Phase 1 Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of H3B-6527 in Participants With Advanced Hepatocellular Carcinoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase 1 Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of H3B-6527 in Participants With Advanced Hepatocellular Carcinoma (NCT02834780), a na phase 1 study. The primary outcome is Part 1, Dose Escalation Phase: Number of Participants With Dose-limiting Toxicities (DLTs) Based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03.

2. Clinical Question

As a Phase 1 study, this trial focused on evaluating an investigational drug across dose cohorts, rather than estimating a comparative treatment effect against a control group. The registry also lists pharmacokinetic outcomes and, in Part 2, response and time-to-event outcomes. These include objective response rate, duration of response, progression-free survival, overall survival, and time to response, with response-related outcomes based on modified RECIST version 1.1. Numerical results for those outcomes are not reported in the registry record.

3. Trial Design

The study is listed as Phase 1, open-label, and single-group, with allocation recorded as not applicable. Its official title describes a multicenter study. The registry status is completed, with a start date of 2016-12-28 and primary completion date of 2022-02-23. The recorded enrollment is 128. These are study-level record details; enrollment does not establish how many participants contributed to any particular outcome analysis.

The design included Part 1, a dose-escalation phase, and Part 2, a dose-expansion phase. The registry’s adverse-event cohort descriptions show escalation cohorts with H3B-6527 doses and schedules including QD and BID, and with fasted or fed conditions in specified cohorts. The expansion cohorts listed are H3B-6527 1000 mg QD and H3B-6527 500 mg BID Fed. The registry does not report the rules used to move between dose levels or the basis for selecting expansion regimens.

Because there was no randomized control group, comparisons between cohorts should not be read as randomized treatment comparisons. Cohorts differ in dose, schedule, food condition, or study phase; any differences in observed events may also reflect differences among the participants or in the time and circumstances of assessment. The registry record does not report a protocol-level statistical plan, a sample-size justification, interim analyses, or the number analyzed in each outcome population.

The primary outcome was defined for the dose-escalation phase only: participants with dose-limiting toxicities in Cycle 1, whose cycle length was 21 days. The DLT analysis population was defined as participants in Part 1 who completed safety assessments through pre-dose on Cycle 2 Day 1 and received at least 17 of 21 study days within Cycle 1, unless the reason for not doing so was a DLT. This is an outcome-specific population definition, not a reported count of participants meeting the criteria. Its size is not reported in the registry record.

The stated study purpose was to determine the maximum tolerated dose and recommended Phase 2 dose and assess safety, tolerability, and pharmacokinetics. The registry lists pharmacokinetic measures including AUC0-t, Cmax, and Tmax. Part 2 outcomes include response and survival measures, but their numerical results 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.

Before assignment: A total of 304 participants were screened, of which 176 were screen failures and 128 were enrolled into two parts: Dose Escalation Phase (Part 1) and Dose Expansion Phase (Part 2) to receive study treatment.

Only the first 6 of 13 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: DLT analysis set included all participants in Dose Escalation phase (Part 1) who must have completed safety assessments through pre-dose on Cycle 2 Day 1 and must have received at least 17 of 21 (approximately 80 percent \[%\]) study days within Cycle 1, unless due to a DLT. This outcome measure was planned to be analyzed for Part 1 only.

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: Full analysis set included all participants who received at least 1 dose of the study drug.

Only the first 6 of 14 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Part 1, Dose Escalation Phase: Number of Participants With Dose-limiting Toxicities (DLTs) Based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, measured over Cycle 1 (Cycle length = 21 days).

The primary endpoint counts participants with a dose-limiting toxicity in the dose-escalation phase. It applies to Cycle 1, defined in the registry as a 21-day cycle. DLTs were toxicities in hematology, gastrointestinal, renal, hepatic, or nonhematologic categories that occurred during Cycle 1 and were judged by the investigator to be related to study drug. The registry specifies severity and duration criteria, including selected Grade 4 events, Grade 3 events, and serum creatinine elevations at Grade 3 or higher.

This kind of endpoint is used in early dose-escalation research to describe treatment-related toxicities that meet prespecified severity or duration criteria during a defined observation period. In general, counting participants with DLTs can help characterize tolerability at the doses studied and inform dose-selection decisions. It does not, by itself, establish a comparative effect against another treatment, and it does not capture every possible safety concern or later event.

The primary analysis population was limited to Part 1 participants who met the specified safety-assessment and treatment-exposure conditions, with an exception for participants who received less study treatment because of a DLT. The registry gives this population definition but does not report how many participants qualified or the number with DLTs. Therefore, the primary endpoint’s observed result and its precision are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a single-group, open-label Phase 1 study with dose escalation and dose expansion. Allocation is listed as not applicable, and the record does not describe randomization or masking. These features matter for statistical interpretation: observations across cohorts are descriptive, and contrasts between cohorts are not randomized comparisons. The cohorts can differ not only by dose, but also by schedule, fed or fasted condition, and study phase.

What does a participant count represent?

The primary outcome is a count of participants who met the DLT definition during Cycle 1. A count needs a clearly defined analysis population to be interpretable. The registry specifies that the DLT analysis set included Part 1 participants who completed safety assessments through pre-dose on Cycle 2 Day 1 and received at least 17 of 21 study days within Cycle 1, unless they received less because of a DLT. The number who met these criteria is not reported in the registry record. The numerical DLT count is also not reported, so neither an event proportion nor its uncertainty can be assessed from the primary outcome information.

In general, a count describes how many observed participants experienced an event. A proportion relates that count to the number assessed, which makes the denominator essential. A count without its analysis denominator cannot show the frequency of the event within the intended population. Even with a numerator and denominator, a confidence interval is useful because it communicates how much uncertainty remains around an estimated event rate. The registry record does not report a primary-outcome confidence interval.

Why distinguish DLTs from serious adverse events?

The primary endpoint uses a specific DLT definition, including timing in Cycle 1, selected toxicity types and grades, duration criteria, and investigator judgment that the event was related to study drug. The safety results separately count participants with serious adverse events and participants with other adverse events. These are not interchangeable categories. A serious adverse event need not meet the protocol’s DLT criteria, and an event that meets DLT criteria is not automatically represented by a serious-event count in the same way. The record does not report a cross-tabulation connecting the DLT outcome with the serious adverse-event counts.

In general, adverse-event summaries can differ according to event definitions, observation windows, attribution rules, and the unit being counted. A participant count is not necessarily the same as an event count: one participant may experience more than one event, while a participant-level summary counts that person once for a category. The registry’s safety fields are participant counts for the listed categories. The record does not provide event-level detail sufficient to reconstruct how multiple events contributed to each participant-level summary.

What can cohort comparisons show?

The registry lists adverse-event results across dose and schedule cohorts. These figures can describe what was recorded in each cohort, but they do not support a causal comparison between regimens. General statistical reasoning: randomized allocation helps balance measured and unmeasured participant characteristics on average, while non-randomized cohorts may differ for many reasons. Here, the record explicitly identifies the study as not a randomized comparison. It does not report adjusted estimates for cohort contrasts, so no adjustment should be assumed.

General statistical reasoning: sparse counts are often imprecise. A difference in observed counts between cohorts can arise from different cohort sizes, participant characteristics, exposure, or chance, as well as from any underlying difference in risk. Percentages may look more direct than counts, but they still depend on their denominator and on a comparable observation process. The registry does not report a formal comparative analysis of the safety cohorts.

What do the planning assumptions mean?

Any sample-size figures framed as planning illustrations are not observed power and are not the study’s reported design justification. The stated illustration assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is described as a stated fraction of the observed effect. Time-to-event illustrations use the total number of events, while other illustrations use participants per arm. These are planning conventions, not evidence that the trial was designed or conducted with a control arm. The registry record does not report the trial’s own sample-size justification, and no numerical planning estimates are stated in the record information.

General statistical reasoning: a planning calculation depends on its assumptions about the effect, variability, allocation, and analysis. If the assumed effect is smaller, detecting it usually requires more information; if the outcome is uncommon or imprecisely estimated, planning can be especially sensitive to the assumptions. A planning illustration based on an observed effect is not a guarantee of future precision and does not describe the probability that a completed study produced a statistically significant result. It must not be interpreted as observed power.

What analyses are documented?

The registry reports zero analyses in its analysis listing. That does not establish that no analyses were conducted; it means analysis details are not reported in that registry listing. The statistical methods for the primary endpoint, interval estimation, handling of missing observations, and any multiplicity adjustments are not reported in the registry record. The registry also does not report whether interim analyses were conducted. Without those details, readers should not infer a particular model, test, or adjustment from the endpoint description alone.

10. Exact Estimates for Each Arm

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

R code and output

arm    <- c("Part 1, Dose Escalation Phase: H3B-6527 300 mg QD ", "Part 1, Dose Escalation Phase: H3B-6527 600 mg QD ", "Part 1, Dose Escalation Phase: H3B-6527 600 mg QD ", "Part 1, Dose Escalation Phase: H3B-6527 1000 mg QD", "Part 1, Dose Escalation Phase: H3B-6527 1000 mg QD", "Part 1, Dose Escalation Phase: H3B-6527 1400 mg QD")
n      <- c(3, 3, 4, 10, 3, 6)
events <- c(0, 0, 0, 0, 0, 0)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Part 1, Dose Escalation Phase: H3B-6527 300 mg QD   3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Part 1, Dose Escalation Phase: H3B-6527 600 mg QD   3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Part 1, Dose Escalation Phase: H3B-6527 600 mg QD   4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2
ARM  Part 1, Dose Escalation Phase: H3B-6527 1000 mg QD  10  0  0.0  0.0  30.8  0.0  27.8  0.2  28.5
ARM  Part 1, Dose Escalation Phase: H3B-6527 1000 mg QD  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Part 1, Dose Escalation Phase: H3B-6527 1400 mg QD  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 13 outcome measures, including the primary DLT count, pharmacokinetic measures, and Part 2 response and survival outcomes. Listing multiple outcomes does not, by itself, indicate which analyses were confirmatory or how error rates were managed. The registry record does not report a multiplicity strategy, such as a hierarchy of hypotheses or an adjustment across outcomes. It also does not report a statistical analysis plan that would clarify whether particular outcomes were exploratory or prespecified for formal testing.

General statistical reasoning: when many hypotheses are tested, the chance of at least one apparently noteworthy result can increase unless the analysis plan accounts for multiplicity. Whether adjustment is appropriate depends on the purpose and structure of the analyses. Since the registry record does not describe such a plan or provide numerical results for the listed response and survival outcomes, it is not possible to assess multiplicity handling or reinterpret outcome-level significance.

The record defines a DLT analysis population using completion of safety assessments through pre-dose on Cycle 2 Day 1 and receipt of at least 17 of 21 study days in Cycle 1, except when a DLT caused lower exposure. It does not report how many participants were excluded, how missing safety assessments were handled, or whether any other missing-data rules were used. The handling of missing data for pharmacokinetic, response, and time-to-event outcomes is also not reported in the registry record.

Analysis populations can differ across outcomes because each measure may require different assessments or follow-up. General statistical reasoning: excluding participants with incomplete data can affect an estimate if missingness is related to health status, treatment exposure, or the outcome. The relevant concern depends on why data are missing and on the analysis method. The record does not provide enough information to evaluate those mechanisms or determine whether sensitivity analyses were performed. The number of participants in each outcome-specific analysis population is not reported.

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 2% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pleural effusion (33.3%), peripheral embolism (33.3%), musculoskeletal pain (33.3%), neck pain (33.3%), asthenia (28.6%).

The safety listing reports, for each cohort, participants at risk and participants affected by serious adverse events, other adverse events, and deaths. These are descriptive cohort counts. For example, the 300 mg QD Fasted cohort lists 0 of 3 participants with serious adverse events, while the 600 mg QD Fed cohort lists 1 of 4. The 1000 mg QD expansion cohort lists 11 of 29, and the 500 mg BID Fed expansion cohort lists 17 of 40. These counts should not be read as randomized comparisons because the study was not randomized and the cohorts differ in dose, schedule, food condition, or phase.

The registry also lists deaths by cohort, including 1 in the 300 mg QD Fasted cohort, 19 in the 1000 mg QD expansion cohort, and 31 in the 500 mg BID Fed expansion cohort. These are counts, not statements about cause or treatment relationship. Timing, cause, and attribution of deaths are not reported in the registry record. The other-adverse-event counts are a separate category and should not be added to the serious-event counts: the record does not establish that the categories are mutually exclusive.

The serious-event terms listed include pleural effusion, peripheral embolism, musculoskeletal pain, neck pain, asthenia, and abdominal pain, with percentages ranging from 25.0% to 33.3% among the listed terms. The registry information does not report enough detail alongside these percentages to establish their denominators or support comparisons. Serious-event counts describe reported safety observations; they do not establish that H3B-6527 caused an event.

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

The record identifies the study’s aims and its primary endpoint, but does not report the numerical primary DLT result. It therefore does not permit a quantitative assessment of how many participants met the DLT definition in the dose-escalation phase, nor of the precision of that estimate. The stated outcome definition and analysis-population criteria are useful for understanding what was intended to be counted, but they are not a substitute for the observed result.

The safety listing provides participant counts for serious adverse events, other adverse events, and deaths across the listed cohorts. These counts describe what the registry records for those groups. They do not establish a causal relationship to H3B-6527, and they do not show that one dose or schedule is safer than another. The study is not a randomized comparison, and cohort differences can reflect factors beyond the regimen. The record does not give the causes or timing of deaths in the listed results.

The registry states that the study’s purpose included determining the maximum tolerated dose and recommended Phase 2 dose and assessing safety, tolerability, and pharmacokinetics. However, numerical results establishing those dose-selection conclusions are not reported in the registry record. The record also lists Part 2 response and survival outcomes, but does not report their numerical results. No conclusion about response, progression-free survival, overall survival, or time to response can be drawn from outcome listings alone.

General statistical interpretation: an estimate is more useful when accompanied by a clear population definition, denominator, and measure of uncertainty. Uncertainty intervals help distinguish a relatively precise estimate from one compatible with a wide range of values. The registry does not report a primary endpoint estimate or its confidence interval. The enrollment figure should not be treated as the denominator for the DLT analysis, because the primary analysis has its own eligibility criteria and its population size is not reported.

Accordingly, the registry record supports a description of the design, endpoint definition, and listed safety counts, but not a complete statistical evaluation of the primary outcome or the listed efficacy outcomes. Missing numerical results and analysis details limit what can be concluded; they do not, on their own, demonstrate either benefit or lack of benefit.

14. Why This Trial Matters Statistically

This study illustrates why early-phase clinical research must be read through its endpoint definition and analysis population, rather than through a study-wide enrollment figure alone. The primary outcome applies only to Part 1 and uses a defined DLT window in Cycle 1. It also has specific eligibility requirements for the DLT analysis set. Without the number analyzed and the number meeting the DLT definition, the main endpoint cannot be assessed quantitatively from the registry record.

The record also makes clear that dose cohorts are not equivalent to randomized treatment groups. Dose, dosing schedule, food condition, and study phase vary across cohorts. Comparing their observed safety counts as if participants had been randomly assigned to like-for-like alternatives would disregard the design and could produce misleading interpretations. This is a general issue in dose-escalation research: descriptive patterns can inform questions, but they do not automatically identify causal differences between regimens.

Another statistical lesson is that adverse-event categories answer different questions. A DLT is defined by a particular period, severity or duration criteria, and investigator attribution. Serious adverse events and other adverse events are reported separately. Counts from these categories should not be treated as interchangeable, and deaths cannot be attributed to study drug without the relevant cause and relationship information.

Finally, a registry can describe planned outcomes without displaying their numerical results or analysis methods. In this record, the primary DLT result, analysis populations, uncertainty estimates, missing-data handling, and multiplicity approach are not reported. Recognizing the difference between an outcome being listed and an outcome being numerically reported is central to transparent statistical interpretation.

15. Limitations

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

The most consequential limitation for interpreting the primary outcome is that its numerical result is not reported in the registry record. The record also does not report the number included in the DLT analysis set or an uncertainty interval. Although the eligibility criteria for that set are described, the available information does not establish how many participants qualified or how many experienced DLTs.

The study is open-label, single-group, and non-randomized. There is no like-for-like concurrent control comparison in the registry description. Cohorts vary across dose, schedule, food condition, and study phase, so their event counts do not provide a randomized comparison of regimens. The registry record does not report adjusted cohort comparisons.

The safety information lists participant counts and selected serious-event terms, but does not provide the timing, causes, or treatment relationship for deaths. The denominators and context for the listed serious-event percentages are not fully described in the record summarized. These details limit causal interpretation and comparison across cohorts.

Further limitations arise from missing analysis information. The registry does not report the statistical analysis plan, multiplicity handling, interim analyses, missing-data methods, outcome-specific analysis populations, or the study’s sample-size justification. It lists multiple Part 2 outcomes but does not report their numerical results. These omissions prevent evaluation of the precision and robustness of the primary and secondary findings. The record’s completed status and enrollment figure do not resolve these gaps.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Phase 1 Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of H3B-6527 in Participants With Advanced Hepatocellular Carcinoma — NCT02834780.
• Registry record last updated 2023-11-13; status last verified 2021-07.
• Results first posted 2023-11-13.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

This completed Phase 1 study evaluated H3B-6527 in participants with advanced hepatocellular carcinoma. The registry describes an open-label, single-group design with dose escalation and dose expansion, and records enrollment of 128. The stated aims included determining the maximum tolerated dose and recommended Phase 2 dose and assessing safety, tolerability, and pharmacokinetics.

The primary outcome was the number of participants with dose-limiting toxicities during Cycle 1 in Part 1. The registry gives the endpoint definition and DLT analysis-population criteria, but the numerical primary result and size of that analysis population are not reported in the registry record. Cohort-level adverse-event counts and deaths are listed, but do not establish causal effects or support randomized comparisons. Numerical results for the listed Part 2 response and survival outcomes are not reported.