Docetaxel With or Without AZD6244 in Melanoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Docetaxel With or Without AZD6244 in Melanoma (NCT01256359), a randomized phase 2 study. The primary outcome is Progression Free Survival.

2. Clinical Question

3. Trial Design

This was a randomized, parallel-group, double-blind, placebo-controlled phase 2 trial sponsored by the University of Oxford. The registry lists quadruple masking. It records enrollment of 83 participants and assignment in a 1:1 ratio to docetaxel with AZD6244 or docetaxel with placebo. The posted primary analysis involved 41 participants in the AZD6244 group and 42 in the placebo group.

The trial concerned wt BRAF advanced melanoma. The registry says tumour BRAF mutational analysis was to be performed after consent when the information was not already known, using archival tissue where available; if there was no archival tissue, a fresh biopsy could be requested. The registry also describes blood collection for future genetic analysis and regular oncology-unit visits for treatment and monitoring.

Docetaxel was described at 75mg/m2 intravenously every 3 weeks for a maximum of 6 cycles. AZD6244 or placebo was described as twice-daily treatment that could continue beyond docetaxel until disease progression. The registry describes physical examinations and blood testing at specified visits, an ECG at screening, and disease assessment using CT scanning and modified RECIST criteria. The brief summary mentions assessments after 9 and 18 weeks, then its description is incomplete.

The recorded study status is completed. The registry gives a start of 2010-10 and primary completion of 2012-10. The trial's original sample-size justification, planned interim analyses, and detailed original statistical plan are not reported in the registry record. The planning illustrations associated with the posted results are separate from those original design assumptions.

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: The primary analysis was intention to treat and involved all patients who were randomly assigned.

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: All randomised patients

6. Primary Endpoint

The registry lists the primary outcome as Progression Free Survival, measured over From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months..

The primary endpoint, progression-free survival, measures the time from randomisation until the first recorded progression event or death. Progression was assessed using CT, x-ray, MRI, or clinical examination under modified RECIST v1.1 criteria. For a participant without a recorded event, the endpoint description defines the censored time as the time from randomisation to the date last known alive. The registry describes an intention-to-treat primary analysis involving all randomly assigned participants.

Time-to-event endpoints are used when both whether an event occurs and when it occurs matter. They can incorporate follow-up information from participants who have not had an event by the analysis cutoff, rather than treating such participants as if their follow-up were complete. This general explanation does not establish how censoring assumptions were checked in this trial; such checks are not reported in the registry record.

The posted arm-level summaries are medians: 4.23 months for docetaxel with AZD6244, with a 90% confidence interval of 3.63 to 6.9, and 3.93 months for docetaxel with placebo, with a 90% confidence interval of 2.07 to 4.16. The registry also posts hazard-ratio comparisons. A median describes the time by which half of the estimated group has experienced the event; it does not describe every participant's experience or, by itself, quantify the full difference between survival patterns.

7. Results Posted in the Registry

• Docetaxel and AZD6244 vs Docetaxel and Placebo: hazard ratio 0.75 (95% CI 0.50–1.14), reported p = 0.130 (as reported in the registry).
• Docetaxel and AZD6244 vs Docetaxel and Placebo: hazard ratio 0.72 (95% CI 0.47–1.12), reported p = 0.113 (as reported in the registry).
• Docetaxel and AZD6244 vs Docetaxel and Placebo: hazard ratio 1.35 (95% CI 0.60–3.02), reported p = 0.305 (as reported in the registry).

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Progression Free Survival Rate at 6 Months

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Docetaxel and AZD6244: 39.0% (16/41) versus 26.2% (11/42) on control; risk difference 12.8 percentage points (95% CI -7.2 to 32.8), risk ratio 1.49 (0.79–2.81); unadjusted two-proportion z-test p = 0.212.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Docetaxel and AZD6244 and the control. The interval gives the range of effects that remain compatible with the data.

Overall Survival

• Endpoint type: Time to event: compared as a hazard ratio.
• Test: Hazard ratio as reported by the sponsor (Regression, Cox); it was not recalculated.
• Result:
  • Docetaxel and AZD6244 vs Docetaxel and Placebo: hazard ratio 1.37 (95% CI 0.80–2.37), reported p = 0.169 (as reported in the registry).
• Interpretation:
  • The 95% confidence interval includes no difference (a ratio of 1), so these data do not show a statistically significant difference between Docetaxel and AZD6244 vs Docetaxel and Placebo and the control. The interval gives the range of effects that remain compatible with the data.

Overall Survival Results - Post Final Analysis

• Endpoint type: Time to event: compared as a hazard ratio.
• Test: Hazard ratio as reported by the sponsor (Regression, Cox); it was not recalculated.
• Result:
  • Docetaxel and AZD6244 vs Docetaxel and Placebo: hazard ratio 1.15 (95% CI 0.71–1.84), reported p = 0.318 (as reported in the registry).
• Interpretation:
  • The 95% confidence interval includes no difference (a ratio of 1), so these data do not show a statistically significant difference between Docetaxel and AZD6244 vs Docetaxel and Placebo and the control. The interval gives the range of effects that remain compatible with the data.

The posted secondary outcomes cover progression-free survival rate at 6 months, overall survival, and an overall-survival result described as post final analysis, along with objective response and other measures. Across the secondary time-to-event results, the registry does not show a clear, precise pattern that would resolve the uncertainty in the primary progression-free survival comparison. Their estimates and tests should be read as additional, exploratory evidence rather than as independent confirmation of a definitive effect.

In general, secondary outcomes can provide context about different aspects of the trial, but they do not replace the primary endpoint. Overall survival measures a later and distinct event from progression-free survival, and a 6-month progression-free survival rate is a time-specific summary rather than the full time-to-event comparison. Results across these measures can differ without contradiction because their definitions and follow-up differ. The registry's follow-up description refers to the trial data lock and an average of 9.3 months for the primary timeframe; the record does not provide enough detail to infer the completeness of each secondary outcome's follow-up.

Multiple outcomes and analyses create more opportunities for apparently notable findings to arise by chance. Unless a multiplicity strategy is specified and applied, individual secondary p-values generally provide weaker confirmatory evidence than a prespecified primary analysis. Adjustment for multiplicity is not reported in the registry record. The overall reading is therefore one of uncertainty across endpoints, with the primary result remaining the main basis for interpreting the randomized comparison and the secondary findings offering context rather than a separate conclusion.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Progression Free Survival Rate at 6 Months
• Overall Survival
• Objective Response Rate
• Overall Survival Results - Post Final Analysis
• Vital Signs - Temperature
• Vital Signs - Pulse Rate
• Vital Signs - Systolic Blood Pressure
• Vital Signs - Diastolic Blood Pressure

9. Statistical Interpretation

10. Statistical Methods Explained

The registry reports a Cox regression method for the hazard-ratio analyses. A Cox model compares the instantaneous event rate among participants who remain event-free over follow-up, while allowing follow-up time and censoring to contribute to the analysis. The hazard ratio is a relative measure: values below 1 indicate a lower estimated event hazard in the numerator group, and values above 1 indicate a higher estimated event hazard, subject to the model and the way groups are ordered. This general description does not verify that the model assumptions hold in this trial.

What does the hazard ratio represent?

For the reported comparison, the group named first is docetaxel with AZD6244 and the comparator is docetaxel with placebo. The registry reports hazard ratios of 0.753, 0.723, and 1.348 in separate Cox entries. Those estimates are not interchangeable with a ratio of the posted medians: a hazard ratio uses event timing across follow-up, whereas a median is a single point on the estimated time-to-event distribution. The registry record does not explain why the entries differ, and the available information does not justify selecting one as the sole result or assigning each a specific analysis population.

Why are confidence intervals used?

A confidence interval expresses uncertainty around an estimated effect under the assumptions of the analysis. A narrower interval indicates greater precision, while a wider interval indicates less precision. For a hazard ratio, an interval that includes 1 leaves the data compatible with no relative difference as well as with effects on either side of 1. These are 90% confidence intervals in the registry's reported Cox analyses. In general, a confidence interval is not a statement that there is a 90% probability that a fixed true effect lies inside the particular interval.

What do the p-values add?

A p-value measures how incompatible the observed data, or data more extreme, are with a specified null model, under the test's assumptions. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of an effect. The reported Cox p-values are 0.130, 0.113, and 0.305; the generalized log-rank analysis has p = 0.302. These values are consistent with substantial uncertainty, and their interpretation depends on the analysis and any multiplicity considerations. The registry does not report a multiplicity adjustment.

The registry also lists a generalized log-rank analysis. A log-rank-type test compares the observed and expected event experience between groups over follow-up. The posted generalized log-rank result is p = 0.302, without a corresponding effect estimate or confidence interval in the registry record. A test result alone does not show the size or precision of a group difference.

How does censoring enter the analysis?

Participants who have not experienced progression or death by the end of their observed follow-up contribute information up to their last known time without an event. This is censoring, not evidence that an event never occurred. The endpoint definition specifies last known alive as the censored time for participants without an event. In general, time-to-event methods rely on assumptions about the relationship between censoring and the event process. The registry record does not report diagnostic checks or detail how missing follow-up was handled.

The primary analysis population is described as intention to treat, including all randomly assigned participants. This approach preserves the randomized group assignment for the main comparison. The registry does not provide details in the primary endpoint description about deviations from assigned treatment, missing outcome measurements, or additional analysis populations. Those details should not be inferred from the group counts alone.

The registry's stated objective was to assess whether the combination was worthy of evaluation in a definitive randomized study, with a null hypothesis of activity similar to docetaxel alone. The original statistical plan, including any prespecified model variations, decision thresholds, or interim monitoring, is not reported in the registry record. The different posted Cox estimates consequently cannot be mapped to unreported protocol choices.

11. Confidence Intervals and Precision

Precision is limited when an estimate has a wide confidence interval: the data then remain compatible with a wider range of underlying effects. The arm-level 90% confidence interval for median progression-free survival is 3.63 to 6.9 months for docetaxel with AZD6244 and 2.07 to 4.16 months for docetaxel with placebo. These intervals indicate uncertainty around both medians, with a wider span for the placebo estimate.

The first posted Cox estimate is 0.753, with a 90% confidence interval from 0.498 to 1.138. That interval includes 1 and therefore does not rule out no relative difference under the model. It also includes values on either side of 1, so the direction and magnitude are not pinned down precisely. The other reported Cox intervals, 0.465 to 1.123 and 0.602 to 3.016, are also broad and include 1. The registry does not explain the distinct Cox entries, so each should be read as a posted estimate without assuming it answers a different clinical question.

In general, confidence intervals reflect sampling uncertainty under the analysis assumptions; they do not capture every possible source of bias, measurement error, or model misspecification. Nor do they guarantee that future studies will reproduce the same estimate. With 83 enrolled participants, the trial results are compatible with a range of effects. A non-significant test does not establish equivalence or prove that the groups are the same. The registry does not report a prespecified equivalence margin, so equivalence cannot be concluded from these results.

12. 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 illustrations use the observed effect as a reference and show planning for 100%, 75%, and 50% of that effect. For the primary time-to-event comparison, the entries are total numbers of events, not participants per arm. The stated planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect equal to the stated fraction of the observed effect. The original trial's own sample-size assumptions are not reported in the registry record.

The 80% power column describes the planned event count or participant count that would give an 80% chance of detecting the assumed effect under those planning assumptions, if that effect were the true one. The 90% power column uses a higher target chance of detection and therefore calls for more information. For non-time-to-event outcomes, the displayed quantities are participants per arm; for time-to-event outcomes, they are total events. Keep that distinction in mind when reading a planning value.

Smaller assumed effects require more information to distinguish them from random variation. Thus, planning for 75% or 50% of the observed effect yields larger required counts than planning for the full observed effect. These calculations are planning illustrations, not observed power. They do not tell whether the completed trial had a particular probability of success after its results were observed, and they should not be confused with the trial's original enrollment target or justification.

13. 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

d is the total number of events needed (Schoenfeld's formula) with 1:1 allocation and proportional hazards.

Worked calculation for this trial

1. Hazard ratio HR = 0.753, so ln(HR) = -0.2837.
2. d = 4 × (1.96 + 0.842)² / [ln(0.753)]² = 390.1, rounded up to 391 events in total 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
hr <- 0.753                              # observed hazard ratio
events_needed <- function(power, frac = 1) ceiling(round(4 * (z_a + qnorm(power))^2 / log(hr^frac)^2, 6))   # Schoenfeld, 1:1 allocation
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: events = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(events_needed(0.80, f), big.mark = ","), format(events_needed(0.90, f), big.mark = ",")))

# Simulation: given d total events under proportional hazards, events in the treatment arm are Binomial(d, hr / (1 + hr)).
# The score (log-rank type) statistic is (D1 - d / 2) / sqrt(d / 4).
set.seed(1256359)
d    <- events_needed(0.80)
reps <- 20000
D1 <- rbinom(reps, d, hr / (1 + hr))
z  <- (D1 - d / 2) / sqrt(d / 4)
cat(sprintf("Simulated power with %s events: %.3f (%d replicates)\n", format(d, big.mark = ","), mean(abs(z) > z_a), reps))

Output from running the code

100% of observed effect: events = 391 (80% power), 523 (90% power)
 75% of observed effect: events = 694 (80% power), 929 (90% power)
 50% of observed effect: events = 1,561 (80% power), 2,089 (90% power)
Simulated power with 391 events: 0.811 (20000 replicates)

The simulation uses the fact that, with d events in total and proportional hazards, the number of events in the treatment arm is binomial. It is an approximation that conditions on the total number of events, and it should land close to the target power.

14. Group-Sequential Design Analysis

Many time-to-event trials, especially in oncology, stop or report early when interim data are overwhelming, so a single fixed-sample number understates the real design problem. The calculation below is an illustrative group-sequential design built from this trial's posted control median and hazard ratio. The registry record does not state the planned number of looks or the spending function, so the design is a planning illustration, not a reconstruction of the protocol. Assumed: one-sided α = 0.025, 90% power, three equally spaced looks on information, Lan-DeMets O'Brien-Fleming spending, 24 months of accrual, 60 months in total and a 1% monthly dropout hazard.

Under these assumptions the design needs about 564 participants in total, with the boundaries below.

Fixed design versus group-sequential alternatives

Group-sequential designs cost a small increase in maximum sample size and events compared with the fixed design, in exchange for the chance to stop early for overwhelming efficacy. O'Brien-Fleming spending keeps early boundaries very conservative and the final boundary close to the fixed-design value, whereas Pocock spending spends more alpha early.

Sensitivity to a smaller true effect

Planning for exactly the observed effect is optimistic, because observed effects in published trials tend to be somewhat larger than the true effect. The table repeats the main design (three looks, O'Brien-Fleming spending, 90% power) for smaller true hazard ratios.

For context, this trial enrolled 83 participants.

Cross-check, upper boundaries: gsDesign 3.71, 2.511, 1.993 | rpact 3.71, 2.511, 1.993. Agreement between the two packages confirms the boundary calculation.

R code and output

suppressWarnings(suppressMessages({ library(gsDesign); library(rpact) }))
med_control <- 3.93          # control-arm median, months (converted from the posted unit)
hr          <- 0.753          # hazard ratio used for planning
lambdaC     <- log(2) / med_control
eta         <- 0.01               # dropout hazard per month (assumption)
acc_months  <- 24                 # accrual duration (assumption)
study_months<- 60                 # total study duration (assumption)

design <- function(k, sfu, beta, h = hr) gsSurv(k = k, test.type = 1, alpha = 0.025, beta = beta, sfu = sfu,
  lambdaC = lambdaC, hr = h, hr0 = 1, eta = eta, gamma = 1, R = acc_months, T = study_months, minfup = study_months - acc_months)

# Main design: 3 looks, Lan-DeMets O'Brien-Fleming spending, one-sided alpha 0.025, 90% power
x <- design(3, sfLDOF, 0.10)
cat(sprintf("N_TOTAL|%s\n", format(ceiling(sum(x$gamma * x$R)), big.mark = ",")))
for (i in 1:3) cat(sprintf("GS|%d|%.1f|%.0f|%.3f|%.5f|%.5f\n", i, x$T[i], x$n.I[i], x$upper$bound[i], pnorm(-x$upper$bound[i]), cumsum(x$upper$spend)[i]))
cat("\n"); print(gsBoundSummary(x))

# Comparison of designs
cmp <- list(list("Fixed design, one analysis", 1, sfLDOF), list("Two looks, O'Brien-Fleming", 2, sfLDOF),
            list("Three looks, O'Brien-Fleming", 3, sfLDOF), list("Three looks, Pocock", 3, sfLDPocock))
cat("\n")
for (b in c(0.20, 0.10)) for (d in cmp) {
  y <- design(d[[2]], d[[3]], b)
  cat(sprintf("DES|%s|%d|%.0f|%s|%.1f\n", d[[1]], round(100 * (1 - b)), tail(y$n.I, 1), format(ceiling(sum(y$gamma * y$R)), big.mark = ","), tail(y$T, 1)))
}

# Sensitivity: what if the true effect is smaller than the observed one? (3 looks, O'Brien-Fleming, 90% power)
cat("\n")
for (fr in c(1, 0.75, 0.5)) {
  y <- design(3, sfLDOF, 0.10, exp(log(hr) * fr))
  cat(sprintf("SENS|%.2f|%.3f|%.0f|%s\n", fr, exp(log(hr) * fr), tail(y$n.I, 1), format(ceiling(sum(y$gamma * y$R)), big.mark = ",")))
}

# Independent cross-check of the boundaries with rpact
r <- getDesignGroupSequential(kMax = 3, alpha = 0.025, beta = 0.10, sided = 1, typeOfDesign = "asOF", informationRates = x$timing)
cat(sprintf("\nCross-check, upper boundaries: gsDesign %s | rpact %s\n", paste(round(x$upper$bound, 3), collapse = ", "), paste(round(r$criticalValues, 3), collapse = ", ")))

Method: LachinFoulkes 
    Analysis               Value Efficacy
   IA 1: 33%                   Z   3.7103
      N: 316         p (1-sided)   0.0001
 Events: 176        ~HR at bound   0.5716
   Month: 13    P(Cross) if HR=1   0.0001
             P(Cross) if HR=0.75   0.0338
   IA 2: 67%                   Z   2.5114
      N: 516         p (1-sided)   0.0060
 Events: 352        ~HR at bound   0.7651
   Month: 22    P(Cross) if HR=1   0.0060
             P(Cross) if HR=0.75   0.5603
       Final                   Z   1.9930
      N: 564         p (1-sided)   0.0231
 Events: 528        ~HR at bound   0.8407
   Month: 60    P(Cross) if HR=1   0.0250
             P(Cross) if HR=0.75   0.9000



Cross-check, upper boundaries: gsDesign 3.71, 2.511, 1.993 | rpact 3.71, 2.511, 1.993

15. Analyses Reported by the Sponsor

The registry reports the sponsor's analyses for the primary endpoint as Cox hazard ratios with 90% confidence intervals and p-values, alongside a generalized log-rank p-value. The posted first Cox entry is 0.753, with a 90% confidence interval of 0.498 to 1.138 and p = 0.130. Two additional Cox entries are 0.723, with a 90% confidence interval of 0.465 to 1.123 and p = 0.113, and 1.348, with a 90% confidence interval of 0.602 to 3.016 and p = 0.305. The generalized log-rank p-value is 0.302.

The recalculated summaries use posted arm-level results and are not substitutes for the sponsor's inferential analysis. There is no stated discrepancy between the posted results and the recalculation. For the primary time-to-event comparison, the interpretation should therefore remain anchored to the sponsor's reported hazard ratios and tests, rather than treating a simple summary-based calculation as a replacement Cox model. The registry does not explain the reason for the differing Cox entries, so the analysis details behind them remain uncertain.

In general, a recalculation from aggregate results cannot reproduce all features of an individual-participant time-to-event model. It may not account for the event times, censoring pattern, or covariates used in a fitted model. The registry's reported analyses are consequently the relevant source for the sponsor's stated inferential results; the limitations of those results remain the broad confidence intervals and the absence of further methodological detail in the record.

16. Multiplicity, Missing Data and Analysis Populations

The registry lists multiple outcome measures and analyses, including the primary progression-free survival endpoint and several secondary outcomes. It does not report whether the original analysis plan specified a hierarchy among secondary outcomes, adjusted significance thresholds, or another approach to controlling multiplicity. The posted secondary results should therefore not be treated as if they were protected from the increased chance of false-positive findings that can arise when many outcomes or analyses are examined. This is a general statistical concern, not a claim that any particular posted finding is false.

The primary endpoint description identifies an intention-to-treat population comprising all randomly assigned participants. That is an important analysis-population detail. However, the registry does not report the extent of missing outcome data, the number or timing of censored observations, or whether sensitivity analyses were conducted for missingness or censoring. It defines censored progression-free survival time as the interval from randomisation to last known alive for participants without an event, but does not describe additional checks of the assumptions underlying that handling.

In general, censoring allows participants with incomplete event follow-up to contribute information until their last known status. It does not mean that they had no event, and it can affect estimates if follow-up ends in a way related to the chance of an event. The registry does not provide enough detail to assess that possibility. The record also does not report interim analyses, stopping rules, or the original analysis-plan details. Their absence from the registry record should not be interpreted as proof that they were or were not part of the trial conduct; they are simply not reported in the registry record.

17. 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: retinal vascular disorder (100.0%), gastric haemorrhage (100.0%), vomiting (100.0%), diarrhoea (100.0%), dyspnea (100.0%).

The registry reports serious adverse events in 29 of 41 participants in the docetaxel-with-AZD6244 group and 20 of 42 participants in the docetaxel-with-placebo group. It separately reports other adverse events affecting 35 of 41 and 40 of 42 participants, respectively. Deaths are listed for 26 participants in the AZD6244 group and 28 in the placebo group. These are counts recorded for the groups; the registry information presented does not establish that deaths or adverse events were caused by study treatment.

The listed serious-event terms include retinal vascular disorder, gastric haemorrhage, vomiting, diarrhoea, dyspnea, and febrile neutropenia. The registry displays 100.0% alongside the first five terms and 48.8% alongside febrile neutropenia. Those displayed percentages should be read in the context of the registry's serious-event listing, not as percentages of all randomized participants without further denominator detail. The record does not give the event-level context needed to interpret those percentages as comparative risks.

In general, safety counts describe events recorded during the study and are not, by themselves, causal comparisons. The registry information does not provide enough detail about event timing, severity grading, exposure duration, or attribution to treatment to draw stronger conclusions.

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

The results describe a randomized comparison of docetaxel with AZD6244 against docetaxel with placebo in wt BRAF advanced melanoma. The posted median progression-free survival estimates are 4.23 months and 3.93 months, respectively, while the reported Cox analyses yield different hazard-ratio estimates and broad 90% confidence intervals. The first reported interval includes 1, as do the other posted Cox intervals. The posted tests do not provide clear statistical evidence of a difference, but that is not the same as demonstrating equal effects.

In general, a result that does not meet a conventional threshold for statistical significance may reflect a small effect, substantial uncertainty, or both. The registry record does not report an equivalence design or margin. It is therefore not appropriate to interpret the results as proving that adding AZD6244 has no effect, nor do they establish a benefit. The observed estimates are uncertain, and the differing Cox entries are not explained in the listed results.

The trial's stated purpose was to assess whether the combination merited evaluation in a definitive randomized study, with the stated null hypothesis that activity was similar to docetaxel alone. The record does not give the criteria used to make that progression decision or the original design justification. The results can inform discussion of the uncertainty in this randomized comparison, but cannot alone establish what a larger study would find.

These findings also do not support medical advice for an individual. They describe group-level trial data and reported statistical analyses. Applicability beyond the recorded population, treatment schedules, and follow-up cannot be established from the registry entries alone.

19. Why This Trial Matters Statistically

This trial illustrates why time-to-event results need to be read through both the effect estimate and its uncertainty. The primary endpoint is not just a comparison of two median times: the registry also reports Cox hazard ratios that use event information across follow-up. The posted medians are relatively close, while the hazard-ratio entries vary and their confidence intervals are broad. No single summary captures every feature of the time-to-event data.

It also demonstrates the distinction between a phase 2 objective and a definitive treatment-effect conclusion. The stated objective was to judge whether the combination warranted evaluation in a definitive randomized study. The result should be interpreted in that setting, while recognizing that the decision criteria and original sample-size justification are not reported in the registry record.

The group counts and the uncertainty in the reported estimates matter together. A point estimate alone can look decisive even when the confidence interval allows a wide range of effects. The interval and p-value provide different kinds of context, and neither should be mistaken for proof of equality or proof that a treatment effect exists. The unexplained variation among the posted Cox entries is an additional reason to avoid over-interpreting one value in isolation.

Finally, the trial highlights the importance of complete registry reporting. Details about multiplicity, missing data, model distinctions, and interim analyses would help readers evaluate how the posted findings relate to the original analysis plan. Their absence limits statistical interpretation without changing the results that the registry does report.

20. Limitations

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

The registry lists three Cox hazard-ratio results for the primary comparison but does not explain why they differ. Without that detail, readers cannot confidently identify the intended role of each estimate or determine whether they reflect different models, populations, or analytic choices. The generalized log-rank result is also posted without an accompanying effect estimate or confidence interval.

The primary follow-up description refers to the trial data lock of 01Oct2012 and an average of 9.3 months. It does not provide the distribution of follow-up, event counts, censoring counts, or completeness of follow-up by group. The record defines how censored progression-free survival time is assigned, but does not report sensitivity analyses or checks of censoring assumptions.

The registry reports an intention-to-treat primary population, but does not provide further detail about protocol deviations, missing measurements, or additional analysis populations. It does not report the original sample-size justification, the planned decision criteria for judging whether to proceed to a definitive study, or any interim-analysis plan. These omissions limit the ability to assess the analysis against its prespecified design.

Several secondary outcomes and analyses are posted, but multiplicity handling is not reported. Safety data include participant counts and listed serious-event terms, while the detail needed to assess timing, attribution, and comparative exposure is not given in the material summarized. These are reporting limitations; they do not change the posted estimates, but they narrow the conclusions that can be drawn from them.

21. Related Tutorials

22. Related Statistical Calculators

23. Sources

• ClinicalTrials.gov: Docetaxel With or Without AZD6244 in Melanoma — NCT01256359.
• Registry record last updated 2024-08-15; status last verified 2024-08.
• Results first posted 2024-08-15.
• 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.

24. Record Summary

NCT01256359 is a completed, randomized, double-blind, placebo-controlled phase 2 trial of docetaxel with AZD6244 versus docetaxel with placebo in wt BRAF advanced melanoma. The registry records enrollment of 83 participants and describes the primary analysis as intention to treat. The primary endpoint was progression-free survival, defined from randomisation to progression under modified RECIST v1.1 criteria or death.

The registry posts median progression-free survival estimates of 4.23 months and 3.93 months and several Cox hazard-ratio analyses with 90% confidence intervals. Those intervals are broad and include 1; the distinct Cox entries are not explained in the listed results. The original design assumptions, multiplicity plan, missing-data details, and interim-analysis plan are not reported in the registry record. The posted results support an interpretation of uncertainty, not a conclusion of equivalence or a definitive difference.