Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Selected Relapsed or Refractory Hematological Malignancies: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Selected Relapsed or Refractory Hematological Malignancies (NCT03465540), a non-randomized phase 1 study. The primary outcome is Number of Participants Who Experienced a Dose-limiting Toxicity (DLT).

2. Clinical Question

3. Trial Design

This was a phase 1, open-label, non-randomized, sequential study of AMG 397 in selected relapsed or refractory hematological malignancies. The registry lists an enrollment of 24 and identifies Amgen as the sponsor. The recorded start date was 2018-08-17, the primary completion date was 2019-07-25, and the study status is terminated. The reason for termination is not reported in the registry record.

The design included dose-escalation cohorts and planned monotherapy and combination-treatment parts. Part 1A included participants with multiple myeloma or non-Hodgkin's lymphoma, while Part 1B included participants with AML. The planned Part 2 monotherapy cohorts covered AML, MDS and MM, including an AML cohort in Japan only. Planned Part 3 combination cohorts paired AMG 397 with azacitidine for MDS or AML, or with dexamethasone for MM. However, Parts 2 and 3 were not initiated and did not enroll participants. The record therefore says that the presented results include Part 1 only.

Because allocation was non-randomized and masking was absent, treatment and dose assignment were not concealed through a randomized comparison. Sequential dose escalation is suited to early evaluation of tolerability and dose-related safety, but it does not create concurrent control groups. Disease-specific cohorts also mean that outcomes across dose groups may reflect differences in underlying malignancy as well as dose. The registry record does not report the detailed dose-escalation rules, the rationale for the planned enrollment, or a statistical analysis plan.

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: Parts 2 and 3 of the trial were not initiated after part 1 data was reviewed. No participants were screened or enrolled for parts 2 or 3.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Parts 2 and 3 were not initiated and did not enrol any participants, therefore results presented only included participants in part 1. DLT evaluable set: All participants who experienced a DLT or who received at least 75% of the planned dose in the DLT window (Day 1 to Day 28).

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: Full Analysis Set (FAS): All participants who were enrolled and received at least 1 dose of AMG 397.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants Who Experienced a Dose-limiting Toxicity (DLT), measured over 28 days.

The primary endpoint was the number of participants who experienced a dose-limiting toxicity during a 28-day evaluation period, from Day 1 to Day 28. A DLT was defined as a specified adverse event during that period that the investigator assessed as related to AMG 397. Adverse-event grading and severity followed the Common Terminology Criteria for Adverse Events, version 4.03.

DLT counts are used in early dose-escalation research to describe whether treatment-related toxicities occur at doses under evaluation. The measure can inform estimates of maximum tolerated doses and/or biologically active doses, which were among the study's stated aims. It is a count of participants meeting the DLT definition, not a count of every adverse event, and it does not by itself summarize the full safety experience or establish efficacy.

The registry defines the DLT-evaluable set as participants who experienced a DLT or received at least 75% of the planned dose during the DLT window. This definition matters because the endpoint depends not only on the toxicity criteria but also on who is considered evaluable. The observed primary endpoint counts and the numbers evaluable by dose are not reported in the registry record. Consequently, the record does not permit assessment of DLT frequency by cohort or an independent evaluation of dose-limiting toxicity.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a DLT count describe?

A dose-limiting toxicity count records how many evaluable participants met a prespecified toxicity definition within the assessment window. It is not interchangeable with the count of all adverse events: a participant may have adverse events that do not meet the DLT definition, and the definition also required investigator assessment of a relationship to AMG 397. The registry states that the DLT window ran from Day 1 to Day 28 and that severity grading used CTCAE version 4.03.

For interpretation, a count needs its relevant denominator and population definition. The record defines the DLT-evaluable set as participants who experienced a DLT or received at least 75% of the planned dose during the window. That rule identifies who contributes to the endpoint, but the registry record does not report the DLT-evaluable counts or the DLT outcome counts by dose. Without those values, a DLT proportion or its uncertainty cannot be assessed.

Why does the study design matter?

In a non-randomized sequential dose-escalation study, dose cohorts are not formed through random allocation. Cohorts may differ in disease type, clinical characteristics, timing or exposure. The record distinguishes Part 1A, which included MM or NHL, from Part 1B, which included AML. A difference in observed counts between these parts could reflect their different populations as well as any dose-related pattern. There is no randomized concurrent comparator to separate these influences.

Open-label means masking was absent. This can matter for outcomes that involve clinical assessment, including an investigator's assessment of whether an adverse event is related to treatment. The registry does not report procedures for independent event review or adjudication. It is not appropriate to assume that such procedures were or were not used beyond what the record states.

How should adverse-event counts be read?

Serious adverse events and DLTs are related safety concepts, but they are not equivalent categories in the record. The DLT definition includes a specified event, its timing within the evaluation window, and an investigator-assessed relationship to AMG 397. The serious adverse-event figures are reported separately by dose group. They should not be relabeled as DLTs, nor should every serious event be assumed to be treatment-related.

Counts are useful for showing how many participants in each listed group had the reported event category. They do not describe event timing, recurrence, severity beyond the serious classification, duration, or causal attribution unless those details are separately reported. The registry record does not report those details for the serious-event counts. Group sizes are limited, and a count from a small cohort can change noticeably with the experience of a participant; descriptive counts should therefore not be treated as stable estimates of risk.

What can confidence intervals and significance tests add in general?

In general, a confidence interval expresses uncertainty around an estimated quantity, such as an event proportion. A wider interval indicates less precision, while a narrower interval indicates greater precision under the method's assumptions. A significance test addresses compatibility with a specified statistical null model; it does not establish clinical importance or causality. These concepts are useful when results and analysis methods are reported, but the registry record does not report DLT analyses, confidence intervals or inferential tests for the primary endpoint.

The registry record lists 14 outcome measures and zero analyses. That listing does not supply the estimates or methods needed to reconstruct an inferential result. The detailed statistical plan, including any planned interval or testing procedures, is not reported in the registry record. No significance conclusion or precision estimate for the primary endpoint can therefore be drawn from the stated endpoint definition alone.

How should planning calculations be distinguished from observed results?

In general, sample-size planning calculations describe what a hypothetical study might require under specified assumptions. They are not observed outcomes and do not indicate the probability that the completed study detected an effect. The planning assumptions described for this study use a two-sided significance level of 0.05, equal allocation between two arms and a normal approximation; the effect to detect is defined as a stated fraction of an observed effect. These are planning assumptions, not evidence that the study used randomized arms or that its observed design matched those assumptions.

For time-to-event outcomes, the stated planning approach refers to a total event count using the Schoenfeld method; other planning results are expressed as participants per arm. Such illustrations should not be confused with the trial's enrollment or actual outcome counts. The record does not report a trial-specific sample-size justification, and planning values cannot replace the missing primary endpoint result or create an observed-power estimate.

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("Part 1a: 80 mg AMG 397", "Part 1a: 160 mg AMG 397", "Part 1a: 320 mg AMG 397", "Part 1b: 80 mg AMG 397", "Part 1b: 160 mg AMG 397", "Part 1b: 320 mg AMG 397")
n      <- c(2, 4, 3, 3, 3, 2)
events <- c(0, 0, 1, 0, 0, 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  Part 1a: 80 mg AMG 397  2  0  0.0  0.0  84.2  0.0  65.8  0.8  70.8
ARM  Part 1a: 160 mg AMG 397  4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2
ARM  Part 1a: 320 mg AMG 397  3  1  33.3  0.8  90.6  6.1  79.2  6.8  80.6
ARM  Part 1b: 80 mg AMG 397  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Part 1b: 160 mg AMG 397  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Part 1b: 320 mg AMG 397  2  1  50.0  1.3  98.7  9.5  90.5  9.4  90.6

11. Multiplicity, Missing Data and Analysis Populations

The registry lists multiple secondary outcomes, including response rates for MM, NHL and AML, progression-free survival, overall survival, time to response, duration of response and maximum observed concentration of AMG 397. It also lists 14 outcome measures overall. When many outcomes are examined, the chance of at least one apparently notable result can increase if each is tested independently. In general, multiplicity can be addressed through prespecified testing hierarchies, adjusted significance thresholds or an explicitly exploratory interpretation. The registry record does not report a multiplicity strategy or explain which outcomes, if any, were treated as confirmatory.

The record lists zero analyses. It does not report outcome estimates, analysis populations, statistical models, missing-data procedures, or confidence intervals for the primary endpoint. It also does not report whether participants with incomplete DLT-window information were excluded, how early discontinuations were handled, or how missing secondary-outcome data were treated. Those details are not reported in the registry record and should not be inferred from the endpoint definition.

The DLT-evaluable population is defined using occurrence of a DLT or receipt of at least 75% of the planned dose during the DLT window. That rule describes eligibility for the primary endpoint analysis, but the number meeting the rule and the handling of other cases are not reported. Parts 2 and 3 were not initiated and enrolled no participants; the reported results included Part 1 only. Thus, neither the proposed later treatment parts nor their planned disease cohorts contribute reported participant outcomes.

12. Safety Results

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

Deaths

Other (non-serious) adverse events

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

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: acute myeloid leukaemia (66.7%), haematemesis (50.0%), melaena (50.0%), lymph gland infection (50.0%), hypercalcaemia (50.0%).

The serious adverse-event counts are presented by Part 1 dose group. The first count in each description is the number of participants affected, and the second is the number at risk. In Part 1A, the counts were 2 among 2 at 80 mg, 4 among 6 at 160 mg, and 2 among 4 at 320 mg. In Part 1B, they were 4 among 4 at 80 mg, 4 among 5 at 160 mg, and 3 among 3 at 320 mg. Recorded deaths by those same groups were 1, 1, and 0 in Part 1A, and 2, 0, and 2 in Part 1B.

These figures are descriptive. They are not randomized comparisons, and the parts include different disease populations. The deaths are not identified as treatment-related in the reported counts, and the serious adverse-event counts are not the primary DLT endpoint. The registry lists acute myeloid leukaemia at 66.7% and haematemesis, melaena, lymph gland infection, hypercalcaemia and plasma cell myeloma each at 50.0% among the top serious-event terms. The denominator and context for those percentages are not reported in the registry record, so they should not be interpreted as cohort-specific risks.

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

The record establishes that AMG 397 was studied in a phase 1, open-label, non-randomized, sequential design and that the primary question concerned DLTs during a 28-day window. It also records serious adverse-event counts and deaths in Part 1 dose groups. Those data describe what was recorded in the listed groups, but the primary DLT counts and analyses are not reported in the registry record.

The record does not establish an efficacy result. Although it lists response and time-to-event outcomes, their estimates and analyses are not reported. Nor does the presence of planned dose-escalation and combination cohorts establish that those cohorts were completed: Parts 2 and 3 were not initiated and enrolled no participants. The registry status is terminated, but the reason for termination is not reported in the registry record.

Because allocation was non-randomized and the study was sequential, comparisons between dose groups cannot be treated as randomized evidence of dose effects. The parts also included different malignancies, which further limits direct comparisons. The serious adverse-event and death counts do not, on their own, establish causal relationships to AMG 397. A count is a description of observed events in a cohort, not a complete assessment of clinical benefit, harm, or uncertainty.

The findings that can be described are therefore limited to the study's design, its stated endpoint, its incomplete planned progression to later parts, and the reported group-level safety counts. The record does not provide enough outcome analysis to determine the frequency of DLTs, compare efficacy across diseases, or estimate a treatment effect against a control group.

14. Why This Trial Matters Statistically

Early-phase studies address questions that differ from those in confirmatory randomized trials. A dose-escalation study may focus on tolerability and on identifying doses for further study, rather than estimating a comparative treatment effect. This study's stated aims were to evaluate safety and tolerability and estimate maximum tolerated doses and/or biologically active doses. Its primary endpoint was defined around DLTs over a specified evaluation window.

The record also illustrates why endpoint definitions and analysis populations matter. The DLT definition includes timing and investigator-assessed relationship to AMG 397, while the DLT-evaluable set depends on either experiencing a DLT or receiving at least 75% of the planned dose during the window. Those rules shape what the endpoint count would mean. Without the actual DLT counts and evaluable population, readers cannot assess the result against the study's stated aims.

The distinction between planned and initiated study parts is also important. The registry describes monotherapy and combination cohorts, but Parts 2 and 3 were not initiated and enrolled no participants. Reading planned cohorts as completed would overstate the evidence available. Likewise, the descriptive adverse-event counts do not provide randomized comparisons or establish causation.

Statistically, the record is a reminder that registry outcomes and analyses are separate: listing an outcome does not provide its estimate, uncertainty or inferential method. Here, the stated endpoint and selected safety counts allow a limited account of the study, while the absence of reported primary analyses precludes a fuller statistical assessment.

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 interpretation is that the primary endpoint result is not reported in the registry record. The DLT-evaluable population is defined, but the number of participants meeting that definition and the DLT counts by dose are absent. Accordingly, the primary safety question cannot be quantified from the record.

The study was non-randomized, open-label and sequential, with no like-for-like control comparison. Its Part 1A and Part 1B cohorts involved different malignancies, which constrains comparisons across groups. The reported serious adverse-event counts and deaths are descriptive, and the record does not provide causal attribution for those events. The reason for the terminated status is also not reported.

Parts 2 and 3 were not initiated and enrolled no participants, so their planned monotherapy and combination cohorts add no observed outcomes to the reported results. Although secondary outcomes are listed, corresponding estimates and analyses are not reported in the registry record. The detailed statistical analysis plan, missing-data handling, multiplicity approach, and sample-size justification are not reported either. These omissions limit assessment of precision, completeness, and the intended interpretation of outcomes.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Selected Relapsed or Refractory Hematological Malignancies — NCT03465540.
• Registry record last updated 2023-04-12; status last verified 2023-04.
• Results first posted 2023-04-12.
• 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

NCT03465540 was a phase 1, open-label, non-randomized, sequential study sponsored by Amgen. It evaluated AMG 397 in selected relapsed or refractory hematological malignancies, with safety and tolerability as central aims. The registry lists an enrollment of 24, a start date of 2018-08-17, a primary completion date of 2019-07-25, and a terminated status.

The primary endpoint counted participants with DLTs during the 28-day window. The registry states that Parts 2 and 3 were not initiated, so reported results included Part 1 only. Serious adverse-event counts and deaths are listed by Part 1 dose group, but the primary DLT result and analyses of listed secondary outcomes are not reported in the registry record. The record therefore supports descriptive reporting of selected safety figures, not a comparative efficacy or causal conclusion.