Trial to Evaluate the Safety and Pharmacokinetics of HMPL-689 in Patients With Lymphomas: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Trial to Evaluate the Safety and Pharmacokinetics of HMPL-689 in Patients With Lymphomas (NCT03786926), a na phase 1 study. The primary outcome is Dose Escalation Stage: Number of Patients With Dose-Limiting Toxicities (DLTs).

2. Clinical Question

The trial also included secondary outcomes concerning tumor response, time to response, duration of response, clinical benefit, progression-free survival, and plasma concentrations of HMPL-689. These outcomes address different aspects of preliminary activity and drug exposure. Their inclusion does not create a controlled comparison: without a separate control group, the study is principally suited to describing safety, tolerability, pharmacokinetics, and preliminary outcomes within the treated groups.

3. Trial Design

This was a phase 1, open-label, single-group study of HMPL-689 in patients with relapsed or refractory lymphoma. The registry record describes dose escalation and dose expansion stages. Participants received HMPL-689 daily. As an open-label study, treatment assignment was not masked; the registry lists no randomized allocation and no comparator intervention.

The registry records an enrollment of 53. That is the enrollment figure for the trial record, not necessarily the number included in the primary endpoint analysis: the primary outcome population is described as the dose-limiting toxicity evaluable analysis set from the dose escalation stage. The number of participants evaluable for that endpoint is not reported in the registry record.

The study started on 2019-08-26, and the listed primary completion date is 2024-06-26. Its status is terminated. The reason for termination, whether the study stopped according to its original plan, and any consequences for the planned analyses are not reported in the registry record.

The dose expansion stage is described by lymphoma cohort labels including CLL/SLL, FL, MZL, LPL/WM, and MCL in the adverse event records. These records should not be treated as randomized comparisons among disease groups or doses. Differences across such cohorts may reflect differences in patient characteristics, disease, dose, or other factors. The registry record does not report a statistical plan that would allow those differences to be interpreted as causal treatment effects.

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: The study consisted of a dose escalation stage (stage 1) and a dose expansion stage (stage 2). A total of 23 patients in dose escalation stage and 30 patients in dose expansion stage were enrolled in this study. The study was terminated based on strategic evaluation of the clinical development of HMPL-689 in the United States, Europe, and Australia with no safety concerns.

Only the first 6 of 11 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The DLT evaluable analysis set (DEAS) was defined as all patients enrolled in the dose escalation stage of the study who were evaluable for DLT assessment. A patient was DLT evaluable if: had received at least 75% of the assigned dose of study drug during the DLT assessment window or had not completed the DLT assessment period due to a DLT.

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 Full Analysis Set (FAS) included all patients who received at least 1 dose of HMPL-689.

Only the first 6 of 12 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Dose Escalation Stage: Number of Patients With Dose-Limiting Toxicities (DLTs), measured over From the first dose of study drug (Day 1) up to Day 28 of Cycle 1 (each cycle is 28 days).

The primary endpoint is the number of patients with dose-limiting toxicities (DLTs) in the dose escalation stage. The assessment window ran from the first dose on Day 1 through Day 28 of Cycle 1, with each cycle lasting 28 days. The endpoint is a count of participants meeting the DLT definition, rather than a measure of tumor response or a comparison with another treatment.

The DLT definition covered specified treatment-emergent adverse events unless they were unequivocally due to the underlying malignancy or an extraneous cause. Non-hematologic toxicity included events graded 3 or higher, except grade 3 nausea or vomiting controlled by supportive therapy. Hematologic criteria included grade 4 neutropenia lasting >5 days, specified grade 3 or grade 4 thrombocytopenia, grade 3 or higher febrile neutropenia, and grade 4 anemia not explained by underlying disease. A dose delay of >=15 days and any case of Hy's Law were also included. Adverse events were graded using NCI CTCAE version 5.0.

In general, a DLT count is used during dose escalation to describe whether toxicities meeting prespecified criteria occurred in the early assessment period. It is a defined safety measure, not a complete account of all adverse events or all later safety experience. The registry record does not report the primary endpoint count, so the observed frequency of DLTs cannot be described.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The study is described as a single-group, open-label phase 1 trial with dose escalation and dose expansion. In general, dose escalation studies describe safety and tolerability as exposure is evaluated across dose levels. An expansion stage can provide further descriptive information in selected groups. Neither feature by itself creates a randomized comparison. Here, allocation is listed as NA, masking as none, and the model as single group, so comparisons across listed doses or cohorts should not be interpreted as comparisons against a control arm.

What does the primary count represent?

The primary endpoint is a count of participants with DLTs in the dose escalation stage. The observation period is from the first dose on Day 1 through Day 28 of Cycle 1. The event definition is based on specified treatment-emergent adverse events and includes exceptions and thresholds. For example, the definition includes non-hematologic events graded 3 or higher, with an exception for grade 3 nausea or vomiting controlled by supportive therapy. It also specifies hematologic events, prolonged dose delay, and Hy's Law. In general, a count describes the number meeting a rule; interpreting it as a frequency also requires the relevant analysis denominator. The count and denominator for this endpoint are not reported in the registry record.

Why distinguish the analysis population from enrollment?

The registry enrollment is 53, while the primary endpoint population is defined as the dose-limiting toxicity evaluable analysis set. The record says this set consists of patients enrolled in dose escalation who were evaluable for DLT assessment. It states that a patient was DLT evaluable if they had received at least 75% of the assigned dose during the assessment window, or had not completed another condition whose full wording is not reported in the registry record. Therefore, the enrollment number cannot be assumed to be the primary endpoint denominator. In general, defining an analysis population clarifies which participants contribute to an endpoint; incomplete or unavailable population details make the result harder to reproduce and interpret.

What can adverse event counts tell the reader?

The adverse event records are grouped by dose or expansion cohort. They include counts of participants at risk, participants affected by serious adverse events, participants affected by other adverse events, and deaths. These counts are descriptive. In general, counts are useful for showing how many participants in each listed group were recorded with an event, but they do not establish that the intervention caused the event. Nor are serious adverse events identical to DLTs: the DLT measure applies a specific definition over a specific window, while seriousness is a separate adverse event classification. The registry record does not provide event-level timing or attribution for the counts.

How should uncertainty and comparisons be understood?

In general, a confidence interval describes a range of values compatible with the data under the assumptions of the analysis. The registry record does not report confidence intervals for the primary endpoint or the adverse event counts. It also does not report an inferential analysis for the primary endpoint. Without estimates and uncertainty intervals, it is not possible to assess the precision of a rate or to distinguish a stable pattern from variation that may arise in a small group.

In general, randomization helps balance known and unknown participant characteristics between intervention groups. This study has no randomized control group, so contrasts between doses or expansion cohorts can be affected by differences in who entered each group and by the way the stages were conducted. The registry record does not report an analysis that adjusts for such differences. The arm and cohort records should therefore be read as descriptive, not as estimates of comparative treatment effects.

What do the planning assumptions mean?

The record describes a planning illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the target effect is a stated fraction of the observed effect. In general, such calculations explore sample sizes under explicit assumptions. They are not observed power, and they do not establish the design justification used by the investigators. The record does not report the trial's own sample-size justification. The illustration's numerical results and the observed effect used for it are not reported in the registry record, so no particular planning estimate can be interpreted from the available record.

Finally, the registry lists 13 outcome measures and zero analysis records. In general, an analysis record can specify the population, measure, statistical method, and result for an outcome. Without those details, the endpoint names alone do not reveal how outcomes were analyzed, what estimates were obtained, or how precise those estimates were. The statistical analysis plan, handling of repeated assessments, and any model assumptions are not reported in the registry record.

10. Exact Estimates for Each Arm

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

R code and output

arm    <- c("Dose Escalation Stage: HMPL-689 5 mg QD", "Dose Escalation Stage: HMPL-689 10 mg QD", "Dose Escalation Stage: HMPL-689 15 mg QD", "Dose Escalation Stage: HMPL-689 20 mg QD", "Dose Escalation Stage: HMPL-689 25 mg QD", "Dose Escalation Stage: HMPL-689 30 mg QD")
n      <- c(3, 3, 5, 3, 6, 3)
events <- c(0, 0, 1, 0, 1, 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  Dose Escalation Stage: HMPL-689 5 mg QD  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Dose Escalation Stage: HMPL-689 10 mg QD  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Dose Escalation Stage: HMPL-689 15 mg QD  5  1  20.0  0.5  71.6  3.6  62.4  4.3  64.1
ARM  Dose Escalation Stage: HMPL-689 20 mg QD  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Dose Escalation Stage: HMPL-689 25 mg QD  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  Dose Escalation Stage: HMPL-689 30 mg QD  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 13 outcome measures, including the primary DLT count and secondary measures of response, time to response, duration of response, clinical benefit, progression-free survival, and plasma concentrations. It does not report how multiple outcomes were handled statistically. In general, testing many outcomes can increase the chance of at least one apparently notable result, so interpretation depends on whether outcomes were exploratory or confirmatory and whether a multiplicity strategy was prespecified. Those details are not reported in the registry record.

The record lists zero analysis records. It does not report outcome-specific analysis populations, statistical models, missing-data methods, censoring rules for time-to-event outcomes, or sensitivity analyses. These details matter because different analysis choices can change which observations contribute to an estimate and how its uncertainty is calculated. In general, missingness may also affect interpretation when the availability of data is related to participants' health status or outcome experience; the registry record does not describe the extent or handling of missing outcome data.

For the primary endpoint, the analysis population is described as the dose-limiting toxicity evaluable analysis set from dose escalation. The record says that a participant was evaluable if they received at least 75% of the assigned dose during the DLT assessment window, or met another condition whose full description is not reported in the registry record. The number in this analysis set and the number with DLTs are not reported. The trial enrollment figure should not be substituted for this endpoint-specific denominator.

The registry record does not report interim analyses, stopping criteria, or a statistical analysis plan. These omissions prevent assessment of whether decisions during the trial depended on accumulating results or how the planned analyses addressed incomplete follow-up and multiple outcomes.

12. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pneumonia (33.3%), colitis (33.3%), neutropenia (33.3%), asthenia (33.3%), multiple fractures (33.3%).

The serious adverse event records are presented by dose escalation dose or dose expansion cohort. Each entry reports the number at risk, the number affected by serious adverse events, the number affected by other adverse events, and deaths. For example, the 5 mg QD dose escalation group records 3 at risk, 0 affected by serious adverse events, 3 affected by other adverse events, and 0 deaths. The other groups are listed separately, and their counts should not be combined into a single comparison because the groups are not randomized control arms.

Across the listed groups, the serious-event terms identified in the registry include pneumonia, colitis, neutropenia, asthenia, multiple fractures, and psychotic disorder, each listed as 33.3%. The record does not give the denominator or event-level detail needed to interpret those percentages further. The counts do not establish that HMPL-689 caused the events. They also do not directly provide the primary DLT result: DLTs use a defined event threshold and assessment window, while serious adverse events are classified separately. Death counts are reported, but the registry record does not state whether deaths were attributed to treatment.

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

This trial record describes the design and selected safety information for an open-label, single-group phase 1 study of HMPL-689 in patients with relapsed or refractory lymphoma. It identifies a primary safety endpoint, a first-cycle assessment window, and a defined set of criteria for dose-limiting toxicity. These details clarify what the endpoint was intended to capture.

The record does not report the number of patients with DLTs, the endpoint denominator, or numerical results for the listed secondary outcomes. Consequently, it does not allow a reader to determine the observed DLT frequency, assess the precision of that frequency, or evaluate response and time-to-event outcomes from the registry record. The adverse event entries provide descriptive counts for the listed groups, but they are not a substitute for the primary endpoint result.

The design also sets limits on what can be concluded. With no randomized comparator, the study cannot provide a controlled estimate of how HMPL-689 compares with another treatment or with no study drug. Differences across dose or disease cohorts may be descriptive, but should not be treated as proof that one dose or cohort had a different causal treatment effect. An open-label design also means masking was not used, though the registry record does not describe how that affected outcome assessment.

The status is terminated, but the reason and its implications are not reported in the registry record. The listed enrollment does not by itself indicate how many participants contributed to each endpoint. The record therefore supports a description of the planned study question and the posted safety counts, while leaving key outcome results and analysis details unavailable. It does not establish a treatment benefit or lack of benefit.

14. Why This Trial Matters Statistically

This study illustrates why early-phase safety endpoints need to be read together with their operational definitions and analysis populations. A DLT is not simply any adverse event: the registry defines specific event types and severity thresholds, allows an exception for certain controlled symptoms, and restricts assessment to a stated window. That definition determines which events count toward the primary endpoint.

The distinction between trial enrollment and endpoint-specific evaluability is also important. The registry records 53 participants enrolled, but the primary endpoint applies to a DLT-evaluable population from the dose escalation stage. Without the size of that population and the endpoint count, the main safety question cannot be answered from the record. This is a practical reminder that a headline enrollment figure does not automatically describe the denominator for every reported outcome.

The single-group design shapes the interpretation of all comparisons. Dose escalation and expansion cohorts can offer descriptive information, but they do not serve as randomized controls. Apparent differences across groups may reflect who entered each cohort or other differences in care and follow-up. Statistical summaries cannot remove this design limitation unless an appropriate comparative design and analysis are available.

Finally, the distinction between listed outcomes and reported results matters. Response and pharmacokinetic endpoints appear among the planned measures, but outcome names alone do not provide estimates, uncertainty, or analysis methods. In general, transparent reporting of endpoint counts, denominators, uncertainty, missing data, and analysis choices is necessary for readers to judge both the content and the limits of clinical trial evidence.

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 important limitation for interpretation is that the registry record does not report the primary DLT count or its analysis denominator. The enrollment figure cannot replace the endpoint-specific evaluable population. The registry's description of that population is also incomplete: it gives a dose exposure criterion and begins an alternative criterion, but the full text is not reported in the registry record.

The trial has no randomized comparator and is open-label. As a result, safety counts can be described within the listed groups, but comparisons across doses or disease cohorts cannot be interpreted as randomized estimates. The registry does not report methods for adjusting comparisons or information about possible differences among those groups.

The record lists secondary response and pharmacokinetic outcomes but does not report their numerical results or analysis details. It also does not report confidence intervals, missing-data handling, outcome-specific denominators, or methods for time-to-event outcomes. The reason for termination, interim analyses, stopping criteria, and the trial's own sample-size justification are not reported in the registry record. These gaps limit assessment of outcome precision, completeness, and the relationship between the planned and reported study conduct.

Finally, adverse event counts and listed serious-event terms do not identify causality. The record does not provide event-level timing or attribution for the displayed counts, and the serious-event records should not be treated as the DLT endpoint. These limitations mean that the record is informative about study structure and selected descriptive safety information, but insufficient for a full statistical assessment of the primary or secondary outcomes.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Trial to Evaluate the Safety and Pharmacokinetics of HMPL-689 in Patients With Lymphomas — NCT03786926.
• Registry record last updated 2025-06-26; status last verified 2025-06.
• Results first posted 2025-06-26.
• 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

NCT03786926 is a phase 1, open-label, single-group study of daily HMPL-689 in patients with relapsed or refractory lymphoma. It included dose escalation and dose expansion stages, recorded enrollment of 53, and has status terminated. The listed start date is 2019-08-26, and the primary completion date is 2024-06-26.

The primary endpoint was the number of patients with DLTs in dose escalation during the first-cycle assessment window. The endpoint count and its analysis denominator are not reported in the registry record. The record lists secondary response and pharmacokinetic outcomes and descriptive adverse event counts by dose or expansion cohort. It does not report analysis records, numerical results for the secondary outcomes, or the statistical plan needed to interpret those outcomes.