prevents assessment of the observed response frequency and its precision. The record also does not report the statistical analysis plan, sample-size justification, interim analysis procedures, multiplicity approach, or endpoint-specific analysis details.

Finally, serious adverse event counts and listed terms are descriptive. The denominator basis for the listed term percentages, event attribution, timing, and causes of deaths are not reported in the registry record. These limits preclude interpreting the safety figures as proof of treatment causation or as comparative risks.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Phase I/II Eval Safety & Prelim Activity Nivolumab Comb W/Vorolanib Pts W/Refractory Thoracic Tumors — NCT03583086.
• Registry record last updated 2024-10-08; status last verified 2024-09.
• Results first posted 2024-10-08.
• 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

NCT03583086 is a completed Phase I/II, open-label, non-randomized study of oral vorolanib plus intravenous nivolumab in refractory thoracic tumors. The registry records enrollment of 88, a start date of 2018-07-10, and a primary completion date of 2024-02-21. The design includes dose escalation and expansion cohorts for non-small-cell lung cancer, small-cell lung cancer, and thymic carcinoma, with non-small-cell lung cancer groups distinguished by checkpoint-inhibitor history.

The Phase II primary endpoint is objective response rate, defined as the percentage of participants with a complete or partial response by RECIST, over up to 1 year. The endpoint population is specified by treatment regimen and availability for response assessment. The numerical response rate, its 95% confidence interval, and endpoint population size are not reported in the registry record. Cohort-level serious and other adverse event counts and deaths are listed, but the non-randomized design does not support a like-for-like control comparison.