This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Open Dose Escalating Trial to Determine the Maximum Tolerated Dose in Paediatric Patients With Advanced Cancers for Whom no Therapy is Known (NCT01971476), a na phase 1 study. The primary outcome is Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD).
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01971476 |
| Phase | Phase 1 |
| Condition | Leukemia, Neoplasms |
| Allocation | Not applicable (single group) |
| Design model | Single Group |
| Masking | None (open label) |
| Enrollment | 22 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Boehringer Ingelheim |
| Results posted | Yes |
2. Clinical Question
Population
Children and adolescents from 2 years to less than 18 years of age with acute leukaemia or an advanced solid tumour for whom no effective treatment was known. The trial description considered the age groups 2 to less than 12 years and 12 to less than 18 years. The primary outcome population was the treated set: participants who received at least 1 dose of trial medication by the clinical cut-off.
Intervention
Volasertib, administered as an intravenous infusion. The trial used dose escalation and listed dose groups of 200 mg/m2 and 250 mg/m2 in both age groups, plus 300 mg/m2 in the younger age group.
Comparator
There was no control group. This was an open, non-controlled, single-group phase I trial, so the listed dose groups are not randomized treatment-versus-control comparisons. Differences between dose groups cannot, by themselves, isolate a treatment effect from differences in participants or other influences.
Primary question
How many participants experienced a dose-limiting toxicity during the first cycle, as defined by the trial, to inform determination of the maximum tolerated dose? The registry record gives the endpoint definition and timeframe of up to 14 days, but the number of participants with DLTs is not reported in the registry record.
The trial also aimed to collect information on safety, tolerability, toxicity, preliminary activity, pharmacokinetics and pharmacodynamics. The registry lists outcomes for safety events, laboratory and cardiac observations, response and survival in leukaemia patients, and volasertib concentrations. These listed objectives describe what the study intended to assess; they do not establish that every result is available in the registry record.
The clinical question is primarily about dose finding and early safety in a paediatric population, rather than a controlled estimate of benefit. With no comparator arm, any response or safety observations would be descriptive of the participants treated at the listed doses. The record does not report a comparative efficacy estimate.
3. Trial Design
This was an open, non-controlled, dose-escalating phase I trial of volasertib. The registry classifies it as a single-group study with no allocation and no masking. The study enrolled 22 participants. Its start date was 2013-10-22, its primary completion date was 2015-06-01, and its status is completed. Boehringer Ingelheim is listed as the sponsor.
The intended population was paediatric patients from 2 years to less than 18 years of age with acute leukaemia or an advanced solid tumour for whom no effective treatment was known. The dose-escalation description separates participants into the age groups 2 to less than 12 years and 12 to less than 18 years. Volasertib was administered by intravenous infusion. The adverse-event listings identify dose groups of 200 mg/m2 and 250 mg/m2 in both age groups, and 300 mg/m2 in the younger age group.
In a dose-escalation study, dose groups are used to examine tolerability at different dose levels and to support a dose-finding decision. This is a general description of the design purpose; the registry record does not report the detailed escalation rules, cohort decision algorithm, or a protocol-defined threshold for selecting the maximum tolerated dose. The record also does not report whether any changes to dose escalation were made during conduct of the trial.
Because the study was open and had no control group, neither participants nor investigators were masked to treatment, and there was no concurrent comparison arm. This design can describe events observed during treatment, but it does not support a like-for-like randomized comparison across dose groups. Group sizes also differ in the posted adverse-event listings, so raw counts should be read in the context of the number at risk in each listed group.
The registry lists 12 outcome measures, including the primary DLT outcome and secondary safety, response, survival and pharmacokinetic outcomes. The detailed analysis plan and the registry record’s full account of how dose escalation informed the final dose decision 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: In the age group 2 to \<12 years, 15 patients were screened, with 3 screen failures. In the age group 12 to \<18 years, 14 patients were screened, with 4 screen failures.
Cohort 1: 2 to <12 Years
| Stage | Volasertib 200 mg/m2 | Volasertib 250 mg/m2 | Volasertib 300 mg/m2 |
|---|---|---|---|
| STARTED | 3 | 3 | 6 |
| COMPLETED | 0 | 0 | 0 |
| NOT COMPLETED | 3 | 3 | 6 |
Reasons for not completing this period:
| Reason | Volasertib 200 mg/m2 | Volasertib 250 mg/m2 | Volasertib 300 mg/m2 |
|---|---|---|---|
| Other not defined | 3 | 3 | 6 |
Cohort 2: 12 to <18 Years
| Stage | Volasertib 200 mg/m2 | Volasertib 250 mg/m2 | Volasertib 300 mg/m2 |
|---|---|---|---|
| STARTED | 6 | 4 | 0 |
| COMPLETED | 0 | 0 | 0 |
| NOT COMPLETED | 6 | 4 | 0 |
Reasons for not completing this period:
| Reason | Volasertib 200 mg/m2 | Volasertib 250 mg/m2 | Volasertib 300 mg/m2 |
|---|---|---|---|
| Other not defined | 6 | 3 | 0 |
| Adverse Event | 0 | 1 | 0 |
Analysis population for the primary outcome, as defined in the registry: Treated Set: The treated set consisted of all patients who have received at least 1 dose of trial medication at the time of clinical cut-off.
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: Treated Set: The treated set consisted of all patients who have received at least 1 dose of trial medication at the time of clinical cut-off. 2 to \<12 years (N=3, 3, 6). 12 to \< 18 years (N=6, 4, 0).
| Characteristic | Unit | Volasertib 200 mg/m2 | Volasertib 250 mg/m2 | Volasertib 300 mg/m2 | Total |
|---|---|---|---|---|---|
| Participants analysed | 9 | 7 | 6 | 22 | |
| Age, Continuous: 2 to <12 years | Years | 7.0 (SD 3.6) | 6.3 (SD 3.1) | 7.0 (SD 3.3) | 6.8 (SD 3.0) |
| Age, Continuous: 12 to <18 years | Years | 14.3 (SD 2.3) | 15.8 (SD 1.5) | NA (SD NA) | 14.9 (SD 2.1) |
| Sex/Gender, Customized: Female (2 to <12 years) | Participants | 1 | 2 | 3 | 6 |
| Sex/Gender, Customized: Male (2 to <12 years) | Participants | 2 | 1 | 3 | 6 |
| Sex/Gender, Customized: Female (12 to <18 years) | Participants | 2 | 0 | 0 | 2 |
| Sex/Gender, Customized: Male (12 to <18 years) | Participants | 4 | 4 | 0 | 8 |
6. Primary Endpoint
The registry lists the primary outcome as Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD), measured over Up to 14 days..
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | Participants |
| Endpoint classification | Binary Endpoint |
The primary endpoint is the number of participants with dose-limiting toxicities in the first cycle, for determination of the maximum tolerated dose. Its stated timeframe is up to 14 days. The endpoint is a count of participants meeting the trial’s DLT definition, rather than a continuous measure of symptom severity or a time-to-event estimate.
The registry defines DLTs as drug-related adverse events of at least CTCAE Grade 3, haematological or nonhaematological, subject to stated exceptions. Reduced blood cell counts without associated clinical complications did not qualify at any grade. Grade 3 febrile neutropenia and Grade 3 infection with neutrophil count <1000/mm3 were exceptions, as was uric acid at Grade 3 or higher. Nausea, vomiting or diarrhoea managed with adequate therapy and recovering to CTCAE Grade 2 or lower also did not qualify.
In general, a first-cycle DLT count is used in dose-finding research because it records whether participants experienced toxicity meeting prespecified criteria during a defined early observation window. The count can help investigators assess tolerability at the doses studied. It is not, on its own, a complete summary of all adverse events, later toxicities, or potential benefit.
The registry record defines the endpoint and the treated set, but does not report the primary endpoint result. It therefore does not establish the observed number of participants with DLTs or the resulting maximum tolerated dose.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The posted record describes a completed, open, non-controlled phase I trial with 22 enrolled participants and an intended dose-finding purpose. The primary outcome is clearly defined as the number of participants with DLTs in the first cycle, but its observed result is not reported in the registry record. Without that count, the registry record does not establish how many participants met the DLT criteria or what maximum tolerated dose was identified.
The adverse-event listings provide counts by age and dose group. In the 2 to <12 Years groups, the serious adverse-event counts are 1 of 3 at 200 mg/m2, 1 of 3 at 250 mg/m2, and 5 of 6 at 300 mg/m2. The pooled total for that age group is 7 of 12. In the 12 to <18 Years groups, the serious adverse-event counts are 6 of 6 at 200 mg/m2 and 4 of 4 at 250 mg/m2, with a pooled total of 10 of 10. These are descriptive counts in small groups; they are not controlled estimates of differences between dose levels.
The registry also lists participants with other adverse events by dose group. In the younger age group, the corresponding counts are 3 of 3 at 200 mg/m2, 3 of 3 at 250 mg/m2, and 6 of 6 at 300 mg/m2, with a pooled total of 12 of 12. In the older age group, the counts are 6 of 6 at 200 mg/m2 and 3 of 4 at 250 mg/m2, with a pooled total of 9 of 10. These counts should not be combined with serious adverse-event counts or treated as mutually exclusive categories unless the registry defines them that way; the record does not provide further detail about event overlap in these listings.
The registry identifies febrile neutropenia and headache as serious adverse-event terms each reported as 50.0%; malignant neoplasm progression, dyspnoea and asthenia are each listed as 33.3%; and myalgia is listed as 25.0%. The record does not give additional context in the listed terms to support causal attribution or a comparison with an untreated group. Serious-event listings describe what was recorded, not whether volasertib caused an event.
In general, counts in small dose cohorts are sensitive to the experience of each participant and are imprecise as estimates of event frequency in a broader population. The unequal group sizes and absence of randomization further limit comparisons across listed doses. The registry provides no confidence intervals or formal comparative analyses. No efficacy conclusion can be drawn from the endpoint definitions or safety counts; although response and survival outcomes are listed for leukaemia patients, their results are not reported in the registry record.
9. Statistical Methods Explained
What the design can answer. A phase I dose-escalation study is generally intended to characterize tolerability and support dose selection, rather than to make a definitive comparative efficacy assessment. This trial had an open, non-controlled, single-group design. In general, open treatment means that treatment assignment is not masked, and a non-controlled design lacks a concurrent control group. The record does not report the detailed dose-escalation algorithm, rules for enrolling additional participants at a dose, or the statistical procedure used to select the maximum tolerated dose. Those details should not be inferred from the dose groups alone.
How to read the primary outcome. The primary outcome is a count of participants with DLTs in the first cycle, within a timeframe of up to 14 days. A participant is counted according to the DLT definition, which is based on drug-related adverse events at or above the stated CTCAE severity threshold, with specified exceptions. In general, a count is straightforward to interpret as the number meeting a definition, but its meaning depends on the event criteria, observation window and population included. The registry record reports the definition and treated-set description, but not the resulting count.
Why the DLT definition matters. Toxicity criteria determine which events contribute to a dose-finding endpoint. The listed exceptions mean that not every event of a given grade automatically qualifies. For example, the endpoint excludes some blood-count changes and specified events, and it treats managed nausea, vomiting or diarrhoea according to recovery to the stated grade. These rules distinguish DLTs from the broader set of adverse events. In general, a DLT count should not be read as a count of all treatment-emergent events or as a summary of every clinically relevant harm.
Counts, denominators and uncertainty. The serious adverse-event listings give counts and numbers at risk for each age-and-dose group, alongside pooled totals. In general, a count should be interpreted with its denominator: the same count can convey different information in groups of different sizes. Small denominators also make group-level proportions unstable, so a small change in observed participants could materially alter a proportion. The registry record does not post confidence intervals for these adverse-event counts. A confidence interval, in general, describes a range of values compatible with the data under a specified statistical method; it does not remove limitations caused by study design or small groups.
Why dose groups are not a causal comparison. The listed groups are not randomized arms in a controlled trial. In general, dose-escalation cohorts can differ in age, disease characteristics, timing of enrolment and other factors. A difference in event counts across groups therefore cannot be attributed to dose alone on the basis of these listings. Pooling within an age group can describe the combined listed experience, but it does not create a randomized comparison or account for differences among dose cohorts. The registry record does not report adjusted estimates for dose-group contrasts.
General statistical concepts. A standard error reflects sampling variability in an estimate; it tends to be larger when information is limited. A confidence interval expresses uncertainty around an estimate and is useful alongside the point estimate, especially when interpreting sparse event data. For binary outcomes, methods may be chosen to account for small counts, but the specific method used for the posted adverse-event summaries is not reported in the registry record. No formal analysis results are listed, and no p-values or confidence intervals are reported for the outcomes described in the record.
Planning illustrations. Any sample-size illustration based on an observed effect is a planning exercise, not observed power and not the trial’s original design justification. The record’s stated illustration assumptions include a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect defined as a fraction of the observed effect. In general, such an illustration depends on its assumptions and the effect used as its reference. It should not be confused with the single-group dose-escalation design, and it does not show that the trial had a particular probability of detecting an effect. The trial’s own sample-size justification is not reported in the registry record.
What is not available. The registry record lists no analyses, and it does not report the analysis methods for the primary endpoint or the other outcomes. It does not give the number of participants with primary-outcome DLTs, a maximum tolerated dose result, or formal uncertainty estimates. These omissions constrain interpretation: the design and endpoint definition can be described, but the dose-finding result cannot be reconstructed from the posted information.
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.
| Arm | Participants | Events | Observed % | Clopper-Pearson 95% CI | Wilson 95% CI | Bayesian 95% credible interval |
|---|---|---|---|---|---|---|
| 2 to <12 Years: Volasertib 200 mg/m2 | 3 | 0 | 0.0% | 0.0% to 70.8% | 0.0% to 56.1% | 0.6% to 60.2% |
| 2 to <12 Years: Volasertib 250 mg/m2 | 3 | 0 | 0.0% | 0.0% to 70.8% | 0.0% to 56.1% | 0.6% to 60.2% |
| 2 to <12 Years: Volasertib 300 mg/m2 | 6 | 0 | 0.0% | 0.0% to 45.9% | 0.0% to 39.0% | 0.4% to 41.0% |
| 12 to <18 Years: Volasertib 200 mg/m2 | 6 | 0 | 0.0% | 0.0% to 45.9% | 0.0% to 39.0% | 0.4% to 41.0% |
| 12 to <18 Years: Volasertib 250 mg/m2 | 4 | 2 | 50.0% | 6.8% to 93.2% | 15.0% to 85.0% | 14.7% to 85.3% |
R code and output
arm <- c("2 to <12 Years: Volasertib 200 mg/m2", "2 to <12 Years: Volasertib 250 mg/m2", "2 to <12 Years: Volasertib 300 mg/m2", "12 to <18 Years: Volasertib 200 mg/m2", "12 to <18 Years: Volasertib 250 mg/m2")
n <- c(3, 3, 6, 6, 4)
events <- c(0, 0, 0, 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 2 to <12 Years: Volasertib 200 mg/m2 3 0 0.0 0.0 70.8 0.0 56.1 0.6 60.2
ARM 2 to <12 Years: Volasertib 250 mg/m2 3 0 0.0 0.0 70.8 0.0 56.1 0.6 60.2
ARM 2 to <12 Years: Volasertib 300 mg/m2 6 0 0.0 0.0 45.9 0.0 39.0 0.4 41.0
ARM 12 to <18 Years: Volasertib 200 mg/m2 6 0 0.0 0.0 45.9 0.0 39.0 0.4 41.0
ARM 12 to <18 Years: Volasertib 250 mg/m2 4 2 50.0 6.8 93.2 15.0 85.0 14.7 85.311. Multiplicity, Missing Data and Analysis Populations
The registry lists 12 outcome measures, including the primary DLT outcome and secondary outcomes covering safety, laboratory changes, cardiac observations, response and survival in leukaemia patients, and pharmacokinetic measures. It reports no analyses. The registry record does not state whether the trial used a prespecified hierarchy among secondary outcomes, adjusted for multiple testing, or treated secondary analyses as exploratory. Because many outcomes are listed, isolated findings across them would generally need to be interpreted in light of multiplicity; the record does not provide a statistical plan that clarifies this issue.
The record defines the primary analysis population as the treated set: all patients who received at least 1 dose of trial medication by the clinical cut-off. It does not report how many participants were included in this population for each outcome, whether any participants were excluded from particular analyses, or how the analysis population related to the enrolled total of 22.
Missing-data handling is not reported in the registry record. In general, incomplete outcome information can affect estimates if the likelihood of missingness is related to the outcome, treatment exposure or participant characteristics. The record does not describe imputation, censoring rules, follow-up completeness, or sensitivity analyses for missing observations. It also does not report whether participants who stopped treatment early were followed for the endpoint timeframe or other outcomes.
These gaps matter because outcome definitions alone do not specify how incomplete observations were handled or which participants contributed to each result. With no posted analyses and no reported primary result, the record supports description of the planned endpoint and population definition, but not an assessment of the analysis choices or their effect on the findings.
12. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| 2 to <12 Years: Volasertib 200 mg/m2 | 1 | 3 | 33.3% |
| 2 to <12 Years: Volasertib 250 mg/m2 | 1 | 3 | 33.3% |
| 2 to <12 Years: Volasertib 300 mg/m2 | 5 | 6 | 83.3% |
| 2 to <12 Years: Volasertib Pooled Total | 7 | 12 | 58.3% |
| 12 to <18 Years: Volasertib 200 mg/m2 | 6 | 6 | 100.0% |
| 12 to <18 Years: Volasertib 250 mg/m2 | 4 | 4 | 100.0% |
| 12 to <18 Years: Volasertib Pooled Total | 10 | 10 | 100.0% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| 2 to <12 Years: Volasertib 200 mg/m2 | 3 of 3 |
| 2 to <12 Years: Volasertib 250 mg/m2 | 3 of 3 |
| 2 to <12 Years: Volasertib 300 mg/m2 | 6 of 6 |
| 2 to <12 Years: Volasertib Pooled Total | 12 of 12 |
| 12 to <18 Years: Volasertib 200 mg/m2 | 6 of 6 |
| 12 to <18 Years: Volasertib 250 mg/m2 | 3 of 4 |
Most frequent serious adverse event terms
| Event term | Organ system | 2 to <12 Years: Volasertib 200 mg/m2 | 2 to <12 Years: Volasertib 250 mg/m2 | 2 to <12 Years: Volasertib 300 mg/m2 | 2 to <12 Years: Volasertib Pooled Total | 12 to <18 Years: Volasertib 200 mg/m2 | 12 to <18 Years: Volasertib 250 mg/m2 |
|---|---|---|---|---|---|---|---|
| Febrile neutropenia | Blood and lymphatic system disorders | 1 of 3 | 1 of 3 | 3 of 6 | 5 of 12 | 2 of 6 | 2 of 4 |
| Malignant neoplasm progression | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 0 of 3 | 0 of 3 | 2 of 6 | 2 of 12 | 1 of 6 | 0 of 4 |
| Leukopenia | Blood and lymphatic system disorders | 0 of 3 | 0 of 3 | 1 of 6 | 1 of 12 | 0 of 6 | 1 of 4 |
| Thrombocytopenia | Blood and lymphatic system disorders | 0 of 3 | 0 of 3 | 1 of 6 | 1 of 12 | 0 of 6 | 1 of 4 |
| Asthenia | General disorders | 0 of 3 | 1 of 3 | 0 of 6 | 1 of 12 | 0 of 6 | 1 of 4 |
| Pneumonia | Respiratory, thoracic and mediastinal disorders | 0 of 3 | 0 of 3 | 1 of 6 | 1 of 12 | 0 of 6 | 0 of 4 |
| Bone marrow toxicity | Blood and lymphatic system disorders | 0 of 3 | 0 of 3 | 1 of 6 | 1 of 12 | 0 of 6 | 0 of 4 |
| Neutropenia | Blood and lymphatic system disorders | 0 of 3 | 0 of 3 | 1 of 6 | 1 of 12 | 0 of 6 | 0 of 4 |
| Headache | Nervous system disorders | 0 of 3 | 0 of 3 | 0 of 6 | 0 of 12 | 0 of 6 | 2 of 4 |
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | 0 of 3 | 1 of 3 | 0 of 6 | 1 of 12 | 0 of 6 | 0 of 4 |
Most frequent non-serious adverse event terms
| Event term | Organ system | 2 to <12 Years: Volasertib 200 mg/m2 | 2 to <12 Years: Volasertib 250 mg/m2 | 2 to <12 Years: Volasertib 300 mg/m2 | 2 to <12 Years: Volasertib Pooled Total | 12 to <18 Years: Volasertib 200 mg/m2 | 12 to <18 Years: Volasertib 250 mg/m2 |
|---|---|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | 1 of 3 | 2 of 3 | 3 of 6 | 6 of 12 | 2 of 6 | 1 of 4 |
| Neutropenia | Blood and lymphatic system disorders | 1 of 3 | 0 of 3 | 3 of 6 | 4 of 12 | 3 of 6 | 1 of 4 |
| Thrombocytopenia | Blood and lymphatic system disorders | 0 of 3 | 2 of 3 | 1 of 6 | 3 of 12 | 3 of 6 | 1 of 4 |
| Vomiting | Gastrointestinal disorders | 1 of 3 | 0 of 3 | 2 of 6 | 3 of 12 | 2 of 6 | 2 of 4 |
| Abdominal pain | Gastrointestinal disorders | 0 of 3 | 1 of 3 | 2 of 6 | 3 of 12 | 2 of 6 | 0 of 4 |
| Nausea | Gastrointestinal disorders | 1 of 3 | 0 of 3 | 1 of 6 | 2 of 12 | 2 of 6 | 2 of 4 |
| Fatigue | General disorders | 1 of 3 | 0 of 3 | 1 of 6 | 2 of 12 | 1 of 6 | 2 of 4 |
| Lymphocyte count decreased | Investigations | 1 of 3 | 0 of 3 | 1 of 6 | 2 of 12 | 1 of 6 | 1 of 4 |
| Platelet count decreased | Investigations | 1 of 3 | 0 of 3 | 1 of 6 | 2 of 12 | 1 of 6 | 1 of 4 |
| White blood cell count decreased | Investigations | 1 of 3 | 0 of 3 | 1 of 6 | 2 of 12 | 1 of 6 | 1 of 4 |
Serious events with the highest arm-level rate: febrile neutropenia (50.0%), headache (50.0%), malignant neoplasm progression (33.3%), dyspnoea (33.3%), asthenia (33.3%).
The registry’s serious adverse-event listings are organized by age group and volasertib dose. For each group, the counts show participants affected and participants at risk; pooled totals are also listed within age groups. In the younger age group, the pooled serious-event count is 7 of 12, and in the older age group it is 10 of 10. The dose-specific counts are 1 of 3, 1 of 3 and 5 of 6 for the younger age group at 200 mg/m2, 250 mg/m2 and 300 mg/m2, respectively; for the older age group they are 6 of 6 at 200 mg/m2 and 4 of 4 at 250 mg/m2.
These are counts of participants, not counts of individual events. A participant may have experienced more than one event, and the registry record does not explain event overlap in the listed summaries. The pooled totals summarize the age-group listings; they should not be treated as an independent set of participants in addition to the dose-specific groups.
The listed serious adverse-event terms include febrile neutropenia and headache at 50.0% each, malignant neoplasm progression, dyspnoea and asthenia at 33.3% each, and myalgia at 25.0%. These percentages are reproduced as listed, without an assumed denominator beyond the registry’s term listing. The record does not give enough detail in that listing to establish causation or compare event risk with an untreated group.
In general, adverse-event counts describe recorded safety observations and do not by themselves determine whether an event was caused by treatment. The small group sizes, lack of a control group, and absence of confidence intervals or comparative analyses limit interpretation of differences across doses.
13. What the Result Does, and Does Not, Mean
The registry record establishes that the study was designed as an open, non-controlled phase I dose-escalation trial of intravenous volasertib in paediatric patients with acute leukaemia or advanced solid tumours. It identifies the primary dose-finding outcome, defines the DLT criteria, describes the treated set and lists adverse-event observations by age and dose. These details make the intended safety question understandable.
The record does not report the observed number of participants with DLTs in the first cycle. It therefore does not establish the maximum tolerated dose, even though determination of that dose was the stated primary purpose. It also does not report outcome analyses for response, event-free survival, overall survival or pharmacokinetic measures. Their presence as listed outcome measures is not evidence of a particular result.
The adverse-event counts show that serious events were recorded among participants in the listed groups. They are descriptive observations in a small, non-randomized study. They cannot establish that volasertib caused each event, quantify how the event rate would compare with no treatment, or demonstrate that one dose is safer than another. The listed age and dose groups may differ in ways that the posted summaries do not address.
In general, a phase I safety and dose-finding study can provide early information about treatment exposure and tolerability in the participants studied. It is not normally designed to provide a definitive estimate of clinical benefit. Here, the absence of a control group and the absence of reported primary and efficacy results further limit what can be concluded from the registry record.
Accordingly, the posted information supports an account of the study design and selected safety counts, but not a conclusion about treatment efficacy, the final dose decision, or comparative safety. Unreported outcomes should remain unknown rather than being inferred from the study’s aims or adverse-event listings.
14. Why This Trial Matters Statistically
This trial illustrates why the statistical question in a phase I study differs from the question in a controlled efficacy trial. The primary purpose was dose finding, and the primary endpoint was a count of participants meeting a defined DLT criterion during the first cycle. The quality of interpretation depends on both the event definition and the time window, not simply on the count of all adverse events.
The design also demonstrates the importance of distinguishing dose cohorts from randomized comparison groups. The listed groups differ in age and dose and do not include a control arm. Their event counts can describe the observed experience in each cohort, but they cannot isolate dose effects from other differences between participants. Pooled age-group counts are descriptive summaries, not a substitute for a controlled contrast.
The record’s missing primary outcome result is statistically consequential. A well-defined estimand or endpoint cannot answer a clinical question if the observed result and its uncertainty are not posted. The DLT definition, enrollment information and safety listings provide context, but they do not allow readers to reconstruct the maximum tolerated dose decision.
More broadly, the record highlights why analysis populations, missing-data rules, multiplicity procedures and uncertainty estimates matter. Those details help readers understand which observations contributed to an estimate and how robust it may be. They are not reported in the registry record for the analyses. For small dose cohorts, presenting counts with clear denominators and appropriate uncertainty is especially useful, while still recognizing the limits of a non-controlled design.
The trial therefore offers a practical lesson in separating design intent from reported evidence: dose-finding objectives describe what investigators sought to learn, whereas conclusions require posted results and transparent analysis methods.
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 main limitation for interpreting the primary question is that the number of participants with DLTs is not reported in the registry record. The maximum tolerated dose result is also not reported. The registry therefore does not allow assessment of the primary dose-finding outcome, regardless of the detail in the endpoint definition.
The study was open, non-controlled and single-group. There was no randomized comparator to help distinguish treatment-related events from events associated with underlying cancer, disease progression or other causes. The posted dose groups are not like-for-like controlled comparisons, and their small sizes limit precision. The registry reports counts but no confidence intervals or formal comparisons for the adverse-event summaries.
The record lists 12 outcome measures but no analyses. It does not report the statistical analysis plan, dose-escalation decision rules, sample-size justification, handling of missing data, outcome-specific analysis populations, multiplicity approach, or sensitivity analyses. These omissions make it difficult to assess how the posted outcomes were analyzed or whether selective reporting could affect interpretation.
The adverse-event listings identify serious events and selected terms, but the record does not provide the full clinical context needed to assess causality, event overlap, timing, duration or relationship to dose. A participant-level account is not reported. The listed response, survival and pharmacokinetic outcomes do not have results in the registry record, so they cannot be used to evaluate preliminary activity or exposure-response patterns.
These limitations are specific to the information posted for this trial. They do not establish that analyses or additional information do not exist elsewhere; they mean those details are not reported in the registry record and cannot be used in interpreting the posted results.
16. Related Tutorials
17. Related Statistical Calculators
18. Sources
- ClinicalTrials.gov: Open Dose Escalating Trial to Determine the Maximum Tolerated Dose in Paediatric Patients With Advanced Cancers for Whom no Therapy is Known — NCT01971476.
- Registry record last updated 2018-07-30; status last verified 2017-10.
- Results first posted 2018-07-30.
- 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.
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19. Record Summary
This completed phase I trial evaluated dose escalation of intravenous volasertib in paediatric patients from 2 years to less than 18 years of age with acute leukaemia or advanced solid tumours. It was open, non-controlled and single-group, with 22 participants enrolled. The primary outcome was the number of participants with DLTs in the first cycle, defined using CTCAE criteria and specified exceptions, with a timeframe of up to 14 days.
The registry lists adverse-event counts by age and dose group, along with secondary outcomes for safety, response, survival and pharmacokinetics. The primary DLT result, maximum tolerated dose, and analyses for the listed outcomes are not reported in the registry record. The posted safety counts are descriptive and do not provide a controlled comparison or establish causality.