A Phase Ib/II Study of the Combination of BYL719 Plus AMG 479 in Adult Patients With Selected Solid Tumors: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Phase Ib/II Study of the Combination of BYL719 Plus AMG 479 in Adult Patients With Selected Solid Tumors (NCT01708161), a na phase 1, phase 2 study. The primary outcome is Dose Limiting Toxicities (DLTs) - Phase Ib.

2. Clinical Question

The study’s broader objectives differed by phase. Phase Ib aimed to estimate the maximum tolerated dose or identify recommended phase II doses for the combination. Phase II was intended to assess clinical efficacy and further assess safety in selected patient populations. The record names response and disease-control measures among secondary outcomes, along with pharmacokinetic measures for both drugs.

These objectives should not be mistaken for evidence of a comparative treatment effect. There was no randomized comparator, and the registry record does not report a primary endpoint result or clinical efficacy result in the registry record for this analysis. The central statistical question that can be identified is therefore what the study set out to measure, and what information the posted record supplies about that measurement—not whether the combination outperformed another treatment.

3. Trial Design

This was a multi-center, open-label phase Ib/II study of BYL719 plus AMG 479 in adults with selected solid tumors. The registry lists PIK3CA mutated and PIK3CA amplified advanced solid tumors as conditions. It records the study as single-group, with allocation listed as NA and masking as none. The recorded enrollment is 47. The study status is terminated; a reason for termination is not reported in the registry record.

The phase Ib purpose was dose finding: estimating the maximum tolerated dose or identifying recommended phase II doses for the combination. The arm description says that sequential cohorts of 3-6 patients were to be enrolled until an MTD or recommended phase II dose was defined. It also says that cohorts could receive different combination doses. This describes the planned approach, not proof that every planned cohort or dose was completed.

The phase II portion was intended to assess clinical efficacy and further assess safety in selected populations. Registry outcome titles refer to HR positive breast and ovarian cancer, as well as phase Ib response, disease control and pharmacokinetics. These labels do not establish that the groups were comparable with one another. The study had no randomized control group, so outcomes across dose cohorts or expansion groups cannot be interpreted as a like-for-like controlled comparison.

The registry lists the study start as 2012-11-27 and primary completion as 2014-12-26. The summary states that treatment was to continue until disease progression, unacceptable toxicity or withdrawal of informed consent, whichever occurred first, and that patients were to be followed up. At a minimum, the planned safety follow-up was 30 days after the last dose. These are descriptions of the study plan; the record does not establish how completely these procedures were carried out.

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: Patients with selected advanced solid tumors who had relapsed or progressed on standard therapy were treated in BYL719X2105J study with a combination of alpelisib and ganitumab. Phase I of the trial was by dose combination of the treatment. Phase II was by patients.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Dose determining set (DDS): DDS includes all patients from the safety set who either met the minimum treatment exposure and safety evaluation requirements without experiencing DLT within Cycle 1 or experienced a DLT at any time during Cycle 1.

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

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Dose Limiting Toxicities (DLTs) - Phase Ib, measured over 28 days.

The primary endpoint is the number of participants with dose-limiting toxicities during phase Ib. The registry specifies a 28 days timeframe and says the endpoint applies to phase Ib only. Its population is the dose-determining set: participants from the safety set who either met minimum treatment exposure and safety evaluation requirements without a dose-limiting toxicity within Cycle 1, or experienced a dose-limiting toxicity at any time during Cycle 1.

A dose-limiting toxicity count is used in dose-finding research because tolerability at a dose helps inform whether that dose, or a different dose, should be considered for later study. Here, that purpose aligns with the phase Ib aim of estimating the MTD or identifying recommended phase II doses. The registry record does not provide the criteria used to define a dose-limiting toxicity, beyond the population and timing description, so the clinical events counted under that definition cannot be independently characterized from this record.

The endpoint is a count, not a direct estimate of comparative benefit. The number of participants meeting the endpoint is not reported in the registry record. The number of participants assessed for this endpoint and any uncertainty interval around the result are also not reported. Consequently, the available record describes what was intended to be measured but does not show the primary endpoint outcome.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The study combines dose escalation in phase Ib with an intended phase II assessment. These phases address different statistical questions. Dose escalation asks whether the combination can be administered at candidate doses while monitoring dose-limiting toxicity; the phase II objective was to assess clinical efficacy and further assess safety in selected populations. The registry identifies these aims but does not report the complete statistical methods used to address them.

What does a single-group design imply?

In a single-group study, participants receive the study intervention without a separate randomized control group. The registry records this study as single-group, with allocation NA and no masking. Such a design can describe outcomes observed among treated participants, but it cannot by itself separate treatment effects from the natural course of disease, participant selection, other care or measurement processes. Comparisons between dose cohorts or disease groups are also not randomized comparisons. Differences in their outcomes could reflect differences in who entered each group, in addition to any difference associated with dose or tumor group.

Why is a dose-limiting toxicity count relevant?

For dose finding, toxicity observations help characterize tolerability at candidate doses and inform selection of a dose for further study. The primary endpoint is a participant count in the dose-determining set during the specified 28 days. The record describes this set using safety-set membership and treatment exposure and evaluation criteria, together with whether a dose-limiting toxicity occurred during Cycle 1. It does not report the operational definition of a dose-limiting toxicity, the observed count, or how that count informed dose selection.

As a general statistical point, a count of participants with an event is often interpreted in relation to the number assessed. The denominator matters because the same count can convey different information in groups of different sizes. The registry record does not report the primary endpoint count or the number assessed in the dose-determining set, so neither an event proportion nor its precision can be described. A confidence interval, when reported, expresses uncertainty around an estimate under specified assumptions; no primary endpoint confidence interval is reported in this record.

What can the safety summaries establish?

The adverse-event information lists counts by group for participants affected by serious adverse events, participants affected by other adverse events, and deaths. These are descriptive summaries. They do not establish that an event was caused by treatment, and they do not create a valid treatment comparison across groups. In general, interpretation of event frequencies depends on clear definitions, the relevant population, exposure and follow-up. The registry entries available do not provide all those details for the listed counts.

General statistical caution also applies when event rates are based on small groups: estimates can be imprecise, and a small change in the observed count can materially alter an estimated proportion. This is a general consideration, not a claim about a calculated estimate in this study. The registry does not provide uncertainty intervals for the adverse-event counts in the registry record for this analysis.

What is known about the analysis plan?

The registry lists 11 outcome measures and 0 analyses. It includes outcome titles for response and disease control based on investigator radiology assessment, and pharmacokinetic measures such as Cmax, AUC, Tmax and half-life. Outcome titles specify intended measurements; they do not provide their numerical results or analysis methods. The statistical analysis plan, including model specifications, hypothesis tests, covariate adjustment and handling of repeated measurements, is not reported in the registry record.

The record also contains planning assumptions for a sample-size illustration: two-sided significance level 0.05, equal allocation between two arms and a normal approximation, with the effect to detect expressed as a stated fraction of the observed effect. Those assumptions describe a planning illustration, not the single-group study design, and no sample-size output or observed effect is available in the registry record for this analysis. Such illustrations are planning aids, not observed power. The trial’s own sample-size justification is not reported in the registry record.

More generally, over-dispersion occurs when variation in count data exceeds what a simple model assumes. If present, it can make model-based uncertainty too small unless the analysis accounts for it. This is a general statistical issue, not a reported feature or method of this trial. Because the analysis methods are not reported, it is not possible to determine whether a particular model or adjustment was used. The same caution applies to multiplicity: without the prespecified testing strategy, the handling of multiple outcomes cannot be assessed.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 11 outcome measures, including the primary dose-limiting-toxicity endpoint and secondary outcomes for response, disease control and pharmacokinetics. It reports 0 analyses. The outcome titles do not state which outcomes were tested, which were descriptive, whether analyses were prespecified, or how any tests across outcomes were handled. The statistical plan for multiplicity is not reported in the registry record.

Multiplicity is a general concern when many outcomes or comparisons are assessed. If several statistical tests are conducted, the chance of at least one apparently unusual result can increase unless the analysis plan addresses that issue. Possible approaches depend on the scientific aims and planned analyses; none is identified in the registry record for this study. The presence of multiple outcome measures does not itself show that a particular adjustment was required or used.

The registry describes the dose-determining set for the primary endpoint and refers to a safety set as part of that definition. It does not report the size of either set, a full definition of the safety set, or the analysis populations used for the secondary outcomes. Handling of missing endpoint data, withdrawals, incomplete follow-up and participants who did not meet evaluation requirements is not reported in the registry record. The record also does not report whether analyses followed an intention-to-treat principle or another population rule.

These omissions limit reproducibility and interpretation. Without analysis-population counts and missing-data methods, it is not possible to judge how closely endpoint analyses reflect enrolled participants or whether missing observations could influence the results. Without a stated multiplicity strategy, the evidential status of results across the listed outcomes cannot be assessed. The registry’s stated objectives and outcome titles should therefore be distinguished from a complete analysis plan or a set of reported findings.

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: hyperglycaemia (50.0%), drug hypersensitivity (25.0%), abdominal pain (16.7%), asthenia (16.7%), pyrexia (16.7%).

The registry reports serious adverse-event counts by group. In the BYL 200mg + AMG 12 mg/kg group, 1 of 4 participants was affected; in the BYL 300mg + AMG 12 mg/kg group, 5 of 10 were affected; and in the BYL 350mg + AMG 12 mg/kg group, 5 of 10 were affected. The HR + BC - Phase II group lists 9 of 16 participants affected, and the Ovarian - Phase II group lists 5 of 6. These are descriptive counts, not randomized comparisons.

For other adverse events, the registry lists 4 of 4, 10 of 10, 10 of 10, 16 of 16 and 6 of 6 participants affected in those groups, respectively. The listed death counts are 4, 8, 8, 13 and 5, respectively. The record does not explain the timing or attribution of these deaths, and does not provide enough information to interpret them as treatment-caused events.

The registry also lists Hyperglycaemia at 50.0%, Drug hypersensitivity at 25.0%, and Abdominal pain, Asthenia, Pyrexia and Blood creatinine increased at 16.7% each among its top serious terms. The denominator and detailed context for these percentages are not reported in the registry record. The group counts and term percentages should not be combined or compared as if they came from equivalent populations with the same follow-up.

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

The posted record establishes that this study was designed to investigate a combination of BYL719 and AMG 479 in adults with selected solid tumors. Its phase Ib objective was dose finding, with dose-limiting toxicity as the primary endpoint; phase II was intended to assess efficacy and further assess safety. The registry entries also describe the single-group design, planned dose-cohort approach, recorded enrollment and selected adverse-event counts.

The record does not report the primary endpoint count, the dose ultimately selected, or numerical phase II efficacy results. It therefore does not establish how often dose-limiting toxicities occurred in the dose-determining set, nor does it establish an estimate of response or disease control. The study’s stated aims should not be treated as findings. Likewise, the listed safety counts are descriptive and do not establish that treatment caused an event.

Because there was no randomized control group, the record does not provide a controlled estimate of the combination’s effect relative to another treatment or to no study treatment. Any differences among dose cohorts or expansion groups would need to be interpreted cautiously; group membership was not randomized, and the registry entries do not establish comparability. The study status is terminated, but a reason for termination is not reported in the registry record. That status cannot by itself be used to infer a safety, efficacy or operational explanation.

In general, estimates are more informative when accompanied by their analysis population, uncertainty and methods. Those details are not available for the primary endpoint in the registry record examined. The registry record is therefore useful for identifying the study question and design, but insufficient for judging the primary dose-finding result or the magnitude and precision of a clinical efficacy result. No medical conclusion about the combination follows from these registry entries alone.

13. Why This Trial Matters Statistically

This trial illustrates why a study’s stated objective, design and reported result must be read separately. Its phase Ib objective was to inform dose selection through dose-limiting toxicity assessment, while phase II was intended to assess clinical efficacy and further safety. Those are distinct tasks, and the primary endpoint is a safety count rather than a direct efficacy measure.

The single-group design is central to the interpretation. Dose cohorts could receive different doses, and the phase II groups included selected patient populations, but the registry does not describe randomized assignment or a control group. A comparison between those groups would not have the protection against baseline differences that randomization can provide. The record itself cautions that the arms are not a like-for-like control comparison.

The available information also demonstrates the importance of complete outcome reporting. The registry identifies 11 outcome measures but lists 0 analyses in the registry record considered. Without the primary endpoint result, analysis population counts, uncertainty estimates and analysis methods, readers cannot evaluate the precision or robustness of the dose-finding result. Outcome titles and study objectives alone are not substitutes for results.

Finally, safety counts require context. Group sizes differ, and the registry entries do not fully specify event timing, exposure, causality or follow-up for the adverse-event summaries. The listed counts can be described, but they should not be treated as comparative risks or evidence of treatment causation. These features make the study a useful example of how design and reporting determine what statistical conclusions are supportable, even when the clinical question is clearly stated.

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 central limitation is that the primary endpoint result is not reported in the registry record. The dose-limiting-toxicity count, the number assessed in the dose-determining set and any uncertainty around the result are absent in the registry record. The record therefore does not permit an assessment of the observed dose-finding outcome.

The study was single-group and had no randomized control group. The registry identifies dose cohorts and phase II groups, but the design does not support a like-for-like controlled comparison among them. Participants could receive different doses, and the groups represent selected populations. The registry entries do not establish whether group differences in outcomes would reflect dose, patient characteristics or other influences.

The registry describes the dose-determining set but does not report its size or the full definition of the safety set. It does not provide missing-data rules, analysis populations for secondary outcomes, the statistical analysis plan, or uncertainty estimates for the primary endpoint. The definition of dose-limiting toxicity is not reported beyond the endpoint’s population and timing description. These gaps limit reproducibility and prevent a detailed assessment of the analysis.

Safety reporting is also limited in context. Counts by group and selected serious-event terms are available, but event timing, exposure, follow-up, causal attribution and the denominator for the listed term percentages are not reported in the registry record examined. The reason the study was terminated is not reported. Consequently, the termination status does not resolve the missing results or explain the study’s completion history.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Phase Ib/II Study of the Combination of BYL719 Plus AMG 479 in Adult Patients With Selected Solid Tumors — NCT01708161.
• Registry record last updated 2018-09-13; status last verified 2018-08.
• Results first posted 2018-06-28.
• 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

The registry record describes NCT01708161, a multi-center, open-label phase Ib/II single-group study of BYL719 plus AMG 479 in adults with selected solid tumors. Recorded enrollment is 47, and the study status is terminated. Phase Ib aimed to estimate the MTD or identify recommended phase II doses; phase II was intended to assess clinical efficacy and further safety.

The primary endpoint was the participant count with dose-limiting toxicities in the dose-determining set during 28 days. The observed primary endpoint result is not reported in the registry record. The record lists 11 outcome measures and 0 analyses. It includes group-level adverse-event counts and selected serious-event terms, but these are descriptive and do not support randomized comparisons or causal conclusions.