Docetaxel in Combination With Zactima (ZD6474) in Patients With Locally Advanced Squamous Cell Carcinoma of the the Head and Neck: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Docetaxel in Combination With Zactima (ZD6474) in Patients With Locally Advanced Squamous Cell Carcinoma of the the Head and Neck (NCT00459043), a randomized phase 2 study. The primary outcome is Partial Response Rate in Both Groups of Patients..

2. Clinical Question

The study was designed to compare the combination with docetaxel alone, rather than to compare either treatment with no treatment. Its brief description also names assessment of side effects as a study purpose. The registry lists progression-free survival and overall survival as secondary outcomes, but their results are not reported in the registry record.

The primary outcome concerns tumor response assessed radiologically using RECIST version 1.0. Under the registry’s description, a partial response requires a decrease of at least 30% in the sum of the longest diameters of target lesions. Complete response is defined as disappearance of all target lesions, and overall response is the combination of complete and partial responses. The reported primary measure is the partial response rate, not a combined overall response rate.

This is a small phase II randomized study: 30 participants were enrolled, with 29 listed as analyzable for the primary outcome. The comparison therefore describes the observed responses in these study groups. It does not, by itself, establish that one regimen is better, and the precision of the estimated rates is important when interpreting the numerical difference.

3. Trial Design

The registry describes a randomized, parallel-group phase II study with no masking. Participants were assigned to docetaxel alone or docetaxel with ZD6474. The primary outcome results include 14 participants in the docetaxel-alone arm and 15 in the combination arm. The registry does not report the allocation ratio or further details of the randomization procedure.

The study concerns locally advanced squamous cell carcinoma of the head and neck. Its title identifies the combination of docetaxel and Zactima (ZD6474) as the treatment under investigation. The brief description says the researchers were comparing that combination with docetaxel alone to assess whether the combination might be more effective, and to assess side effects associated with the drug.

The registry lists a total enrollment of 30 and says 29 patients were analyzable for the primary response outcome. It does not explain why one enrolled participant was not included in that analysis, describe the analysis population in further detail, or report whether participants were analyzed according to their randomized assignment. These matters are not reported in the registry record.

The primary endpoint was partial response rate, with a stated timeframe of 3 years. The outcome description says tumor response was evaluated radiologically using RECIST version 1.0. Progression-free survival and overall survival appear among the secondary outcomes, but outcome results and analysis details for those endpoints are not reported in the registry record. The record also lists no posted analyses.

The study started in 2007-03, had a primary completion date of 2010-03, and is marked completed. The trial’s original sample-size justification, the assumptions used to design the study, and any interim analysis plan are not reported in the registry record. The planning illustrations associated with the posted response comparison are separate from the original design and should not be read as the study’s planned enrollment.

4. Participant Flow and Accounting

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

Before assignment: Patients were randomized in a 1:1 ratio to receive docetaxel alone or docetaxel and vandetanib as combination therapy. No stratification at randomization was made for the study

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: 29 patients were analyzable

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: One patient withdrew consent after being randomized to docetaxel alone arm and did not receive any treatment, therefore, 29 patients were analyzable.

6. Primary Endpoint

The registry lists the primary outcome as Partial Response Rate in Both Groups of Patients., measured over 3 years.

The primary endpoint is the partial response rate in each group, reported as a percentage of participants. It measures the proportion of the analyzed participants whose tumors met the registry’s radiological definition of partial response. In the RECIST version 1.0 description, that requires a decrease of at least 30% in the sum of the longest diameters of target lesions. The registry defines complete response as disappearance of all target lesions and overall response as complete response plus partial response, but the primary measure reported is partial response rate alone.

A response rate is a binary-outcome summary at the participant level: each participant either meets the specified response definition or does not. General statistical context: this kind of endpoint gives a direct summary of how often the defined response occurred in each group. Comparing rates between randomized groups can describe the observed difference, while confidence intervals convey uncertainty in the rates and in that difference.

The registry gives a 3 years timeframe and states that 29 patients were analyzable. The reasons for the analysis population, the timing and details of response assessments, and handling of any missing response evaluations are not reported in the registry record. Those details matter because they clarify exactly which participants contribute to the denominator and how the response classification was made over the stated timeframe.

7. Results Posted in the Registry

• 2 Combination Docetaxel and ZD6474: 13.3% (2/15) versus 7.1% (1/14) on control; risk difference 6.2 percentage points (95% CI -15.7 to 28.1), risk ratio 1.87 (0.19–18.38); unadjusted two-proportion z-test p = 0.584.

8. Statistical Interpretation

9. Statistical Methods Explained

What does a response rate represent?

The primary outcome is a binary percentage: participants are classified according to whether their tumors met the registry’s partial response definition. The registry specifies radiological evaluation using RECIST version 1.0, with partial response requiring at least a 30% decrease in the sum of the longest diameters of target lesions. A percentage is useful because it expresses the frequency of response relative to the analyzed participants in each group. The numerator and denominator are important context: the response results use groups of 14 and 15, and 29 patients were described as analyzable.

General statistical explanation: a rate estimated from a small group can vary substantially from the rate that would be seen in a larger population. A confidence interval communicates some of that sampling uncertainty. It does not account automatically for every possible limitation, such as missing assessments, measurement differences, or deviations from the analysis plan.

How should the difference be read?

The comparison reports a risk difference of 0.062 for the combination arm relative to docetaxel alone. A risk difference expresses the difference between two event probabilities on the absolute probability scale. The reported 95% confidence interval is -0.157 to 0.281. Since the interval contains zero, values consistent with no difference remain plausible under the interval procedure. It also covers negative and positive differences, so the estimate does not tightly establish the direction of the contrast.

The unadjusted p-value is 0.584. General statistical explanation: a p-value is calculated under a particular null hypothesis and analysis model; it does not measure the size or clinical importance of a difference. A relatively large p-value does not establish equivalence, and a small one would not by itself establish that a difference matters clinically. No equivalence margin or noninferiority question is reported in the registry record.

What do the relative measures add?

The reported relative risk is 1.867, with a 95% confidence interval from 0.190 to 18.38. The reported odds ratio is 2.0, with a 95% confidence interval from 0.161 to 24.87. A relative risk compares the probability of the event between groups, while an odds ratio compares event odds. General statistical explanation: relative measures can express the contrast in a different way from an absolute risk difference, but neither removes uncertainty arising from sparse observations. The broad intervals in these results show that the relative magnitude is also poorly determined.

The outcome counts are limited, and the confidence intervals extend across a broad range of possible effects. Relative measures can appear especially unstable when outcomes are uncommon; this is a general statistical consideration, not a separate finding about the biology of the treatments. The registry does not report an adjusted model or covariate-adjusted estimate for the primary response comparison.

Why does the confidence interval matter?

General statistical explanation: a confidence interval is a range generated by a method intended to have a stated coverage rate across repeated studies under its assumptions. It is not a guarantee that the specific interval contains the true value, nor does it list every value as equally likely. Here the arm-specific intervals are 0.2% to 33.8% and 1.6% to 40.4%, and the difference interval is -0.157 to 0.281. Their breadth is a practical indication that the study provides limited precision for estimating response rates and their contrast.

These intervals should be interpreted in relation to the analysis population and the endpoint definition. The registry identifies 29 analyzable patients but does not provide details about exclusions, missing response assessments, or the statistical method used for the intervals. Those details are not reported in the registry record. The posted results therefore support a descriptive account of the observed response rates and uncertainty, but they do not resolve every methodological question that could affect the estimates.

What is known about the analysis plan?

The record identifies the study as randomized and reports the primary outcome, but does not report the original statistical analysis plan, a sample-size justification, or interim analyses. No analysis results are posted for the secondary outcomes. The p-value and interval estimates describe the posted comparison; the registry does not explain whether the trial had a prespecified testing hierarchy or which analysis was designated as primary beyond the endpoint description. General statistical explanation: knowing these plans helps readers assess whether analyses were prespecified and how multiple outcomes or repeated looks at data were handled. Their absence from the record means those aspects cannot be evaluated from the registry entries.

10. Confidence Intervals and Precision

Precision is limited for the primary response rates. The docetaxel-alone rate is 7.0%, with a 95% confidence interval from 0.2% to 33.8%; the combination rate is 13.0%, with a 95% confidence interval from 1.6% to 40.4%. Both intervals span a substantial range of possible rates, so the point estimates should not be treated as exact descriptions of the underlying response probabilities.

The comparison is also imprecise. The risk difference is 0.062, with a 95% confidence interval from -0.157 to 0.281. The interval includes zero and extends to differences in either direction. The relative risk interval, 0.190 to 18.38 around an estimate of 1.867, and the odds ratio interval, 0.161 to 24.87 around an estimate of 2.0, are also broad.

General statistical explanation: wider confidence intervals indicate less precision, often because the data contain limited information for estimating the quantity. Here the primary comparison includes 14 participants in one arm and 15 in the other. Confidence intervals quantify sampling uncertainty under their methods and assumptions; they do not account automatically for unreported features such as missing-data handling or analysis choices. The registry does not state the interval calculation method.

The p-value of 0.584 does not substitute for the confidence interval. The interval is useful for seeing both the range of uncertainty and the possible direction of the difference, while the p-value summarizes compatibility with a specified null under an analysis. Together, the posted results show that the observed rates are not estimated precisely enough to settle the size or direction of the between-group difference.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures describe participants per arm, not total event counts. They are illustrations based on the observed effect, not the trial’s original enrollment plan. The stated planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set as the stated fraction of the observed effect. The original design assumptions and sample-size justification are not reported in the registry record.

For the scenario labelled 100% of the observed effect, the planning display gives 376 participants per arm for 80% power and 502 participants per arm for 90% power. For the scenario labelled 75% of the observed effect, it gives 623 participants per arm for 80% power and 834 participants per arm for 90% power. For the scenario labelled 50% of the observed effect, it gives 1,300 participants per arm for 80% power and 1,739 participants per arm for 90% power.

In plain language, the 80% power column gives the planned per-arm size under which the calculation has an 80% chance of detecting the specified effect if that effect and the stated assumptions hold. The 90% column uses a higher probability of detecting that same specified effect and therefore requires a larger planned group in each scenario. The curve should be read as the relationship between the assumed effect size and the number of participants needed under those planning assumptions. Smaller effects need more participants to distinguish them from random variation. These are planning illustrations, not observed power.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.071; treatment proportion p₁ = 0.133; average p̄ = 0.102.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.4287 = 0.8403.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.4265 = 0.3589.
4. n = (0.8403 + 0.3589)² / (0.0619)² = 375.3, rounded up to 376 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.0714285714285714                          # control proportion
p1 <- 0.133333333333333                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(459043)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 376 (80% power), 502 (90% power)
 75% of observed effect: n per arm = 623 (80% power), 834 (90% power)
 50% of observed effect: n per arm = 1,300 (80% power), 1,739 (90% power)
power.prop.test: 375.3 
Simulated power at n = 376 per arm: 0.806 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary outcome, partial response rate, and two secondary outcomes: progression-free survival and overall survival. However, it does not report the statistical analysis plan, any prespecified hierarchy among outcomes, or a multiplicity adjustment. These details are not reported in the registry record. Without them, it is not possible to determine how the investigators intended to control the chance of false-positive findings across multiple endpoints or analyses.

No secondary outcome results are posted, and the registry lists no analyses. Thus, the available statistical interpretation is restricted to the primary response comparison. The record does not state whether there were additional exploratory outcomes, subgroup analyses, repeated assessments, or interim analyses. It would be inappropriate to assume that such analyses did or did not occur.

The record says that 29 patients were analyzable for the primary endpoint, although enrollment was 30. It does not explain the difference, define a full analysis population, or identify the participant’s response status if excluded. The handling of missing response assessments and the denominator rules are not reported in the registry record. These gaps matter because the response rate depends on which participants are included and how unevaluable cases are handled.

General statistical explanation: missing outcomes can affect estimates when the probability of missingness is related to response or differs between groups. Randomization supports a fair comparison at assignment, but it does not by itself resolve missing outcome data or establish that an analyzed subset remains comparable. The registry does not provide enough detail to assess these issues for this study.

The analysis method for the reported confidence intervals and the comparison is not described in detail. There is no reported adjusted analysis, prespecified model, or sensitivity analysis for the primary outcome. The study’s original statistical plan and procedures for controlling multiplicity are not reported in the registry record, so the statistical interpretation should remain focused on the posted unadjusted response comparison and its uncertainty.

14. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

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: hemorrhage (7.1%).

The registry reports one participant with a serious adverse event in the docetaxel-alone group, among 14 at risk, and one in the docetaxel-plus-ZD6474 group, among 15 at risk. The listed leading serious adverse event term is hemorrhage, with 7.1% reported. The record does not identify the treatment attribution for that term or provide additional event-level details.

Other adverse events are reported for 14 participants among 14 at risk in the docetaxel-alone group and 15 among 15 at risk in the combination group. These figures indicate that all participants in each listed group were counted as affected by an other adverse event, but the registry summary does not specify the event types, severity distribution, or whether participants could experience multiple events. The participant counts should not be interpreted as a count of distinct events.

Deaths are not reported in the safety summary. The registry does not provide the definitions, observation period, event collection procedures, or detailed breakdowns needed for a fuller comparison of safety. These figures are descriptive counts from small groups and do not establish whether the regimens differ in safety.

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

The posted results describe partial response rates of 7.0% with docetaxel alone and 13.0% with docetaxel plus ZD6474 among the analyzable participants. The estimated risk difference is 0.062, and its 95% confidence interval ranges from -0.157 to 0.281. The unadjusted p-value is 0.584. These results show a higher observed percentage in the combination arm, but the uncertainty is wide and includes no difference as well as differences in either direction.

The data do not establish that the groups have equal response rates. A non-significant comparison is not proof of equivalence, especially when the estimates are imprecise. Nor do the results establish a reliable advantage for either group. The study enrolled 30 participants, and 29 were analyzable for the primary outcome; the small group sizes limit precision.

The endpoint is radiological partial response, assessed using the registry’s RECIST version 1.0 description. It does not directly measure progression-free survival, overall survival, symptoms, quality of life, or other outcomes. Although progression-free survival and overall survival are listed as secondary outcomes, their results are not reported in the registry record. The response findings cannot be used as substitutes for those outcomes.

The registry describes a randomized phase II comparison and reports limited safety counts, but those counts alone do not support a complete safety comparison. One serious adverse event is reported in each arm, and other adverse events are reported for all participants in both arms. Event details and deaths are not reported in the registry record.

Overall, the posted response data are compatible with a range of underlying effects. They provide a description of this trial’s analyzable participants rather than a precise estimate that settles the comparative effect. The study’s original sample-size rationale, analysis plan, and missing-data procedures are not reported, which further limits assessment of how the study was designed and how its findings should be generalized.

16. Why This Trial Matters Statistically

This trial illustrates why a point estimate should not be read in isolation. The observed partial response rates differ numerically, but the risk-difference confidence interval extends from negative to positive values and includes zero. The p-value is 0.584. Considering the estimate together with its interval makes the uncertainty more visible than treating the two percentages as definitive evidence of a difference.

The group sizes are small: 14 participants in the docetaxel-alone arm and 15 in the combination arm contributed to the primary outcome. This is reflected in wide intervals for both arm-specific response rates and the between-group comparison. General statistical explanation: sparse outcomes and limited sample sizes typically provide less information about the true rate or contrast, so conclusions should emphasize uncertainty rather than only the observed point estimates.

The trial also shows the distinction between an observed study result and a planning illustration. The sample-size scenarios use the observed effect under stated assumptions and show how planned participants per arm change as the assumed detectable effect changes. They are not the original study’s design justification, and they are not observed power. The registry does not report the trial’s original sample-size assumptions.

Finally, the primary response outcome is not interchangeable with survival outcomes. Progression-free survival and overall survival are listed as secondary outcomes, but their results are not reported in the registry record. A careful statistical reading keeps the inference tied to the endpoint and population actually reported, while recognizing that analysis details and missing-data handling are also not documented.

17. 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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The primary analysis includes 29 patients, while 30 participants were enrolled. The registry does not explain the difference or report the excluded participant’s outcome status. It also does not describe the analysis population, missing response assessments, or how such assessments were handled. The effect of these matters on the response-rate estimates cannot be assessed from the registry record.

The primary comparison is based on small groups, with 14 participants in the docetaxel-alone arm and 15 in the combination arm. The response-rate and contrast intervals are wide. The posted estimates therefore have limited precision, and the results do not determine the direction or magnitude of the underlying difference with confidence.

The registry does not report the original sample-size rationale, a detailed statistical analysis plan, the method used to calculate the confidence intervals, or any interim-analysis plan. It also does not report multiplicity procedures or adjusted analyses. The record lists progression-free survival and overall survival as secondary outcomes, but their results are not reported in the registry record.

The trial is described as having no masking, so participants and study personnel were not masked according to the registry’s masking field. The record does not provide further information about radiological assessment procedures, independent review, or safeguards against assessment bias. The available safety summary lacks event-level detail, and deaths are not reported. These trial-specific gaps constrain interpretation beyond the reported primary response rates and the limited adverse-event counts.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Docetaxel in Combination With Zactima (ZD6474) in Patients With Locally Advanced Squamous Cell Carcinoma of the the Head and Neck — NCT00459043.
• Registry record last updated 2013-07-03; status last verified 2013-07.
• Results first posted 2013-07-03.
• 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.

21. Record Summary

NCT00459043 is a completed randomized phase II parallel-group study of docetaxel alone versus docetaxel with ZD6474 in locally advanced squamous cell carcinoma of the head and neck. The registry lists no masking, enrollment of 30, a start date of 2007-03, and primary completion in 2010-03.

The primary outcome was partial response rate over 3 years, assessed radiologically using RECIST version 1.0. Among 29 analyzable patients, the reported rates were 7.0% with docetaxel alone and 13.0% with the combination. The risk difference was 0.062, with a 95% confidence interval from -0.157 to 0.281, and the unadjusted p-value was 0.584.

Progression-free survival and overall survival are listed as secondary outcomes, but their results are not reported in the registry record. Safety results include one serious adverse event in each arm; event details are limited, and deaths are not reported.