Clinical Study With Blinatumomab in Pediatric and Adolescent Patients With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Clinical Study With Blinatumomab in Pediatric and Adolescent Patients With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (NCT01471782), a na phase 1, phase 2 study. The primary outcome is Phase I: Number of Participants With Dose-limiting Toxicities (DLTs).

2. Clinical Question

The study also aimed to determine a blinatumomab dose and assess whether that dose was effective. The registry record identifies outcomes related to adverse events, drug concentration, response duration, survival, transplantation during remission, anti-blinatumomab antibodies, and cytokine levels. However, the primary endpoint result and efficacy results are not reported in the registry record. The study therefore poses both a dose-evaluation question and broader safety and efficacy questions, but the posted information does not answer them with outcome estimates.

3. Trial Design

This was a multicenter Phase I/II study, with dose evaluation preceding the Phase II part. The registry describes it as single-arm, with no randomized allocation and no masking. Enrollment was 93 participants. The study began in 2012-01, had primary completion in 2014-08, and is listed as completed. The sponsor was Amgen Research (Munich) GmbH.

During treatment, blinatumomab was given as a continuous intravenous infusion at a constant daily flow rate for 4 weeks, followed by a treatment-free interval of 2 weeks. The stated dose range was 5 to 30 µg/m²/day, and each participant could receive up to five cycles. The primary endpoint specifically concerns the Phase I dose-evaluation/escalation population and DLTs during Cycle 1, 28 days. Thus the primary endpoint is not a result for all 93 participants considered as one undifferentiated group.

The registry lists several dose-labelled safety groups, including Phase I groups, a Phase I+II group at 5/15 µg/m²/day, and a Phase I group at 15/30 µg/m²/day. These labels describe the reported safety groupings; they do not make the groups randomized treatment arms. Differences between such groups could reflect how participants entered dose evaluation and the study phases, as well as other factors not reported in the registry record. The record does not report a randomized comparison or a concurrent control group, so these groupings should not be interpreted as controlled contrasts.

The design includes a Phase I dose-finding objective as well as Phase II investigation. The registry record does not report the detailed dose-escalation protocol, the rationale for the enrollment target, or a statistical analysis plan. Although the brief study description refers to assessing effectiveness, the registry information available for this analysis does not report an efficacy estimate or primary endpoint result.

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 Phase 1 part of the study comprised 2 parts: * a dose evaluation/escalation part in patients aged 2 to 17 years to define the recommended phase 2 dose of blinatumomab (4 arms), * a pharmacokinetic (PK) expansion part in patients less than 18 years. The Phase 2 efficacy part enrolled patients at the recommended dose determined in phase 1.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Participants in the Phase 1 dose evaluation/escalation part of the study

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.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Phase I: Number of Participants With Dose-limiting Toxicities (DLTs), measured over Cycle 1, 28 days.

The Phase I primary endpoint is the number of participants with dose-limiting toxicities during Cycle 1, defined as 28 days. A DLT was defined as a study-drug-related adverse event of Grade 3 or higher, subject to stated exceptions. Grade 3 fatigue, headache, insomnia, fever, hypotension, or infection were not considered DLTs. Some laboratory abnormalities of Grade 3 or higher were also excluded when they were not clinically relevant or responded to routine medical management; thrombocytopenia, leukopenia, including neutropenia and lymphopenia, and anemia were specifically not considered DLTs.

Counting DLTs in the initial cycle is used in dose evaluation because the Phase I question is whether toxicity at a dose meets the prespecified rule for selecting a tolerated dose. In this study, the registry definition says the maximum tolerated dose was one or fewer DLTs among 6 participants, or the maximum administered dose. This decision rule is distinct from an estimate of treatment efficacy: it classifies observed toxicity against a dose-selection criterion.

The registry record gives the endpoint definition and timeframe but does not report the number of Phase I participants with DLTs at each dose, whether the rule selected a maximum tolerated dose, or which dose was selected. Therefore, the endpoint's intended interpretation is clear, but its observed result cannot be assessed from the posted registry information.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The posted information supports a limited statistical reading: the study is single-arm, the primary endpoint is a count of participants with DLTs, and safety outcomes are reported as participant counts and selected percentages. The registry does not report analysis entries, inferential estimates, confidence intervals, or a detailed statistical analysis plan. The explanations below describe general statistical concepts and distinguish them from results actually reported for this study.

What does a count endpoint represent?

For a participant-level event outcome, each participant can be classified according to whether the event occurred within the stated observation window. The endpoint count is the number classified as having the event. For this study, the DLT outcome is defined over Cycle 1, 28 days, and the registry specifies which adverse events qualify and which are excluded. The count is not the same as the total number of adverse-event episodes: one participant could have multiple episodes, while the endpoint counts participants meeting the DLT definition.

In general, a count can be interpreted alongside its denominator to describe how many participants experienced the event among those assessed. The registry record does not report the Phase I DLT counts or their denominators by dose, so no DLT proportion or dose-specific uncertainty can be interpreted from the posted information. No such value should be inferred from the overall enrollment or from the separate adverse-event summary.

How does the dose-selection rule work?

The registry defines the maximum tolerated dose (MTD) as one or fewer DLTs among 6 participants, or the maximum administered dose (MAD). This is a decision rule for the Phase I dose-evaluation part. It is not, by itself, an estimate of efficacy, and it does not mean that every participant at the selected dose has the same risk of toxicity. In general, dose-finding rules use observed safety outcomes to guide which dose is considered for further study; the rule and the observed data both matter when interpreting the decision.

In this case, the registry provides the rule but not the dose-level DLT results or the resulting MTD decision. The detailed escalation procedures and any additional decision criteria are not reported in the registry record. It is therefore not possible to reconstruct the dose-selection process from the rule alone.

What would uncertainty estimates add?

In general, a confidence interval describes the range of values reasonably compatible with an estimate under a specified statistical method. For a participant event rate, an interval can convey how much uncertainty remains because only a finite number of participants were observed. Small groups commonly yield imprecise estimates, so a point estimate alone may give an overly definite impression. This is a general statistical consideration, not a reported finding for this study.

No confidence interval for DLTs or the listed serious adverse-event percentages is reported in the registry record. The safety counts and percentages can be quoted as registry summaries, but their precision cannot be quantified from the posted information. The denominator and method underlying the percentages for individual serious adverse-event terms are also not reported.

Why does the single-arm design matter?

In general, randomization helps create groups that can be compared as a basis for estimating the effect of assigning one intervention rather than another. Here, there was no randomized allocation and no separate control group. The dose-labelled groups are not a like-for-like randomized comparison, and contrasts between them could reflect differences in dose, phase, participant selection, or other unreported factors. Their event summaries are descriptive and cannot isolate a treatment effect.

Because this study is single-arm, there is no concurrent control estimate against which to compare the observed safety or efficacy outcomes. General statistical adjustment cannot remove the limitations of an absent control group unless suitable information and an appropriate design are available; such an approach is not described in the registry record.

How should planning calculations be read?

General sample-size calculations describe the size of a future study under specified assumptions; they are not observed results. The registry's planning assumptions describe a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with an effect to detect defined as a stated fraction of the observed effect. These are planning assumptions, not the design description of this single-arm trial. Any resulting sample sizes are planning illustrations, not observed power, and should not be read as evidence that this trial had a particular probability of detecting an effect.

The calculation inputs, effect estimate, and resulting sample sizes are not reported in the registry record. The rationale for the trial's enrollment of 93 participants is also not reported. General power calculations depend on the assumed effect, variability or event frequency, allocation, and analysis method; changing those assumptions changes the planning result. No numerical planning result can therefore be interpreted from the registry information discussed in this analysis.

Finally, the registry record reports no analysis entries. This means that the posted record does not include registered analysis results in the information considered; it does not establish that no analysis was conducted outside the registry. The statistical methods actually used for efficacy and safety analyses, including any modeling, handling of repeated events, or uncertainty estimation, 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("Phase 1: Blinatumomab 5 µg/m²/Day", "Phase 1: Blinatumomab 15 µg/m²/Day", "Phase 1: Blinatumomab 30 µg/m²/Day", "Phase 1: Blinatumomab 15/30 µg/m²/Day")
n      <- c(5, 7, 5, 6)
events <- c(0, 1, 2, 1)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Phase 1: Blinatumomab 5 µg/m²/Day  5  0  0.0  0.0  52.2  0.0  43.4  0.4  45.9
ARM  Phase 1: Blinatumomab 15 µg/m²/Day  7  1  14.3  0.4  57.9  2.6  51.3  3.2  52.7
ARM  Phase 1: Blinatumomab 30 µg/m²/Day  5  2  40.0  5.3  85.3  11.8  76.9  11.8  77.7
ARM  Phase 1: Blinatumomab 15/30 µg/m²/Day  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9

11. Multiplicity, Missing Data and Analysis Populations

The registry lists multiple outcome domains, including DLTs, adverse events, drug concentration, duration of response, overall survival, relapse-free survival, transplantation during remission, anti-blinatumomab antibodies, and cytokine peak levels. Assessing many outcomes can raise multiplicity concerns: in general, the more statistical tests performed, the greater the chance that at least one result appears notable by chance when all null hypotheses are true. A prespecified hierarchy or adjustment can help address this issue, but neither a multiplicity strategy nor a detailed statistical analysis plan is reported in the registry record.

The record identifies ten outcome measures and contains no analysis entries. It does not report which outcomes were formally tested, how many tests were performed, whether any adjustment was used, or which outcomes were designated for confirmatory interpretation. Thus multiplicity handling cannot be evaluated from the posted registry information.

Missing-data methods are also not reported in the registry record. The information does not state how participants who discontinued, missed assessments, or had incomplete follow-up were handled for the listed outcomes. It also does not describe imputation, censoring rules, or sensitivity analyses. These details matter because estimates can depend on which participants contribute data and how incomplete observations are treated.

The analysis populations are not reported in the registry record. In particular, the record does not specify the population used for the primary DLT endpoint, the efficacy outcomes, or the safety summaries beyond the stated at-risk counts. There is no basis to infer whether the analyses used all enrolled participants, participants who received treatment, or another defined group. The Phase I endpoint population is identified as participants in the dose evaluation/escalation part, but the exact analysis set and exclusions are not described.

12. Safety Results

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

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: pyrexia (40.0%), cytokine release syndrome (40.0%), respiratory failure (28.6%), histiocytosis haematophagic (20.0%), cardiac failure (20.0%).

The registry reports 54 participants with serious adverse events among 93 at risk, and 93 participants with other adverse events among 93 at risk. These figures count participants recorded with events, not the total number of event episodes. They do not indicate that each participant experienced only one event, and the same participant may be represented in more than one safety category.

The listed top serious terms are pyrexia (40.0%), cytokine release syndrome (40.0%), respiratory failure (28.6%), histiocytosis haematophagic (20.0%), cardiac failure (20.0%), and colitis (20.0%). The registry record does not report the denominators or calculation details for these term-specific percentages. It also does not provide the event counts underlying them in this summary, or explain whether the terms refer to participants, event episodes, or another summary convention.

The safety groups include different dose and phase labels. Their sizes and descriptions do not support direct causal comparisons because treatment allocation was not randomized and there was no control group. The record does not report deaths in the safety summary. These reported counts and terms are descriptive observations; they do not by themselves establish causation, comparative risk, or the frequency of all possible events.

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

The registry record establishes the study structure and the outcomes the investigators intended to assess. It describes a multicenter, single-arm Phase I/II study in pediatric and adolescent participants with relapsed or refractory B-precursor acute lymphoblastic leukemia. It also gives the Phase I DLT definition, its 28-day Cycle 1 timeframe, and the MTD decision rule. These details explain what the primary dose-evaluation question was.

The record does not report the number of participants with DLTs by dose, whether the MTD rule was met, or the dose selected. It also does not report the primary endpoint result or a posted efficacy result. Accordingly, the registry information does not allow a conclusion about the observed Phase I DLT outcome or the study's efficacy findings. The stated aim to assess efficacy should not be confused with a reported efficacy result.

The safety summary does show that 54 of 93 participants at risk were recorded with serious adverse events and that 93 of 93 were recorded with other adverse events. It also lists selected serious adverse-event terms and percentages. These are descriptive summaries, not controlled comparisons. Without a randomized control group, the study cannot use these data alone to estimate how the event experience differs from an alternative treatment. Nor do the summary counts determine whether an individual event was caused by the study drug.

In general, a result should be interpreted with its endpoint definition, denominator, observation period, and uncertainty in view. Here, some of that context is available for DLTs, but the observed DLT data and uncertainty estimates are not reported. For the selected serious adverse-event terms, the percentage denominators are not reported. The record therefore supports a careful description of the study design and posted safety counts, but not broader claims about comparative safety, efficacy, or the precision of estimates.

The listed survival, response-duration, transplantation, antibody, concentration, and cytokine outcomes indicate additional areas of assessment, not findings. Their numerical results and analysis methods are not reported in the registry record. Missing registry results do not establish that results were not collected or analyzed elsewhere; they mean only that the posted registry information does not provide them.

14. Why This Trial Matters Statistically

This trial illustrates how Phase I dose evaluation and later-phase investigation can be combined within one study while addressing different statistical questions. The Phase I primary endpoint is a participant count tied to a specific DLT definition and a 28-day observation window. Its interpretation depends on the dose-level observations and the stated decision rule, not simply on the total enrollment. Since the registry record does not report those observations, the core dose-finding result cannot be reconstructed from the posted information.

It also demonstrates why a single-arm design constrains interpretation. The study can describe events observed among participants receiving blinatumomab, but its dose-labelled groups do not provide randomized control comparisons. In general, a comparison between groups is most informative when the groups are designed to differ only in the intervention being evaluated. Differences in phase or dose grouping, combined with nonrandom allocation, limit causal interpretation of contrasts.

The safety summary further shows why denominators and definitions matter. Participant counts, event episodes, and term-specific percentages answer different questions. The registry reports the overall at-risk counts and selected percentages but does not report the percentage denominators or all event-level details. Those omissions affect how precisely the summaries can be interpreted and compared.

Finally, this study is a useful example of the distinction between an outcome being named and its result being posted. The registry lists several efficacy and safety outcomes, but their inclusion alone does not provide estimates, confidence intervals, or analysis methods. Statistical interpretation requires the observed values and the analytic context; where those are not reported, the appropriate conclusion is that the registry record leaves the question unanswered.

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 direct limitation for interpretation is that the registry record does not report the primary endpoint result. It gives the Phase I DLT definition and dose-selection rule, but not the number of DLTs at each dose, the dose-level denominators, or the MTD decision. Therefore, the central Phase I question cannot be answered from the posted record.

The study is single-arm, with no randomized allocation or separate control group. As a result, the dose-labelled safety groups cannot be treated as randomized comparison groups. The safety summaries do not estimate relative risk against a control, and the absence of a comparator limits causal conclusions about observed events. The record also does not report the detailed dose-escalation procedures or explain how participants entered each dose group.

The adverse-event information is incomplete for some interpretive purposes. The overall counts for serious and other adverse events are reported, along with selected serious-event percentages, but the percentage denominators and calculation details are not. The registry record does not report the event-level counts, attribution criteria in the safety summary, or a statistical uncertainty estimate. It also does not report deaths in the safety summary.

The registry record does not report efficacy results, detailed statistical methods, analysis populations, missing-data handling, or multiplicity procedures. It also does not report a sample-size justification. These omissions prevent assessment of precision, robustness, and whether analyses followed a prespecified plan. The absence of registry analysis entries should not be interpreted as evidence that no analyses were conducted; it indicates that analysis results are not posted in the registry information considered.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Clinical Study With Blinatumomab in Pediatric and Adolescent Patients With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia — NCT01471782.
• Registry record last updated 2017-02-08; status last verified 2016-12.
• Results first posted 2017-02-08.
• 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

NCT01471782 is a completed, multicenter Phase I/II, single-arm study of blinatumomab in pediatric and adolescent participants with relapsed or refractory B-precursor acute lymphoblastic leukemia. Enrollment was 93. Treatment was administered by continuous intravenous infusion, with doses ranging from 5 to 30 µg/m²/day, and participants could receive up to five cycles.

The Phase I primary endpoint was the number of participants with DLTs in Cycle 1, 28 days. The registry defines the MTD using a rule of one or fewer DLTs among 6 participants, or the MAD, but does not report the observed DLT results or dose selected. Safety summaries report 54 participants with serious adverse events and 93 with other adverse events among 93 at risk. Efficacy results, analysis methods, and uncertainty estimates are not reported in the registry record.