Blinatumomab in Combination With AMG 404 for the Treatment of Adults With Relapsed or Refractory B Cell Precursor ALL: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Blinatumomab in Combination With AMG 404 for the Treatment of Adults With Relapsed or Refractory B Cell Precursor ALL (NCT04524455), a na phase 1 study. The primary outcome is Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs).

2. Clinical Question

This is a dose-finding question rather than a randomized comparison of treatments. Investigators assessed whether adverse events met protocol-defined criteria for dose-limiting toxicity (DLT). The primary endpoint is a count of participants with a DLT, not a measure of how long participants lived, how long remission lasted, or whether the combination outperformed another regimen.

The registry also lists secondary outcomes concerning remission, remission duration, and drug concentrations. Those outcomes indicate areas the study intended to assess, but their results are not reported in the registry record. The stated primary objective centers on safety, tolerability, and dose selection. The record does not report the observed DLT count or a selected maximum tolerated dose or recommended phase 2 dose.

3. Trial Design

The registry describes a completed, open-label phase 1b study with a single-group model. Enrollment is listed as 17. The study began on 2020-10-02, and primary completion is listed as 2023-01-24. The two dose cohorts described in the safety information received blinatumomab with AMG 404 at 240 mg or 480 mg. The registry does not describe these cohorts as randomized groups, and allocation is listed as not applicable.

Participants and investigators were not masked. The record therefore describes an open-label study, not a blinded trial. Its purpose was to evaluate safety and tolerability and estimate the maximum tolerated dose and recommended phase 2 dose of AMG 404 when combined with continuous intravenous infusion of blinatumomab. Dexamethasone premedication is listed as an intervention, but its timing and regimen are not reported in the registry record.

The primary endpoint is the number of participants experiencing DLTs. The DLT assessment window is listed as up to 67 days for Cohort 1 and up to 56 days for Cohort 2a. The endpoint description says investigators applied protocol-defined criteria to adverse events. The record does not provide the full protocol criteria, and the DLT result itself is not reported.

Secondary outcomes listed include complete remission, complete remission with partial hematological recovery, duration of remission, and pharmacokinetic measures for both drugs. The registry record does not report results for these outcomes. It also does not report a statistical analysis plan or analysis records. The design and available results therefore support describing the study’s aims and the safety figures recorded for the cohorts, but not drawing treatment-effect comparisons or summarizing efficacy findings.

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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: DLT Analysis Set: included DLT-evaluable participants in the Safety Analysis Set. A participant was DLT-evaluable if the participant had completed DLT-evaluable period which begins with the first AMG 404 dose and includes 28 days after the second AMG 404 dose is administered or experienced a DLT any time during the DLT-evaluable 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: All enrolled participants.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs), measured over Cohort 1: Up to 67 days; Cohort 2a: Up to 56 days.

The primary endpoint is the number of participants who experienced dose-limiting toxicities. A DLT is not simply any adverse event: investigators were to determine whether an event met the protocol-defined DLT criteria. The registry defines an adverse event as an untoward medical occurrence, regardless of whether it was considered causally related to study treatment. The full DLT criteria are not reported in the registry record.

In general, early-phase dose-finding studies use DLT assessments to help characterize tolerability at tested doses and inform dose selection for later study. This endpoint is a count of participants, rather than an event rate calculated from person-time or a comparison with a control treatment. The assessment periods differ by cohort: up to 67 days for Cohort 1 and up to 56 days for Cohort 2a.

The registry defines a DLT-evaluable participant as someone in the Safety Analysis Set who completed the DLT-evaluable period, which begins with the first AMG 404 dose and includes 28 days after the second AMG 404 dose, or who experienced a DLT. The available description ends before completing the eligibility definition, so the full population rule is not reported in the registry record. Most importantly, the observed primary endpoint count is not reported. The endpoint’s purpose and assessment window can be described, but the registry record does not establish how many participants met the DLT criteria.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies the primary outcome as a count: the number of participants who experienced DLTs. A count answers how many participants had the defined event, rather than estimating an average change or a time-to-event contrast. However, the observed count is not reported in the registry record. The endpoint definition and its cohort-specific assessment windows are available, but the result needed to describe the primary finding is absent.

What does a DLT assessment mean?

Investigators were to judge whether an adverse event met protocol-defined DLT criteria. The registry defines an adverse event broadly as an untoward medical occurrence, without requiring that it be caused by study treatment. DLT status is narrower: it depends on the prespecified criteria. In general, this distinction matters because safety summaries may include events that are not DLTs, while a DLT count includes only events meeting the protocol definition. The registry record does not give the full criteria or the observed DLT count.

The listed assessment periods are up to 67 days for Cohort 1 and up to 56 days for Cohort 2a. The record also describes the DLT-evaluable period as beginning with the first AMG 404 dose and extending through 28 days after the second AMG 404 dose, with an exception for participants who experience a DLT. The eligibility description is truncated before its full rule is stated. This means the precise handling of participants who did not complete the assessment period cannot be reconstructed from the registry record.

Why is the design not a treatment comparison?

The trial is described as open-label, with allocation listed as not applicable and a single-group model. The safety information separates participants into cohorts receiving AMG 404 at 240 mg or 480 mg alongside blinatumomab. These are dose cohorts within an early-phase study, not randomized groups with a control treatment. In general, randomization helps balance measured and unmeasured factors between groups; without it, differences in participant characteristics, follow-up, or treatment exposure can contribute to observed differences. The registry explicitly notes that the arms are not a like-for-like control comparison.

Consequently, a difference between the cohort safety figures cannot by itself establish a dose-related causal effect. The record does not report an adjusted comparison, a statistical test, or an analysis plan that would support such an inference. Nor does the absence of a reported difference mean the doses have equivalent safety. The data can be read descriptively, with the design limitations kept in view.

How should uncertainty be considered?

In general, a confidence interval expresses the range of values compatible with the data under a specified statistical method. Wider intervals indicate less precision. The registry record does not report confidence intervals for the safety figures or the primary endpoint, so there is no reported interval with which to assess their precision. No confidence limits should be inferred from the counts alone in this explanation.

For counts or proportions from small cohorts, observed values can vary substantially across studies. In general, that variability makes a descriptive result useful for identifying safety signals and informing further study, but insufficient on its own to estimate a stable frequency or comparative treatment effect. No unadjusted recalculation is presented: the primary DLT result is absent, and there is no randomized comparator for an effect estimate.

What do the planning illustrations represent?

In general, a sample-size calculation asks how many participants a future study might need under specified assumptions about the target effect, significance level, allocation, and statistical model. It is a planning exercise, not a result observed in the current trial. The registry record describes planning assumptions for illustrations, including a two-sided significance level of 0.05, equal allocation, and a normal approximation. Those assumptions do not establish that the current study was designed or powered for a particular comparison. The record does not report a sample-size justification or a statistical plan for the trial. Any planning illustration based on an observed effect should not be interpreted as observed power or as evidence that the current trial demonstrated that effect.

Finally, the registry lists twelve outcome measures and zero analysis records. The outcome list alone does not reveal which analyses were conducted, how they were specified, or what their findings were. The listed remission and pharmacokinetic measures therefore describe planned or registered outcomes, not results that can be interpreted from the 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("Cohort 1: Blinatumomab + AMG 404 (240 mg)", "Cohort 2a: Blinatumomab + AMG 404 (480 mg)")
n      <- c(3, 7)
events <- c(0, 0)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Cohort 1: Blinatumomab + AMG 404 (240 mg)  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Cohort 2a: Blinatumomab + AMG 404 (480 mg)  7  0  0.0  0.0  41.0  0.0  35.4  0.3  36.9

11. Multiplicity, Missing Data and Analysis Populations

The registry lists multiple secondary outcomes, covering remission, remission duration, and pharmacokinetic measures, in addition to the primary DLT count. It does not report analysis records or a statistical analysis plan. The approach to multiple testing, including whether any adjustment was planned, is not reported in the registry record. Without that information and without outcome results, the chance of false-positive findings across multiple analyses cannot be evaluated.

Missing-data handling is also not reported in the registry record. The DLT population description specifies that participants were DLT-evaluable if they completed the assessment period or experienced a DLT, but the available definition is incomplete. The record does not explain how participants who discontinued, missed assessments, or otherwise had incomplete follow-up were handled beyond that stated rule. No missingness counts or reasons are reported.

The record distinguishes a Safety Analysis Set from the DLT-evaluable population, but it does not report full analysis-population counts or the complete population definitions. It is therefore not possible to determine whether all enrolled participants contributed to each outcome or to reconcile the listed enrollment figure with the cohort-specific safety figures. The registry also does not report an analysis population for the secondary outcomes. These omissions limit interpretation of both the denominator and the completeness of outcome reporting.

In general, prespecified rules for multiplicity, missing data, and analysis populations help readers judge how reliably estimates reflect the planned analysis. Since these details are not reported, no assumptions about them should be made.

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: cytokine release syndrome (25.0%), febrile neutropenia (12.5%), leukocytosis (12.5%), lymphopenia (12.5%), atrial flutter (12.5%).

The registry records serious adverse events for 6 of 8 participants in Cohort 1 and 7 of 8 in Cohort 2a. Other adverse events are recorded for 8 of 8 participants in each cohort. Deaths are recorded as 3 in each cohort. These are descriptive figures, not evidence that blinatumomab, AMG 404, or their combination caused the events. The record defines adverse events irrespective of a causal relationship with treatment.

The serious-event terms listed are cytokine release syndrome at 25.0%; febrile neutropenia, leukocytosis, lymphopenia, atrial flutter, and cardiac arrest at 12.5% each. The record does not provide additional detail in the registry record about event timing, severity grading, attribution, or overlap among participants. The term percentages should not be added together or treated as mutually exclusive categories.

These cohort figures do not support a controlled comparison. The study was not randomized, and the dose cohorts are not like-for-like controls. Small cohort figures are descriptive and may be imprecise; confidence intervals are not reported in the registry record. The listed serious events warrant careful clinical interpretation, but these registry figures alone do not establish comparative risk or causation.

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

The registry record establishes that a completed phase 1b study investigated blinatumomab with AMG 404 in adults with relapsed or refractory B-cell precursor ALL. Its stated primary purpose was to evaluate safety and tolerability and estimate the maximum tolerated dose and recommended phase 2 dose of AMG 404 in combination with continuous intravenous infusion of blinatumomab. The record also lists safety figures for cohorts receiving AMG 404 at 240 mg and 480 mg.

It does not report the primary DLT count, a selected maximum tolerated dose, or a recommended phase 2 dose. It also does not report findings for the listed remission or pharmacokinetic outcomes. As a result, the registry information cannot establish how often participants achieved remission, how long remission lasted, or what drug concentration measurements showed. A completed status does not fill in these missing results.

The serious adverse event figures describe occurrences recorded in the two cohorts. They do not show that treatment caused the events, and they do not provide a randomized comparison of doses. The registry’s adverse-event definition includes medical occurrences regardless of causal relationship to treatment. The cohort data should therefore be interpreted as descriptive safety information, not as a comparative estimate of harm.

In general, an early-phase, nonrandomized study can provide information relevant to safety assessment and future study planning, but its results do not by themselves establish comparative efficacy or safety. Here, interpretation is further restricted because the primary endpoint result and statistical analysis details are not reported in the registry record. The available information supports describing the study’s question and registered safety data, not claiming that the combination is effective, ineffective, safe, or unsafe.

14. Why This Trial Matters Statistically

This study is statistically important as an example of a question that differs from a conventional treatment-effect comparison. The stated objective was to examine safety and tolerability and estimate a dose for later study, rather than to test a treatment against a randomized control. Its primary outcome was a count of participants with DLTs, judged using protocol criteria. Such an endpoint is closely tied to the dose-finding purpose, but its value depends on knowing both the definition and the observed result.

The record gives the DLT assessment windows and describes the DLT-evaluable population, making clear that endpoint interpretation depends on a defined follow-up period and eligibility rule. However, the primary count is not reported and the population definition is incomplete. This illustrates why a registry entry’s outcome description is not a substitute for a reported result.

The two dose cohorts also illustrate an important comparison issue. Different doses may be of interest in dose selection, but cohorts in a nonrandomized, open-label study do not automatically form a controlled comparison. In general, differences in observed outcomes can reflect factors other than dose. The design should be interpreted according to its stated purpose, without treating cohort contrasts as causal effects.

Finally, the registry lists safety, remission, and pharmacokinetic outcomes, yet provides no analysis records. The distinction between registered outcomes and reported findings is essential for transparent evidence assessment. The safety figures offer descriptive information, while absent primary and secondary results limit the conclusions that can be drawn. These features make careful separation of study aim, observed data, and unavailable analysis especially important.

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 principal limitation of the available registry information is that the primary endpoint result is not reported. Although the study is marked completed and the endpoint is defined as a count of participants with DLTs, the record does not state that count or report the dose-finding conclusion. The full protocol-defined DLT criteria are also not reported, and the DLT-evaluable population definition is incomplete.

The study has no randomized control group. The record describes a single-group, open-label design and notes that the dose cohorts are not a like-for-like control comparison. Therefore, the cohort-specific safety figures cannot establish a causal dose effect or be read as a randomized estimate of comparative risk. The record does not provide confidence intervals for these figures, so their statistical precision is not reported.

Although the registry lists secondary outcomes for remission, remission duration, and pharmacokinetics, it does not report their results. It also lists zero analysis records. The statistical analysis plan, multiplicity approach, and methods for handling missing data are not reported in the registry record. Full analysis-population definitions and counts are not available, which limits assessment of who contributed to each outcome.

The safety information is descriptive and does not provide, in the record, further detail on attribution, timing, or severity grading for the listed events. Enrollment is listed as 17, while the safety figures are presented by cohort; the record does not explain the relationship between all enrolled participants and the cohort-specific figures. These omissions limit interpretation of denominators, follow-up completeness, and generalizability. No broader inference about treatment benefit or comparative safety is supported by these registry entries alone.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Blinatumomab in Combination With AMG 404 for the Treatment of Adults With Relapsed or Refractory B Cell Precursor ALL — NCT04524455.
• Registry record last updated 2024-04-08; status last verified 2023-10.
• Results first posted 2024-04-08.
• 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

NCT04524455 is a completed, open-label phase 1b study of blinatumomab with AMG 404 in adults with relapsed or refractory B-cell precursor ALL. Enrollment is listed as 17. The study’s primary objective was to assess safety and tolerability and estimate the maximum tolerated dose and recommended phase 2 dose of AMG 404 with continuous intravenous infusion of blinatumomab.

The primary endpoint was the number of participants with DLTs. Its result is not reported in the registry record. Safety information describes Cohort 1 with AMG 404 at 240 mg and Cohort 2a with AMG 404 at 480 mg; these cohorts are not randomized controls. The registry lists secondary remission and pharmacokinetic outcomes, but does not report their results or analysis records.

Serious adverse event and other adverse event figures are descriptive and do not establish causation. The record does not report the statistical analysis plan, full DLT criteria, missing-data methods, or complete analysis-population details. Interpretation is therefore limited to the study’s stated aims and the safety figures recorded.