Open Label Study to Evaluate Safety and Efficacy of 2 Doses of Quizartinib in Patients With Relapsed or Refractory Acute Myeloid Leukemia: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Open Label Study to Evaluate Safety and Efficacy of 2 Doses of Quizartinib in Patients With Relapsed or Refractory Acute Myeloid Leukemia (NCT01565668), a randomized phase 2 study. The primary outcome is Number of Participants Who Achieved Composite Complete Response (CRc) (Intent-to-Treat Population).

2. Clinical Question

The question is narrow: whether the recorded early CRc counts differed between the two randomized dose groups. It is not a comparison of quizartinib against another drug or against no treatment. Nor does the primary outcome alone summarize all later disease, survival, or safety outcomes. Those outcomes were listed separately, and their interpretation depends on their own definitions, follow-up, and completeness of reporting.

3. Trial Design

This was a phase 2, randomized, open-label, parallel-group study. The registry record lists 76 participants and two quizartinib dose arms: 30 mg and 60 mg. The study summary describes random assignment in a 1:1 ratio. Both groups received the same drug, with dose as the planned contrast. Masking was absent, so the study was open label.

Treatment was oral and given in 28-day cycles. The study summary says treatment continued until disease progression or unacceptable toxicity. The primary endpoint was assessed at the end of Cycle 2, after two complete 28-day cycles post treatment, according to its registry timeframe. The record also lists survival follow-up at three-month intervals after the end of treatment. The recorded start was 2012-04, primary completion was 2015-03, and study status is completed.

Randomization can support a fairer comparison between groups by reducing systematic differences at allocation, but the registry record does not describe the randomization sequence, concealment procedures, or any stratification factors. The dose comparison is clinically and statistically different from a placebo-controlled efficacy test: observed outcomes in both arms may reflect the drug, the participants' disease course, supportive care, and other influences, while the randomized contrast focuses on differences between assigned doses.

The arm descriptions do not provide further dose schedules or modifications. The record does not report the protocol's sample-size justification, target effect, planned statistical model, interim analyses, or stopping boundaries. These details should not be inferred from enrollment or from the posted outcome counts. The enrollment figure is not evidence of a particular power target, and the completed status does not by itself establish whether every planned outcome was fully reported.

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: Participants were randomized (1:1) to receive 30 or 60 mg/day quizartinib. These doses were selected based on evidence of efficacy and safety observed in studies AC220-001 and AC220-002, and preclinical data.Two participants who were randomized to quizartinib (60 mg/day) did not receive study drug and are not included in the safety data.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Composite complete remission was assessed in the intent-to-treat (ITT) analysis set.

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.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants Who Achieved Composite Complete Response (CRc) (Intent-to-Treat Population), measured over At end of Cycle 2 (after two complete 28-day cycles post treatment).

The primary endpoint is a count: the number of participants who achieved composite complete response (CRc) in the intent-to-treat analysis set. The registry defines CRc as the combined categories CR, CRp, and CRi. CR requires a morphologic leukemia-free state, normal hematopoietic cells, specified blood-count recovery, and independence from red blood cell and platelet transfusions. CRp allows incomplete platelet recovery while otherwise meeting CR criteria. CRi allows residual neutropenia while meeting the other CR criteria; transfusion independence is not required for CRi.

A composite endpoint can capture clinically relevant response states that share remission characteristics even when some blood-count recovery criteria differ. Including CRp and CRi means the endpoint is broader than complete remission under the strictest CR definition alone. The count therefore reflects participants meeting any of the three listed response categories by the specified assessment time; it should not be read as a count of CR alone.

The endpoint is assessed at the end of Cycle 2. That fixed assessment point defines the response being counted and makes the primary comparison an early response comparison, rather than a measure of the duration of response or long-term survival. The registry record does not report further details about response adjudication, assessment blinding, or handling of missing response assessments.

7. Results Posted in the Registry

• Quizartinib 60 mg: 47.4% (18/38) versus 47.4% (18/38) on control; risk difference 0.0 percentage points (95% CI -22.5 to 22.5), risk ratio 1.00 (0.62–1.61); unadjusted two-proportion z-test p = 1.000.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Number of Participants Who Achieved Complete Remission (CR) (Intent-to-Treat Population)

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Quizartinib 60 mg: 2.6% (1/38) versus 5.3% (2/38) on control; risk difference -2.6 percentage points (95% CI -11.4 to 6.1), risk ratio 0.50 (0.05–5.28); unadjusted two-proportion z-test p = 0.556.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Quizartinib 60 mg and the control. The interval gives the range of effects that remain compatible with the data.

The registry lists several secondary outcomes spanning remission, survival, duration of response, transplantation, and QTcF prolongation. These outcomes address different aspects of disease response, follow-up, and safety; they are not interchangeable with the primary CRc count at the end of Cycle 2. The registry record contains a posted result for the CR outcome, but does not report analyses for the other listed secondary outcomes. Their numerical results therefore cannot be used to establish whether the primary pattern was reinforced or contradicted over longer follow-up.

The secondary CR result is based on few events, and its uncertainty is correspondingly important. It should not be treated as a decisive confirmation of the primary comparison or as a stable estimate of a dose effect. The sample-size planning illustrations attached to that outcome are based on the observed effect and are illustrations for future planning, not evidence of the power achieved in this study.

Unadjusted secondary comparisons generally carry less weight than a prespecified primary comparison because multiple outcomes create more opportunities for apparently notable findings, especially if no multiplicity plan is reported. In general, testing many outcomes without adjustment can increase the chance of at least one nominally positive result even when no true effect exists. Whether any multiplicity procedure was planned or used is not reported in the registry record. The reported secondary results should therefore be interpreted as descriptive and exploratory unless a fuller analysis plan establishes otherwise.

Because the additional outcomes are not accompanied by reported analyses in the registry record, there is no basis for describing an overall pattern of dose effects across them. The primary result remains a comparison of early composite response, and it cannot stand in for unreported survival, durability, transplant, or safety findings. Outcome listings indicate what was intended for assessment, not the direction or strength of findings.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Number of Participants Who Achieved Complete Remission (CR) (Intent-to-Treat Population)
• Overall Survival (OS) After Approximately 3 Years (Intent-to-Treat Population)
• Event Free Survival (EFS) After Approximately 3 Years (Intent-to-Treat Population)
• Leukemia Free Survival (LFS) After Approximately 3 Years (Intent-to-Treat Population)
• Duration of Remission After Approximately 3 Years (Intent-to-Treat Population)
• Time to Composite Complete Remission (CRc) in Participants Who Achieved CRc After Approximately 3 Years (Intent-to-Treat Population)
• Percentage of Participants Undergoing Hematopoietic Stem Cell Transplantation (HSCT) After Approximately 3 Years (Intent-to-Treat Population)
• Percentage of Participants With Grade 2 or Higher QT Interval Corrected for Heart Rate Using Fridericia's Formula (QTcF) Prolongation After Receiving Quizartinib (Safety Analysis Set)

9. Statistical Interpretation

10. Statistical Methods Explained

For a binary endpoint, each participant is classified according to whether the event occurred. In this study the primary event is achieving CRc by the stated assessment. The arm-level count is the number meeting that definition, and the group size supplies the denominator for interpreting that count. The posted result reports 18 events among 38 participants in each dose arm.

What does the risk difference represent?

The risk difference is the event proportion in one arm minus the event proportion in the comparator arm. It is expressed on the absolute probability scale, so zero corresponds to equal observed proportions. The estimated risk difference for quizartinib 60 mg compared with quizartinib 30 mg was 0.0. Unlike a relative measure, a risk difference directly describes the absolute separation between the observed response probabilities. General statistical interpretation: the estimate is a summary of the observed comparison, not a guarantee that the population-level difference is exactly that value.

How should the p-value be read?

A p-value measures how unusual data at least as incompatible with a null hypothesis would be under the assumptions of a specified statistical test. It is not a measure of clinical importance, a probability that the null hypothesis is true, or a direct measure of the chance of error. The registry reports an unadjusted p-value of 1.0. The test and its assumptions are not reported in the registry record, so the calculation method cannot be identified from the record. The p-value should not be used alone to decide whether doses are equivalent or whether a meaningful difference has been ruled out.

What does the confidence interval add?

A confidence interval expresses uncertainty around an estimate using a method with stated long-run coverage properties. In general, wider intervals indicate less precision than narrower intervals. For the primary risk difference, the interval includes zero and extends in both directions. It therefore does not isolate a single direction of difference. The exact interval limits are not repeated in the narrative; the registry record does not state the interval method.

For a binary outcome, precision depends in part on the amount of information in the observed counts. Here, each arm contains 38 participants, and the event count is 18 in each. With finite group sizes, an estimate can match across arms while the interval still allows meaningful departures from zero. General statistical explanation: sparse or limited event information tends to make the estimated probability difference less precise. The posted confidence interval is the appropriate summary of that uncertainty, rather than the equality of the counts by itself.

What is the role of randomization?

Random assignment is intended to make treatment groups comparable, on average, with respect to both measured and unmeasured baseline factors. It does not ensure exact balance in a particular study, especially when groups are modest in size. The registry confirms randomization and a 1:1 allocation plan, but details of sequence generation, allocation concealment, and stratification are not reported in the registry record. Open-label assignment means participants and study personnel were not masked to the assigned dose; possible effects of awareness on assessment or care cannot be evaluated from the registry summary.

Were adjusted analyses or a prespecified model reported?

The registry reports zero analyses in the analysis listing and no formal analyses for the posted secondary outcomes. The primary comparison includes an unadjusted p-value, but its statistical test, covariate adjustments, missing-data method, and analysis plan are not reported in the registry record. It is therefore not appropriate to attribute an adjusted model, a particular test, or an interim-monitoring scheme to the study.

General statistical explanation: adjustment can account for prespecified prognostic variables and can sometimes improve precision, but it must be planned and reported to be evaluated. Multiple looks at accruing data or repeated outcome testing can affect the interpretation of nominal p-values; whether such procedures were planned or used is not reported in the registry record. No claims about their presence or absence as actual trial procedures can be made beyond that reporting limitation.

What do the planning illustrations mean?

The registry includes sample-size planning illustrations based on the observed effect for the secondary CR comparison. These are planning illustrations, not observed power and not the trial's own design justification. They assume a two-sided significance level of 0.05, equal allocation, and a normal approximation, with target effects expressed as fractions of the observed effect. The illustrations describe participants per arm for 80% power and participants per arm for 90% power. Because the observed secondary effect is based on very few events, those illustrations are sensitive to the observed estimate and should not be treated as a reliable reconstruction of the study's original planning. The study's actual sample-size assumptions and justification are not reported in the registry record.

11. Confidence Intervals and Precision

The primary risk-difference estimate is 0.0, but precision is not established by the point estimate alone. The confidence interval extends both below and above zero. It therefore includes the possibility of a lower observed response probability in the 60 mg arm as well as a higher one, relative to the 30 mg arm. The interval is broad enough that equal observed counts should not be mistaken for a precise demonstration of no difference.

A confidence interval is a range produced by a statistical procedure that, under its assumptions, has a specified long-run coverage interpretation. It is not a range containing a known proportion of individual participant outcomes, nor does it assign probabilities to possible true values after the data are observed. General statistical explanation: the interval helps show which effect sizes remain compatible with the data under the chosen method. The method used for the primary interval is not reported in the registry record, limiting assessment of its assumptions.

Both groups had 38 participants, with 18 CRc events in each. Those counts make the observed comparison transparent, while the confidence interval conveys that the underlying response difference remains uncertain. No numeric interval limits are repeated in this narrative because the posted limits have more than three decimal places, beyond the permitted display precision. The practical reading remains that the estimate is centered at zero but does not precisely rule out a difference in either direction.

Precision is distinct from statistical significance. A result can have a large p-value and still leave substantial uncertainty about the range of plausible effects. Nor does a confidence interval that contains zero establish equivalence; an equivalence conclusion requires an appropriate prespecified margin and analysis, neither of which is reported in the registry record. The posted primary result supports a cautious description of no observed difference in counts, not a claim of proven sameness.

12. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary endpoint and multiple secondary outcomes. Testing multiple outcomes can complicate interpretation because each comparison may generate a chance finding. General statistical explanation: a multiplicity strategy may control the overall false-positive rate through prespecified testing order, adjustment, or another stated procedure. Such a strategy, including any adjustment or hierarchy, is not reported in the registry record. The unadjusted p-value for the primary comparison should not be treated as proof that all endpoint comparisons were controlled for multiplicity.

The record lists no reported analyses for the secondary outcomes. It is also not clear from the registry record whether all planned outcomes were measured, whether any were omitted from reporting, or whether outcome definitions changed. No selective-reporting conclusion can be established from the available information alone. The listed endpoints and the analyses actually posted are distinct pieces of information.

The primary population is described as the intent-to-treat analysis set, which generally refers to analyzing participants according to randomized assignment. The registry provides arm denominators of 38 and 38 for the primary endpoint. It does not describe how missing response assessments, withdrawals, or participants without an evaluable assessment were handled. Therefore, the handling of missing outcome data cannot be assessed, and the reported counts should not be assumed to reflect a particular imputation or missing-as-nonresponse rule.

The safety data use different denominators in the two dose groups: 38 for the 30 mg group and 36 for the 60 mg group. The reason for the difference is not reported in the registry record. These safety denominators should not be conflated with the primary intent-to-treat group sizes. The record also does not describe the precise analysis populations for each secondary endpoint, the completeness of follow-up, or methods for censoring time-to-event outcomes.

Further statistical details are not reported in the registry record, including the prespecified analysis plan, any interim analyses, missing-data assumptions, or procedures for handling multiplicity. These absences limit the ability to assess whether the posted estimates follow the planned analysis. They do not establish that a particular procedure was or was not used outside what the record reports.

13. 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 leukemia (19.4%), febrile neutropenia (18.4%), pneumonia (16.7%), pyrexia (13.9%), nausea (5.6%).

The registry reports serious adverse events for 25 of 38 participants in the quizartinib 30 mg group and 23 of 36 in the 60 mg group. The corresponding counts in the registry's other adverse-event category are 37 of 38 and 36 of 36. Death counts are 9 and 13, respectively. These are descriptive counts within the listed safety group sizes; they do not by themselves establish a causal relationship to treatment or a dose effect.

The registry also lists acute myeloid leukemia, febrile neutropenia, pneumonia, pyrexia, nausea, and vomiting among the most frequent serious adverse event terms, with percentages reported for those terms. The registry does not state the denominator used for each term percentage in the summary, so those percentages should be read as registry-reported frequencies rather than recalculated rates.

Safety comparisons require attention to follow-up time, exposure, event definitions, and whether events were counted by participant or episode. Those details are not fully reported in the registry record. The serious-event counts should therefore be interpreted descriptively, with the differing safety denominators in mind, rather than as a direct, adjusted comparison between doses.

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

The primary finding is that the recorded CRc count was the same in the two dose groups at the end of Cycle 2: 18 of 38 participants in each arm. The estimated risk difference was 0.0, and the unadjusted p-value was 1.0. These registry entries describe the posted comparison; they do not establish that the underlying response probabilities are identical.

The confidence interval includes effects in either direction, so the study's primary estimate remains imprecise. A failure to observe a difference is not the same as evidence of equivalence. Equivalence requires a prespecified margin defining what differences would be considered acceptably small and an analysis designed to test that question. No equivalence margin or equivalence analysis is reported in the registry record.

The result also does not establish whether either dose is beneficial compared with another treatment or no treatment. Both randomized groups received quizartinib, so the study contrast concerns the two doses. Nor does the early CRc count answer questions about long-term survival, duration of remission, event-free survival, transplant, or the full safety profile. These endpoints require their own reported outcomes and analyses.

Randomization strengthens the interpretation of the between-dose comparison, but open-label conduct and unreported analysis details remain relevant when considering response assessment and possible sources of bias. The registry record does not provide enough information to assess all aspects of trial conduct, missing data, or endpoint adjudication. The result is best described as equal observed primary counts with substantial remaining uncertainty about the size of any underlying dose difference.

Accordingly, the posted data support a limited statistical conclusion about the early composite response count in this study. They do not support a broader treatment recommendation, a claim of no difference for all outcomes, or a conclusion about the comparative safety of the doses beyond the descriptive adverse-event figures recorded.

15. Why This Trial Matters Statistically

This trial illustrates why a point estimate and its uncertainty should be read together. The two arms had identical primary event counts, and the estimated risk difference was 0.0. Yet the confidence interval extends in both directions, showing that equal observed counts do not eliminate uncertainty about the underlying dose contrast. A comparison based only on event counts or a p-value would miss that central statistical point.

It also highlights the distinction between an active-dose comparison and a control-based efficacy trial. Randomization can make the dose groups comparable for the question of relative dose differences, but both groups received quizartinib. The design does not directly estimate the effect of quizartinib compared with no quizartinib or another treatment. Keeping the estimand aligned with the randomized comparison prevents the primary result from being overinterpreted.

The endpoint's composite definition matters as well. CRc groups three remission categories, including states with incomplete platelet or hematological recovery. The count is therefore informative about the defined composite, but it should not be relabeled as strict CR alone. Clear endpoint definitions are essential when interpreting counts and comparing outcomes across studies.

Finally, the registry record demonstrates the limits of an outcome listing without corresponding analyses. Multiple secondary outcomes were named, but results and statistical details are not reported for most of them. This restricts assessment of the broader efficacy and safety pattern, multiplicity, and missing data. Statistical interpretation depends not only on the numerical estimate, but also on a transparent account of populations, assumptions, and analysis decisions.

16. 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 planned sample-size justification, target effect, or assumptions underlying the original design. The sample-size illustrations attached to the secondary CR outcome are based on an observed effect and are not a reconstruction of the trial's planning. The observed secondary effect is based on few events, making those illustrations especially sensitive to the particular counts.

Although the study is described as randomized, details of sequence generation, allocation concealment, and stratification are not reported in the registry record. The study was open label. The record does not describe blinded response review or provide enough information to evaluate whether knowledge of assigned dose could have affected assessment or other trial procedures.

The primary outcome is reported as a count in the intent-to-treat set, but methods for handling missing assessments and withdrawals are not reported. The record does not provide detail on response adjudication, the completeness of follow-up, or whether all randomized participants had an evaluable endpoint. The safety group sizes also differ, and the reason is not reported.

The primary comparison has a confidence interval spanning both directions around zero, limiting precision. The registry does not report the interval method, the test used for the p-value, or a complete statistical analysis plan. Multiplicity procedures and interim analyses are also not reported. These gaps make it difficult to assess the prespecification and assumptions behind the inferential results.

Several secondary outcomes are listed without reported analyses. As a result, the registry record does not permit a full assessment of longer-term response, survival, remission duration, transplantation, or QTcF findings. The serious adverse event summaries are descriptive, and important details such as event-level follow-up and exposure are not given. These limitations constrain conclusions to the posted primary counts and the adverse-event summaries rather than a comprehensive comparison of the two doses.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Open Label Study to Evaluate Safety and Efficacy of 2 Doses of Quizartinib in Patients With Relapsed or Refractory Acute Myeloid Leukemia — NCT01565668.
• Registry record last updated 2019-12-27; status last verified 2019-12.
• Results first posted 2019-12-27.
• 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.

20. Record Summary

The registry record describes a completed, randomized, open-label phase 2 parallel-group study of quizartinib in people with FLT3-ITD-positive relapsed or refractory AML. Enrollment was 76, with 38 participants assigned to quizartinib 30 mg and 38 to quizartinib 60 mg. Treatment was oral in 28-day cycles, and the primary endpoint was CRc at the end of Cycle 2.

The primary count was 18 of 38 in each arm. The estimated risk difference was 0.0, with an unadjusted p-value of 1.0; the confidence interval includes differences in either direction. This is an early response comparison between two doses, not a placebo-controlled comparison or proof of equivalence.

The record lists several secondary outcomes, but reports no analyses for most of them. It does not report the original sample-size justification, detailed statistical plan, missing-data methods, or multiplicity procedures. Safety summaries are descriptive and use group sizes of 38 and 36.