A Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-Tumor Activity of the Oral Anaplastic Lymphoma Kinase (ALK)/Epidermal Growth Factor Receptor (EGFR) Inhibitor Brigatinib (AP26113): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-Tumor Activity of the Oral Anaplastic Lymphoma Kinase (ALK)/Epidermal Growth Factor Receptor (EGFR) Inhibitor Brigatinib (AP26113) (NCT01449461), a non-randomized phase 1, phase 2 study. The primary outcome is Objective Response Rate (ORR).

2. Clinical Question

The study asked whether orally administered brigatinib could be evaluated for safety, tolerability and pharmacokinetics during dose escalation, and whether preliminary anti-tumor activity could be assessed after a recommended Phase 2 dose was established. The record describes participants with anaplastic lymphoma kinase (ALK) and non-small-cell lung cancer (NSCLC), including participants with active brain metastases, as well as participants with mutated EGFR or other cancers with abnormal targets against which brigatinib is active.

The primary endpoint was objective response rate (ORR), assessed by the investigator using RECIST v1.1. It counted participants whose best qualifying response was complete response or partial response after starting study treatment. The registry describes assessments from screening and at 8-week intervals thereafter through the end of the study, up to 8.4 years.

The registry record does not report the numerical ORR result or its 95% confidence interval. It therefore does not establish the observed response proportion or its precision. The record also does not report a randomized control group or a like-for-like comparison between treatment groups. The findings available in the registry should be read as descriptions of participants receiving different brigatinib regimens, not as a randomized estimate of brigatinib’s effect relative to another treatment or to no treatment.

In general, an early-phase study can characterize dose-related safety and drug exposure while also gathering preliminary response data. Such response data are descriptive unless the design and analysis support a comparative causal conclusion. For this study, the actual response estimate and the analysis details needed to interpret it are not reported in the registry record.

3. Trial Design

This was a completed Phase 1/2, non-randomized, unmasked, parallel-group study sponsored by Ariad Pharmaceuticals. The registry lists enrollment of 137. The study began on 2011-09-20, and its primary completion date was 2015-11-16. These registry dates describe the study record; they do not supply the timing of individual participants’ outcomes.

The study had two stated aims. During dose escalation, investigators sought to characterize safety, identify dose-limiting toxicities, determine the maximum tolerated dose and recommended Phase 2 dose, and describe brigatinib pharmacokinetics. The expansion phase was intended to assess preliminary anti-tumor activity after the recommended Phase 2 dose was established. The registry record does not report the protocol’s detailed dose-escalation decision rules or the rationale used to select the dose levels.

Six brigatinib regimen labels are listed. They include 30 mg QD/60 mg QD; 90 mg QD; 120 mg QD/60 mg BID; 90 mg QD-180 mg QD; 180 mg QD/90 mg BID; and 240 mg QD/120 mg BID/300 mg QD. The regimen descriptions include differing doses, once-daily or twice-daily schedules, and, for one regimen, an initial dose period followed by a higher dose. Treatment was described in cycles of 28 days. Some descriptions state that treatment could continue for approximately up to 7.3 years.

Because allocation was non-randomized and masking was absent, observed differences across regimens may reflect differences in participant characteristics, disease groups, dose selection, or other factors as well as dose. The groups should not be interpreted as randomized comparison arms. The registry record does not report a control arm, a method for adjusting comparisons between groups, or a statistical plan for causal comparisons.

Alongside ORR, the listed outcomes include treatment-emergent adverse events, maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic measures such as maximum observed plasma concentration, time to maximum concentration, and area under the concentration-time curve. The record lists 19 outcome measures. Their numerical results, apart from the serious-event group figures described separately, are not reported in the registry record.

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 with advanced malignancies, all histologies other than leukemia were enrolled in dose-escalation and participants with non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) rearrangements were enrolled in dose expansion phase. Participants received brigatinib 30 mg - 300 mg, tablets, orally once daily or twice daily.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety population included all enrolled participants who received at least one dose of study drug.

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: Safety population included all enrolled participants who received at least one dose of study drug.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Objective Response Rate (ORR), measured over From Screening and at 8-week intervals thereafter up to end of the study (up to 8.4 years).

Objective response rate is the percentage of participants who meet the study’s criteria for complete response or partial response after starting treatment. In this study, an investigator assessed response using RECIST v1.1. A complete response for target lesions required disappearance of extranodal lesions and reduction of pathological lymph nodes to <10 mm in short axis. The record also specifies disappearance of non-target lesions, non-pathological lymph node size, and normalization of tumor-marker level for complete response involving non-target lesions. A partial response required at least a 30% decrease in the sum of the longest diameters of target lesions, compared with the baseline sum.

ORR is used as a summary of tumor response: it focuses on whether participants meet a defined threshold for tumor shrinkage or disappearance, rather than describing every change in tumor measurements. In general, a response proportion is straightforward to interpret only when its eligible population, assessment rules, follow-up, and handling of participants without evaluable assessments are clear.

The registry specifies assessment from screening and at 8-week intervals thereafter through the end of the study, up to 8.4 years. It also describes the full analysis set as participants who received at least one dose, and says that participants with ALK and NSCLC were evaluated for this endpoint. The number analyzed and the numerical ORR with its 95% confidence interval are not reported in the registry record. The endpoint definition is therefore available, but the observed response rate and its precision cannot be interpreted from this record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a Phase 1/2 study with non-randomized allocation and no masking. Those design features shape what statistical conclusions can be drawn. The primary endpoint is a binary response status at the participant level: a participant either meets the stated response definition or does not. The registry expresses the outcome as a percentage of participants and specifies a 95% confidence interval, but the ORR estimate and interval are not reported in the registry record.

What does a response percentage represent?

In general, a response percentage is the number of participants meeting the endpoint definition divided by the endpoint’s analysis denominator, expressed as a proportion or percentage. Its interpretation depends on who was eligible for analysis and how missing or unevaluable assessments were treated. In this study, the record says the full analysis set included participants who received at least one dose and that participants with ALK and NSCLC were evaluated for ORR. It does not report the number analyzed or the handling of participants without an evaluable response assessment. Thus the denominator used for the primary result cannot be recovered from the registry record.

What does a confidence interval add?

In general, a confidence interval gives a range of values compatible with the observed data under the assumptions of the method used. A narrower interval indicates greater statistical precision, while a wider interval indicates more uncertainty. An interval does not represent a guarantee that the true value lies within its endpoints, nor does it account automatically for bias arising from the study design. The registry names a 95% confidence interval for ORR but does not report its endpoints or the method used to calculate it.

Why does non-randomized allocation matter?

In general, random allocation helps balance both measured and unmeasured participant characteristics across treatment groups, on average. Without randomization, differences between groups may be associated with the treatment regimen, participant selection, or other factors. This study’s groups include different brigatinib dose levels and schedules, and no like-for-like randomized control comparison is reported. Any comparison across those groups would therefore be descriptive unless supported by additional design or analytical methods. The registry record does not report an adjusted comparative model or the covariates that might have been used.

How should the dose-escalation context be read?

The stated dose-escalation aims were to characterize safety, identify dose-limiting toxicities, determine the maximum tolerated dose and recommended Phase 2 dose, and describe pharmacokinetics. In general, early-phase dose escalation examines tolerability and dose-related information to guide later study stages; its design is not automatically a randomized dose-comparison experiment. The record does not report dose-escalation rules, cohort decision thresholds, or the statistical method used to select the recommended Phase 2 dose. Those details should not be inferred from the regimen labels alone.

What can the adverse-event counts show?

The posted serious-event figures give, by regimen, the number at risk and the number affected. In general, counts describe how many participants experienced an event in the recorded group, while a rate or percentage requires a clearly defined denominator and observation period. Comparing counts across groups can be misleading when group sizes and follow-up differ. The registry record does not describe the follow-up duration used for each group’s serious-event count or provide a time-to-event analysis. The figures should therefore be read as descriptive summaries, not as comparative risk estimates.

What is the role of sample-size calculations?

In general, a planning calculation asks how many participants might be needed to detect a prespecified effect under stated assumptions about the outcome, allocation, significance level, and power. It is distinct from the number enrolled or analyzed in a completed study, and it does not show that the study had a particular observed power. The record describes planning illustrations based on a fraction of the observed effect, a two-sided significance level of 0.05, equal allocation, and a normal approximation. It also states that calculations for time-to-event outcomes use a total event count, while other illustrations use participants per arm. The numerical illustrations and the trial’s own sample-size justification are not reported in the registry record. The planning assumptions should not be mistaken for the protocol’s original design rationale.

Are the statistical analyses fully specified?

The registry lists 19 outcome measures and 0 registered analysis entries. It does not report the full statistical analysis plan, methods for handling missing data, adjustments for multiple testing, or interim-analysis procedures. In general, these details matter because they affect which participants contribute to each result, how uncertainty is calculated, and how multiple outcomes are interpreted. Their absence from the registry record prevents a detailed assessment of the analysis choices. It does not establish that analyses were or were not conducted outside what the registry reports.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists 19 outcome measures, spanning response, safety, dose-finding, and pharmacokinetic outcomes. It lists 0 registered analysis entries. The record does not report a multiplicity strategy, such as a hierarchy of confirmatory hypotheses or an adjustment to account for testing multiple outcomes. In general, when many outcomes or comparisons are examined, the chance of seeing an apparently notable result by chance can increase. Whether and how that concern was addressed is not reported in the registry record.

Missing-data handling for the primary endpoint is also not reported. The record describes the full analysis set as participants who received at least one dose and identifies participants with ALK and NSCLC as the population evaluated for ORR. It does not report the number analyzed, how many had an evaluable assessment, how missing assessments were classified, or whether participants who stopped treatment or lacked follow-up were included in the denominator. These details matter because response proportions depend on the analysis population and endpoint rules.

The record specifies repeated response assessment from screening and at 8-week intervals thereafter, but it does not report how assessments outside the schedule or assessments after treatment discontinuation were handled. It also does not report whether any interim analyses were planned or performed. These items should be treated as not reported in the registry record rather than inferred from the study’s Phase 1/2 design.

The record’s sample-size description is a planning illustration based on the observed effect, not a report of the trial’s original justification. It states assumptions for the illustrations, but the trial’s own sample-size rationale is not reported in the registry record. Planning illustrations are not observed power and do not resolve uncertainty about missing outcomes or multiple testing.

11. Safety Results

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

Deaths

Other (non-serious) adverse events

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

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: dyspnoea (26.7%), neoplasm progression (22.2%), pneumonia (16.7%), metastases to central nervous system (16.7%), hypoxia (13.3%).

The registry lists serious adverse-event figures by brigatinib regimen. Each entry below gives the number at risk and the number affected by at least one serious event as recorded in the group fields. These are descriptive counts, not randomized comparisons.

• For Brigatinib 30 mg QD/60 mg QD, 6 were at risk and 1 was affected.
• For Brigatinib 90 mg QD, 18 were at risk and 10 were affected.
• For Brigatinib 120 mg QD/60 mg BID, 18 were at risk and 10 were affected.
• For Brigatinib 90 mg QD-180 mg QD, 32 were at risk and 14 were affected.
• For Brigatinib 180 mg QD/90 mg BID, 48 were at risk and 30 were affected.
• For Brigatinib 240 mg QD/120 mg BID/300 mg QD, 15 were at risk and 11 were affected.

The listed serious-event terms and percentages are dyspnoea, 26.7%; neoplasm progression, 22.2%; pneumonia, 16.7%; metastases to central nervous system, 16.7%; hypoxia, 13.3%; and cough, 13.3%. The registry record does not report the denominator or calculation method for these term percentages. It also lists deaths by regimen, but the definition, timing, and attribution details for those counts are not reported in the registry record.

In general, adverse-event counts depend on group size, follow-up, and event definitions. They do not establish that an event was caused by treatment. The available figures should not be used as direct comparisons between regimens because allocation was non-randomized and the record does not report a comparative safety analysis.

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

The registry record establishes that this was a completed, non-randomized Phase 1/2 study of oral brigatinib with dose-escalation and expansion aims. It describes an investigator-assessed ORR endpoint, the response criteria, the planned assessment schedule, several dosing regimens, and group-level serious adverse-event figures. These details help readers understand what the study set out to evaluate and how the primary outcome was defined.

The record does not report the numerical ORR, its 95% confidence interval, or the endpoint-specific number analyzed. It therefore does not allow the reader to state what response proportion was observed or how precisely it was estimated. The registry’s endpoint definition is not a substitute for the endpoint result.

The record also does not support a causal comparison between brigatinib regimens or against a control treatment. Allocation was non-randomized, and no randomized comparator is reported. In general, differences between non-randomized groups can reflect differences in participant characteristics, disease, regimen selection, and follow-up, as well as treatment exposure. The posted counts alone cannot separate these influences.

The listed adverse-event figures describe recorded participants and events in the regimen groups. They do not establish treatment attribution, comparative risk, or the relationship between an event and dose. The registry record does not provide the event-term denominators, follow-up details, or a comparative safety analysis needed for stronger claims.

More broadly, a study’s stated purpose and its available registry results are different kinds of evidence. The purpose describes intended questions; numerical outcome estimates are needed to answer them empirically. Here, the registry records the intended ORR assessment and several safety and pharmacokinetic outcomes, while many numerical results and analysis details are not reported in the registry record. The appropriate conclusion is limited to the design and information actually recorded, without inferring efficacy, comparative benefit, or absence of uncertainty.

13. Why This Trial Matters Statistically

This trial is statistically informative as an example of an early-phase study addressing several questions across dose escalation and expansion. Its stated aims connect tolerability, dose-limiting toxicities, maximum tolerated dose, recommended Phase 2 dose, pharmacokinetics, and preliminary anti-tumor activity. Those aims call for different kinds of outcomes: event counts, dose-selection decisions, drug-concentration measures, and a response proportion.

The design also illustrates why the structure of a study matters when interpreting results. The registry describes multiple brigatinib dose levels and schedules, but allocation was non-randomized and no randomized control group is reported. In general, dose groups in an early-phase study do not automatically provide fair comparative estimates. The reasons participants receive different regimens and the sequence in which regimens are studied can affect who is included in each group.

The ORR definition is another important statistical feature. By specifying RECIST v1.1 criteria, the record sets rules for what qualifies as complete or partial response. A clear definition makes the endpoint more reproducible, but interpretation still depends on the analysis denominator, evaluability, missing-data handling, and the reported estimate with its uncertainty. Those primary-result details are not reported in the registry record.

The record also provides a useful reminder that counts and percentages require context. Serious-event counts are listed by regimen, but groups differ in size and the study was not randomized. Without event follow-up and denominator details, these summaries do not support direct comparative risk conclusions.

Finally, the registry lists many outcome measures but no registered analysis entries. In general, statistical interpretation benefits from knowing which outcomes were prioritized, how multiplicity was handled, and how missing data were treated. Their absence from the registry record limits what can be concluded, even when outcome definitions and study aims are available.

14. Limitations

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

The main limitation for interpreting the primary endpoint is that the numerical ORR result, 95% confidence interval, and number analyzed are not reported in the registry record. Although the endpoint and assessment schedule are defined, the observed response proportion and its precision cannot be evaluated from the record.

The study was non-randomized and had no reported randomized comparator. The listed regimens differ in dose and schedule, and the record describes distinct disease populations for expansion. Consequently, the groups are not like-for-like control groups. The registry record does not report adjusted comparisons that could account for differences between them.

The endpoint population is not fully specified in the available description. The record states that the full analysis set included participants who received at least one dose and that participants with ALK and NSCLC were evaluated for ORR. It does not report the endpoint-specific denominator or how unevaluable and missing response assessments were handled. Enrollment of 137 should not be treated as the ORR analysis denominator.

For safety, the record provides serious-event counts by regimen and selected term percentages, but does not report the denominator behind those term percentages, detailed follow-up, or the method used to summarize events. Death counts are listed, but their definition, timing, and attribution are not reported in the registry record. The counts therefore have limited value for comparative interpretation.

Further limitations include the absence of a reported statistical analysis plan, missing-data methods, multiplicity approach, interim-analysis details, and the trial’s sample-size justification. These items are not reported in the registry record. Their absence should not be filled by assumptions about typical Phase 1/2 practice. The record lists 19 outcome measures and 0 registered analysis entries, but does not provide enough analysis detail to assess how the full set of outcomes was handled.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-Tumor Activity of the Oral Anaplastic Lymphoma Kinase (ALK)/Epidermal Growth Factor Receptor (EGFR) Inhibitor Brigatinib (AP26113) — NCT01449461.
• Registry record last updated 2021-08-17; status last verified 2021-07.
• Results first posted 2017-06-21.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

This completed Phase 1/2 study evaluated oral brigatinib through non-randomized dose escalation and expansion. The stated aims included safety, tolerability, pharmacokinetics, dose-limiting toxicities, maximum tolerated dose, recommended Phase 2 dose, and preliminary anti-tumor activity. The registry lists enrollment of 137 and six brigatinib regimen labels.

The primary endpoint was investigator-assessed ORR by RECIST v1.1, measured from screening at 8-week intervals through study end, up to 8.4 years. The record describes the response criteria and specifies a 95% confidence interval, but the numerical ORR, interval, and number analyzed are not reported in the registry record.

Serious adverse-event counts are listed by regimen, along with selected event terms and percentages. Because allocation was non-randomized and no randomized control group is reported, those figures are descriptive rather than like-for-like treatment comparisons. The registry record does not report the full analysis plan, missing-data handling, or multiplicity approach.