Ketoconazole, Hydrocortisone, Dutasteride and Lapatinib (KHAD-L) in Prostate Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Ketoconazole, Hydrocortisone, Dutasteride and Lapatinib (KHAD-L) in Prostate Cancer (NCT00953576), a non-randomized phase 1, phase 2 study. The primary outcome is Lapatinib Dose Limiting Toxicity (DLT) [Phase I].

2. Clinical Question

3. Trial Design

NCT00953576 was registered as a Phase I/II trial of ketoconazole, hydrocortisone, dutasteride and lapatinib in castration-resistant prostate cancer. The sponsor was Dana-Farber Cancer Institute. The study began on 2009-09-29, had a primary completion date of 2013-04-11, and is listed as terminated. Enrollment was 11.

The study was non-randomized, unmasked and based on a single-group model. The Phase I descriptions identify two lapatinib dose levels: 250 mg and 500 mg, each with KHAD. Participants received KHAD during the initial four-week cycle, then began lapatinib on day 29 or the first day of cycle 2. The registry also lists an all-Phase-I-participants description, but the dose instruction in that description is incomplete. The record does not explain the allocation procedure between dose levels or identify a randomized comparison.

The primary endpoint is a Phase I DLT count, evaluated continuously through one treatment cycle of 28 days. Its analysis population is described as all DLT-evaluable participants. The record also lists Grade 3-4 treatment-related adverse events as a secondary outcome. Four outcome measures are listed, but the registry record reports zero analyses. A Phase II design, its analysis population, and Phase II efficacy results are not reported in the registry record.

Because allocation was non-randomized and the study is described as single-group, the dose-level groups should not be treated as controlled arms. The enrollment total does not by itself identify the number of DLT-evaluable participants or explain how many were assigned to each dose level. The safety summaries list groups of 4 and 5 participants at risk, but those counts do not account for the full registered enrollment in a way the record explains.

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 analysis dataset is comprised of all DLT evaluable participants.

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: The analysis dataset is comprised of all enrolled participants.

6. Primary Endpoint

The registry lists the primary outcome as Lapatinib Dose Limiting Toxicity (DLT) [Phase I], measured over The evaluation for DLT occurred continuously through one cycle of treatment (28 days)..

The primary endpoint is the number of participants with a lapatinib dose-limiting toxicity during the first cycle of KHLAD treatment. The DLT evaluation window is one cycle of 28 days, and the analysis population is described as all DLT-evaluable participants. A DLT is defined using specified adverse-event criteria: a treatment-related Grade 3 or greater non-hematological event, including diarrhea; a Grade 4 or greater hematological toxicity regardless of attribution; or a Grade 3 skin or pulmonary reaction regardless of attribution. The definition also requires that the event occur during the first cycle and, for the first criterion, be attributed as possible, probable or definite to lapatinib or the combination.

In general, dose-limiting toxicity is used in early-phase studies to describe adverse events considered important when assessing a drug regimen or dose. A count is directly interpretable only alongside the number of participants evaluated and the endpoint definition. The registry record does not report the DLT count, the number of DLT-evaluable participants, or a dose-level estimate. It therefore does not support a numerical description of the primary endpoint result. Although the record identifies a Phase I/II study, a Phase II primary endpoint result is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The endpoint is a count of participants with an event, rather than a continuous measurement such as a laboratory value. The relevant event is a DLT as defined in the record, and its assessment is restricted to the first cycle of KHLAD treatment, lasting 28 days. The endpoint description also restricts the analysis population to DLT-evaluable participants. A count should be interpreted with its denominator: a count alone does not indicate how often an event occurred among those evaluated. The DLT count and the size of the DLT-evaluable population are not reported in the registry record.

What does a binary endpoint represent?

As a general statistical concept, a binary endpoint classifies each participant as having or not having the specified event during the defined period. The underlying data can be represented by event counts and participant counts. A count is useful for documenting the number of events, but comparison across groups typically requires the corresponding denominators and a clearly defined analysis. For this trial, the endpoint is listed as a number of participants with DLT. The registry record does not provide the endpoint count, the DLT-evaluable denominator, or an analysis estimating the event probability.

The DLT definition combines several types of adverse events with different severity and attribution rules. One criterion requires a Grade 3 or greater non-hematological treatment-related event, including diarrhea, with possible, probable or definite attribution to lapatinib or the combination. Another covers Grade 4 or greater hematological toxicity regardless of attribution, and another covers Grade 3 skin or pulmonary reactions regardless of attribution. The definition makes the endpoint clinically specific, but a reader cannot reproduce the count without participant-level event details and adjudication information. Those details are not reported in the registry record.

What can dose-level counts establish?

The record lists two Phase I dose groups and reports serious and other adverse-event counts for each. These are descriptive summaries, not a randomized comparison. In general, randomization helps balance measured and unmeasured characteristics between groups; with non-randomized allocation, group differences can reflect the way participants entered or were assigned to groups as well as any dose-related difference. The registry record does not state the allocation process. It also does not report a statistical comparison of the groups. The counts should therefore be read as observations within the listed groups, not as an estimate of a causal dose effect.

Small group counts can make estimates uncertain. In general, confidence intervals communicate the range of values reasonably compatible with the observed data under a specified method and assumptions. No confidence interval for the primary DLT endpoint or adverse-event counts is reported in the registry record. Without endpoint denominators and an analysis, readers should not infer precision from the counts alone. The absence of a reported interval is not evidence that an estimate is precise.

What is missing from the statistical analysis?

The registry record lists four outcome measures and zero analyses. It does not report a statistical analysis plan, an inferential method for DLT, a method for missing observations, or a formal comparison between dose levels. It also does not report interim analyses, a sample-size justification, or the number of participants included in each outcome analysis. Those design and analysis details are not reported in the registry record and should not be reconstructed from the dose descriptions.

The sample-size planning illustrations are described as calculations based on an observed effect, using a two-sided significance level of 0.05, equal allocation between two arms and a normal approximation. The stated effect to detect is a fraction of the observed effect; non-time-to-event illustrations are described in participants per arm for 80% or other stated power levels, while time-to-event illustrations use a total event count. These are planning illustrations, not the trial's own design justification and not observed power. They also do not convert this non-randomized study into a controlled comparison. Numerical planning values and a primary endpoint estimate are not reported in the registry record, so no numerical sample-size implication can be interpreted.

In general, multiplicity arises when several outcomes, time points, subgroups or comparisons are tested, because repeated testing can increase the chance of a false-positive finding. The record lists four outcome measures but does not describe a multiplicity procedure or an analysis hierarchy. It also does not report which outcomes were analyzed. Consequently, the record does not establish whether multiplicity adjustments were planned or used. This does not show that such procedures were absent from the study; it means their use 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("Phase I Dose Level 1: KHAD+L (250 mg)", "Phase I Dose Level 2: KHAD+L (500 mg)")
n      <- c(3, 5)
events <- c(0, 2)
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  Phase I Dose Level 1: KHAD+L (250 mg)  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Phase I Dose Level 2: KHAD+L (500 mg)  5  2  40.0  5.3  85.3  11.8  76.9  11.8  77.7

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists four outcome measures and zero analyses. It identifies a primary Phase I DLT endpoint and a secondary outcome of Grade 3-4 treatment-related adverse events, but does not report results for those endpoints. The outcome details and analysis populations for the other measures are not reported in the registry record. It also does not provide a statistical analysis plan or describe a hierarchy that would indicate which outcome was intended to carry the main inferential interpretation.

In general, multiplicity is a concern when a study examines multiple endpoints, groups, time points or subgroup analyses. Testing many questions can increase the chance of finding an apparently notable result by chance. Methods such as prespecified testing hierarchies or adjusted significance thresholds can address that issue, but the registry record does not say whether any such method was planned or used. With zero analyses listed, there is no posted inferential result to evaluate for multiplicity.

The DLT analysis population is described as all DLT-evaluable participants, but the criteria for being DLT-evaluable and the number of participants who qualified are not reported in the registry record. The registry does not describe missing outcome data, withdrawals during the DLT window, handling of participants with incomplete follow-up, or any imputation procedure. The enrollment count of 11 is not a substitute for the outcome-specific analysis denominator.

Similarly, a sample-size justification, interim analysis plan and reason for termination are not reported in the registry record. Their absence from the record does not establish what was done in practice. It limits assessment of whether the study was sized for its endpoint, how incomplete data were handled, and how the posted results relate to planned analyses.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: cardiac-other (20.0%), hypophosphatemia (20.0%).

The Phase I safety summaries list serious adverse events and other adverse events separately. For Dose Level 1, 4 participants were at risk for serious adverse events, 0 were affected, and 4 were at risk for other adverse events, with 4 affected. For Dose Level 2, 5 participants were at risk for serious adverse events, 2 were affected, and 5 were at risk for other adverse events, with 5 affected. Deaths are recorded as 0 for each group. These are counts within the listed groups; they are not a randomized comparison and do not establish a causal difference between dose levels.

The serious adverse-event terms listed as most frequent are Cardiac-other and Hypophosphatemia, each at 20.0%. The registry record does not clarify the denominator or provide further event-level detail for those percentages. The adverse-event summaries should also be distinguished from the primary DLT endpoint. DLT uses specific timing, severity and attribution criteria during the first cycle, while the posted safety categories do not indicate which events met those criteria. The registry record does not report a DLT count or identify a participant-level link between these safety counts and DLT classification.

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

The registry record establishes that NCT00953576 was a Phase I/II study of KHAD with lapatinib in castration-resistant prostate cancer. Its registered Phase I primary question was dose-limiting toxicity during the first cycle, with a defined event window and criteria. The posted safety summaries give counts for serious and other adverse events at two lapatinib dose levels. These registry entries describe the study and its reported safety categories; they do not answer the primary DLT question because the DLT result is not reported in the registry record.

The counts also do not show whether lapatinib added benefit to KHAD, whether one dose level was safer than the other, or how the regimen compares with another treatment. The study was non-randomized, had no control group and used a single-group model. The dose-level groups are not a like-for-like randomized comparison. The record does not report a Phase II efficacy result or a formal analysis of differences between groups.

In general, a study result is most informative when the endpoint, analysis population, event count, denominator and uncertainty estimate are all available. Here, the record gives an endpoint definition but not its event count or denominator, and lists zero analyses. The enrollment of 11 does not establish how many participants were evaluable for DLT or included in each endpoint analysis. The termination status does not explain why the study ended; the reason is not reported in the registry record.

These limits do not erase the descriptive safety information, but they constrain what can be concluded from it. The serious-event counts and listed terms are observations reported for the Phase I dose groups. They cannot be used to infer efficacy or to make a causal treatment claim. The record is insufficient to quantify the primary DLT outcome or the precision of any treatment effect.

14. Why This Trial Matters Statistically

This trial is statistically notable because its registered primary question is an early-phase safety question, but the record does not report the primary endpoint result. The DLT definition is detailed, including the first-cycle time window, event severity and attribution requirements. Yet the event count and number of DLT-evaluable participants are not reported. This illustrates why an endpoint definition alone is not enough to assess an outcome: the count, denominator and analysis are also needed.

The study also illustrates the distinction between a dose-level description and a comparative treatment estimate. Non-randomized allocation and the single-group model mean that the two Phase I dose levels are not randomized control arms. Even when event counts are listed for each group, differences may reflect factors other than dose. The registry record does not report the allocation process or a formal comparison, so the safety summaries remain descriptive.

Finally, the registry lists four outcome measures but zero analyses, while the study status is terminated. Neither fact explains why the study ended or what conclusions investigators reached. A statistical reading should distinguish information that is present—the design, endpoint definition and safety counts—from results and methods that are not reported in the registry record. This distinction is especially important in small early-phase studies, where limited counts make careful attention to denominators and uncertainty essential.

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 trial-specific limitations constrain interpretation. Enrollment was 11, but the number of participants evaluable for the primary DLT endpoint is not reported in the registry record. The safety groups list 4 and 5 participants at risk, without explaining the relationship of those group counts to the total enrollment. The record does not describe the allocation process, so the dose-level groups cannot be assumed to be comparable.

The primary endpoint result is absent: neither the number with DLT nor the DLT-evaluable denominator is reported. The registry also lists zero analyses, and does not provide confidence intervals, a formal comparison, or a statistical analysis plan. The secondary Grade 3-4 treatment-related adverse-event outcome is listed, but its result is not reported in the registry record. Phase II results and the analyses for the other listed outcome measures are also not reported.

The DLT definition depends in part on toxicity grading and attribution to lapatinib or the combination, but participant-level adjudication information is not reported in the registry record. The listed serious adverse-event terms have percentages but no clearly described denominator or further detail. The record does not explain missing observations, withdrawals, or how incomplete follow-up was handled. It also does not report a sample-size justification, interim analysis plan or reason for termination. These gaps prevent assessment of endpoint precision, missing-data effects, planned-versus-reported analyses and the implications of the terminated status.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Ketoconazole, Hydrocortisone, Dutasteride and Lapatinib (KHAD-L) in Prostate Cancer — NCT00953576.
• Registry record last updated 2018-09-04; status last verified 2018-07.
• Results first posted 2018-09-04.
• 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

NCT00953576 was a Dana-Farber Cancer Institute-sponsored Phase I/II study of ketoconazole, hydrocortisone, dutasteride and lapatinib in castration-resistant prostate cancer. It was non-randomized, unmasked and listed as a single-group study, with enrollment of 11. The registry lists lapatinib dose levels of 250 mg and 500 mg in Phase I and describes a primary endpoint of DLT during the first 28-day cycle among DLT-evaluable participants.

The record lists four outcome measures and zero analyses. It reports Phase I serious and other adverse-event counts by dose level, with 0 deaths listed in each group. It does not report the primary DLT count or denominator, Phase II results, a statistical analysis plan, a sample-size justification, or the reason for termination. The study is listed as terminated.