Bortezomib With Chemotherapy for Relapsed Pediatric Acute Lymphoblastic Leukemia (ALL): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Bortezomib With Chemotherapy for Relapsed Pediatric Acute Lymphoblastic Leukemia (ALL) (NCT00440726), a non-randomized phase 1, phase 2 study. The primary outcome is Occurrence of a Dose-Limiting Toxicity (Phase 1).

2. Clinical Question

3. Trial Design

This is a Phase I/II, non-randomized, unmasked study with a sequential model. The registry lists enrollment of 31 and a completed status. The study start is recorded as 2006-08-04, and primary completion as 2011-02-26. The sponsor is the Therapeutic Advances in Childhood Leukemia Consortium.

The Phase 1 portion is described as dose escalation using a 3+3 design. Its intervention combines bortezomib with dexamethasone, PEG-asparaginase, doxorubicin, cytarabine, methotrexate, and vincristine. Triple IT therapy is specified for patients who are CNS 2 or 3 at study entry. The Phase 2 arm description states that participants receive bortezomib at the maximum tolerated dose established in Phase 1, alongside the chemotherapy combination. The description ends before providing further details, so additional Phase 2 procedures are not reported in the registry record.

The adverse-event record lists a 1 mg/m2 dose group with 4 participants at risk and a 1.3 mg/m2 dose group with 27 participants at risk. These groups should not be treated as randomized arms or as a controlled comparison. A sequential dose-escalation study can assign participants to dose cohorts at different stages, and the record explicitly identifies the allocation as non-randomized. The registry record does not report further details on cohort assignment, treatment duration, or the criteria used to select participants for each dose group.

The primary endpoint is dose-limiting toxicity in Phase 1. Although the registry identifies three outcome measures, it records no statistical analyses. It does not report results for the primary endpoint, an efficacy estimate, or a formal comparison between dose groups.

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.

Phase 1

Reasons for not completing this period:

Phase 2

Reasons for not completing this period:

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: 31 unique individual participants were enrolled into the study collectively for both Phase 1 and 2. The breakdown is as follows: 10 in the Phase I study and 21 in the Phase II study. There was, however, one patient that started on Phase I, Cohort 2 that was later eligible and rolled into the Phase II study.

6. Primary Endpoint

The registry lists the primary outcome as Occurrence of a Dose-Limiting Toxicity (Phase 1), measured over Beginning with the first dose of investigational product until 30 days following the last dose of bortezomib.

The primary endpoint is the occurrence of a dose-limiting toxicity among participants in Phase 1. It is measured as a count of participants, rather than as a continuous measurement or a time-to-event estimate. The observation period begins with the first dose of investigational product and continues until 30 days following the last dose of bortezomib.

The registry defines dose-limiting toxicity by specified events considered by the investigator to be possibly, probably, or definitely attributable to bortezomib. The listed events include Grade 3 or 4 sensory neuropathy; Grade 3 or 4 neuropathic pain lasting longer than 24 hours despite medical intervention; marrow hypoplasia continuing 6 weeks from the start of each course with less than 10% cellularity; and Grade 4 non-hematologic toxicity, with stated exclusions. The exclusions include certain infections, fever/neutropenia, fatigue, electrolyte abnormalities, hyperglycemia or hypoglycemia, nausea or vomiting, and specified liver-test elevations that return to grade 1 by the time of the next course.

In an early-phase dose-escalation study, a toxicity endpoint can help describe tolerability at the doses under study and inform dose selection. That is a general statistical purpose, not a claim about what this study found. The registry record does not report how many Phase 1 participants met the dose-limiting toxicity definition, so the endpoint’s observed result cannot be interpreted from the posted record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The study is identified as Phase I/II, non-randomized, unmasked, and sequential. These design features shape which statistical conclusions are possible. In a randomized comparison, assignment is intended to create groups that can support a treatment contrast. Here, the registry explicitly says allocation was non-randomized and notes that the arms are not a like-for-like control comparison. The dose-group counts therefore describe participants in each group; they do not, by themselves, estimate a causal difference between doses.

What does a 3+3 dose-escalation design mean?

As general background, a 3+3 design is a rule-based approach to dose escalation in early-phase research. Participants are assessed for dose-limiting toxicities, and cohort decisions follow prespecified rules. The registry states that the Phase 1 portion used a 3+3 escalation design, but does not report the full decision rules, cohort-by-cohort results, or the observed dose-limiting toxicity counts. The specific escalation pathway and its conclusions are therefore not reported in the registry record.

What does the primary endpoint count?

The endpoint is a count of participants meeting a defined toxicity criterion during a stated follow-up window. The registry describes which adverse events qualify and includes investigator attribution to bortezomib as part of the definition. Counting participants is a binary-outcome approach: each participant is classified according to whether the defined event occurred. General statistical interpretation of such an outcome usually depends on the numerator, denominator, and uncertainty around the resulting estimate. The registry record does not post the primary endpoint counts or an uncertainty interval, so neither an observed rate nor its precision can be assessed.

How should the dose groups be compared?

The groups contain 4 participants at risk in the 1 mg/m2 dose group and 27 in the 1.3 mg/m2 dose group. The unequal group sizes and non-randomized sequential design matter when interpreting the adverse-event summaries. A raw difference between group counts would not account for differences in allocation, follow-up, or participant characteristics. No adjusted comparison is reported, and a formal group comparison should not be inferred from descriptive counts.

What do the planning assumptions mean?

The registry 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. It states that the effect to detect is a stated fraction of the observed effect. For time-to-event outcomes, the illustration concerns a total number of events; for other outcomes, it concerns participants per arm. These are planning assumptions, not evidence that the study enrolled randomized equal-sized groups, and not a report of observed power. No resulting sample-size values are included in the registry record, and the assumptions are not identified as the trial’s own design justification.

Why do uncertainty and over-dispersion matter generally?

General statistical interpretation should consider uncertainty as well as point estimates. A confidence interval describes a range of values compatible with the data and model, rather than certifying a single true value. Small cohorts can yield imprecise estimates, and a count of participants with an event does not by itself convey that uncertainty. For event counts that vary more than a simple model expects, over-dispersion can make standard errors too small if it is ignored. These are general considerations; the registry record does not report confidence intervals, a model for the primary endpoint, or an assessment of over-dispersion.

There are no listed statistical analyses in the registry record. It does not report an analysis model, an estimation procedure, a confidence level for primary outcome inference, or a statistical test. Accordingly, the posted safety counts should be treated as descriptive, and no inferential result can be attributed to the study from this record.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists three outcome measures, but does not report statistical analyses. It does not describe a multiplicity plan, such as how inference would be controlled across outcomes or comparisons. Without such information, the record does not establish whether any formal testing across multiple endpoints was planned or how results would have been interpreted. No multiplicity-adjusted results are posted.

Missing-data methods are not reported in the registry record. The record does not state how incomplete toxicity assessments, withdrawals, missed visits, or missing endpoint information were handled. It also does not provide an accounting of participants with evaluable primary endpoint data. As a result, the posted enrollment and adverse-event group counts cannot establish whether every enrolled participant contributed data to each outcome.

Analysis populations are not reported in the registry record. It does not specify an intention-to-treat, safety, per-protocol, or other analysis set for the primary endpoint or other outcomes. The adverse-event summaries do give participants at risk by dose group, but do not explain the criteria used to define those denominators or whether they differ from the population used for any other outcome.

These omissions limit reproducibility and interpretation. They do not show that analyses or data-handling procedures were absent; they mean those details are not reported in the registry record. No conclusion about the impact of missing data or multiple testing can be made from the posted information alone.

11. 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: infection w/ gr 3/4 anc, blood (29.6%), caecitis (25.0%), febrile neutropenia (25.0%), hyponatremia (25.0%), lipase increased (25.0%).

The serious adverse event figures are presented by dose group. The 1 mg/m2 Dose Group lists 4 participants at risk and 2 affected; the 1.3 mg/m2 Dose Group lists 27 at risk and 17 affected. These figures are participant counts. The record also lists 0 deaths in the 1 mg/m2 group and 5 in the 1.3 mg/m2 group. Attribution of deaths to study treatment is not reported in the registry record.

The serious-event terms are accompanied by percentages: Infection w/ Gr 3/4 ANC, Blood, 29.6%; Caecitis, 25.0%; Febrile neutropenia, 25.0%; Hyponatremia, 25.0%; Lipase increased, 25.0%; and Neutrophil count, 11.1%. The record does not provide denominators or event-level detail for those listed percentages, so they should not be interpreted as comparative rates between dose groups. It is also not reported whether a participant could contribute more than one event term.

As general guidance, serious adverse events are safety summaries, not proof of causation. Here, non-randomized dose assignment, different cohort sizes, and the absence of a reported control group limit comparative interpretation. The figures describe what the registry lists; they do not establish whether the treatment caused an event or whether the groups differed because of dose.

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

The registry record documents a completed Phase I/II study of bortezomib combined with chemotherapy for relapsed or refractory acute lymphoblastic leukemia. It identifies a Phase 1 dose-limiting toxicity endpoint and specifies its follow-up period and event criteria. It also posts descriptive adverse-event counts for two dose groups and lists serious adverse event terms with percentages.

Those details do not amount to a reported primary endpoint result. The record does not give the number of participants with a dose-limiting toxicity, nor does it post a treatment-effect estimate for an efficacy outcome. No statistical analyses are listed. The record therefore cannot establish from the posted results how often the defined primary event occurred, how precisely it was estimated, or whether an efficacy endpoint changed.

The adverse-event counts are informative as descriptions of the recorded safety experience, but they are not a controlled dose comparison. Assignment was non-randomized, the study was sequential, and the groups are not described as like-for-like controls. The event counts and death counts do not by themselves establish treatment causation, comparative safety, or the effect of dose.

The planning assumptions described in the record are illustrations, not observed power and not a substitute for outcome results. They also are not reported as the study’s original design justification. Overall, the posted information supports a description of the design, primary endpoint definition, and selected safety summaries, while leaving key outcome, analysis, and data-handling details unreported. No clinical recommendation follows from these registry entries.

13. Why This Trial Matters Statistically

This study is statistically notable because it combines early-phase dose escalation with a later Phase 2 portion, while the registry identifies the allocation as non-randomized and the model as sequential. That context is essential: dose-cohort summaries can describe observed safety experience, but they do not provide the same kind of controlled treatment contrast as randomized assignment.

The primary endpoint is explicitly tied to dose-limiting toxicity in Phase 1 and has a detailed event definition and observation window. A clearly defined endpoint helps readers understand what the study intended to count. Yet the registry record does not post the endpoint results or statistical analyses. The contrast between a detailed endpoint definition and absent outcome estimates illustrates why design information alone cannot answer the outcome question.

The record also makes the distinction between participant counts and causal comparisons important. Its serious adverse event summaries show counts in groups of different sizes, and the study was not randomized. Without a reported analytic comparison and sufficient context on group assignment, the counts should remain descriptive. The listed planning assumptions likewise need to be kept separate from the trial’s actual observed results; the registry describes a planning illustration, not observed power.

Finally, the omissions around analysis populations, missing data, multiplicity, and uncertainty limit what readers can reproduce or infer. These limitations do not negate the value of a transparent endpoint definition or safety reporting. They define the boundary between what the registry documents and what cannot be concluded from its posted record.

14. Limitations

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

The registry record does not report the primary endpoint result, despite identifying dose-limiting toxicity as the Phase 1 primary outcome. It also records no statistical analyses, so there is no posted model, test, confidence interval, or inferential comparison to evaluate. Efficacy results are not reported in the information described.

Interpretation of the safety summaries is limited by the non-randomized, sequential design and the absence of a like-for-like control group. The dose groups differ in their reported numbers at risk, and the record does not describe cohort assignment in sufficient detail to support a comparative analysis. The serious adverse event term percentages are not accompanied by denominators or event-level information in the record, and attribution of the listed deaths is not reported.

The registry record does not report eligibility details for the primary endpoint population, analysis populations, missing-data handling, follow-up completeness, or how participants with incomplete assessments were treated. It also does not report a multiplicity plan or the full statistical plan. The Phase 2 arm description ends after stating that participants receive bortezomib at the maximum tolerated dose established in Phase 1, leaving further details not reported in the registry record.

These limitations concern the information posted in the registry record. They do not establish that the study team failed to conduct analyses or collect additional data; they mean those details are not reported there. The available record supports design and descriptive safety context, but not a full evaluation of efficacy, primary endpoint frequency, or comparative safety.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Bortezomib With Chemotherapy for Relapsed Pediatric Acute Lymphoblastic Leukemia (ALL) — NCT00440726.
• Registry record last updated 2020-02-19; status last verified 2020-02.
• Results first posted 2020-02-19.
• 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.

18. Record Summary

The registry describes a completed, non-randomized, unmasked, sequential Phase I/II study of bortezomib with chemotherapy for relapsed or refractory acute lymphoblastic leukemia. Enrollment is 31. The Phase 1 portion used a 3+3 dose-escalation design, and the primary endpoint was occurrence of dose-limiting toxicity during the stated observation period.

The record lists 1 mg/m2 and 1.3 mg/m2 dose groups with serious adverse event counts, other adverse event counts, and deaths. It also lists serious adverse event terms with percentages. No primary endpoint results or statistical analyses are reported. The record does not provide a randomized control comparison, analysis populations, missing-data methods, or a multiplicity plan.