This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record.
1. Trial at a Glance
IPATunity150 was a randomized phase 1 study comparing ipatasertib plus palbociclib and fulvestrant with placebo plus palbociclib and fulvestrant in hormone receptor positive and HER2 negative locally advanced unresectable or metastatic breast cancer. The study enrolled 20 participants and was terminated before initiation of Phase III.
| Feature | IPATunity150 |
|---|---|
| Study name | IPATunity150 |
| ClinicalTrials.gov identifier | NCT04060862 |
| Phase | Phase 1 |
| Status | Terminated |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Triple |
| Primary purpose | Treatment |
| Enrollment | 20 |
| Number of arms | 2 |
| Lead sponsor | Hoffmann-La Roche |
| Sponsor type | Industry |
2. Clinical Question
The registered study compared an ipatasertib-containing combination with a matching placebo-containing combination in patients with hormone receptor positive and HER2 negative locally advanced unresectable or metastatic breast cancer. The registered Phase III endpoint was progression-free survival, but the study was terminated before Phase III was initiated.
Population
Patients with hormone receptor positive and HER2 negative locally advanced unresectable or metastatic breast cancer.
Intervention
Ipatasertib plus palbociclib and fulvestrant.
Comparator
Placebo plus palbociclib and fulvestrant.
Primary question
The registered Phase III question concerned whether progression-free survival differed between the two treatment strategies.
3. Trial Design
Ipatasertib combination
- Ipatasertib
- Palbociclib
- Fulvestrant
Placebo combination
- Placebo
- Palbociclib
- Fulvestrant
4. Study Timeline
Study start
The registry lists November 21, 2019 as the study start date.
Primary completion
The registry lists August 29, 2023 as the primary completion date.
Study stopped before Phase III
The study was terminated before initiation of Phase III according to the sponsor's decision.
5. Endpoints
The registered primary endpoint is a Phase III progression-free survival endpoint. Its wording and time frame are specific to the planned Phase III component of the study.
| Endpoint | Registry definition | Time frame |
|---|---|---|
| Phase III: Progression-Free Survival (PFS), as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) | PFS was defined as the time from randomization to the first occurrence of disease progression as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurred first. Progressive disease (PD) is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters at prior timepoints (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of ≥ 5 millimeters (mm). | From randomization in Phase III until the first occurrence of disease progression or death from any cause, whichever occurs first, up to approximately 36 months |
6. Statistical Methodology
Time-to-event endpoint
Progression-free survival is a time-to-event endpoint. The statistical analysis must account for both the timing of an event and participants who have not experienced progression or death by the end of their available follow-up.
The registry's definition makes progression and death competing ways for a participant to reach the PFS event. A participant without either event at the relevant follow-up point is typically treated as right-censored for a time-to-event analysis.
RECIST v1.1 assessment
The registered endpoint specifies investigator determination according to RECIST v1.1. Under the registry definition, progressive disease requires at least a 20% increase in the sum of diameters of target lesions relative to the smallest prior sum, together with an absolute increase of at least 5 mm.
Typical statistical comparison
For a randomized trial with this type of endpoint, a conventional analysis would typically estimate PFS using Kaplan-Meier methods, compare randomized groups using a log-rank test, and estimate a treatment hazard ratio with a Cox proportional-hazards model. Those methods preserve the time dimension rather than reducing every participant to a simple progression/no-progression indicator.
Kaplan-Meier
Estimates the probability of remaining progression-free over time while accommodating right-censored observations.
Log-rank test
Provides a statistical comparison of time-to-event distributions between randomized treatment groups.
Cox model
Provides a hazard-ratio framework for describing the relative instantaneous event rate between treatment groups.
RECIST endpoint
Defines the radiologic progression event according to the prespecified lesion-size criteria in the registry.
7. Planned Analysis
The registry reports results as posted, but it does not contain posted statistical analyses for the registered primary endpoint. The record states that the study was terminated before initiation of Phase III and that no primary efficacy and secondary efficacy, safety and pharmacokinetic outcome measures were assessed or analyzed for Phase III.
How the planned PFS analysis would be interpreted
A Kaplan-Meier curve would describe the estimated progression-free probability over time in each randomized group. A hazard ratio below 1 would indicate a lower estimated instantaneous rate of progression or death in the ipatasertib combination group relative to the placebo combination group, under the Cox model.
That interpretation would not mean that the same percentage of participants were protected from progression, nor would it imply a fixed proportional reduction in individual risk at every time point. The Cox interpretation depends on the model and, importantly, on the proportional-hazards assumption.
A hazard ratio is a relative time-to-event measure. It is not the same as an absolute difference in PFS probability, a difference in median PFS, or the proportion of participants who benefit.
8. Safety
The registry reports a serious-adverse-event count for the Phase Ib ipatasertib combination arm. The record states that 4 of 20 participants were affected.
| Safety measure | Arm | Affected / at risk |
|---|---|---|
| Serious adverse events | Phase Ib: Ipatasertib + Palbociclib + Ful | 4/20 |
The reported figure means that 4 participants were affected by serious adverse events among 20 participants at risk in the specified Phase Ib ipatasertib combination arm. It is a count of participants affected, not a measure of event severity, duration, causality, or comparative treatment effect.
Because the registry supplies this figure for one specified arm, it should not be converted into a between-arm safety comparison. A comparative safety interpretation requires corresponding information for the relevant comparison group and a defined safety analysis population.
9. Statistical Methods Explained
Why is PFS analyzed as a time-to-event endpoint?
PFS contains information about when progression or death occurs, not simply whether it occurs. Time-to-event methods allow participants with different lengths of observation to contribute information without treating an individual who remains event-free at last follow-up as equivalent to someone who experienced an event.
What does the RECIST v1.1 definition contribute?
A statistical analysis needs a reproducible definition of the event being analyzed. Here, the registry defines progression using changes in the sum of target-lesion diameters. The requirement for both a relative increase of at least 20% and an absolute increase of at least 5 mm helps distinguish meaningful progression from very small numerical changes.
Why would Kaplan-Meier estimation be appropriate?
Kaplan-Meier estimation is designed for time-to-event data with right censoring. It produces an estimated progression-free survival function, allowing the analysis to show how the probability of remaining free of progression or death changes over follow-up.
What would a PFS hazard ratio mean?
A PFS hazard ratio would compare the modeled instantaneous rate of progression or death between the randomized groups. A value below 1 would correspond to a lower estimated event rate in the numerator group, while a value above 1 would correspond to a higher estimated event rate. It would not directly state how many additional months an individual participant would remain progression-free.
Why does censoring matter?
Participants may reach the end of available follow-up without a qualifying PFS event. Their information is not simply discarded, but it also cannot be treated as though they remained progression-free indefinitely. Time-to-event methods account for this partial observation through censoring.
Why is the proportional-hazards assumption important?
The Cox model summarizes relative event rates with a hazard ratio. That summary is most straightforward when the relative hazards are reasonably represented by a proportional-hazards structure. If treatment effects change substantially over time, a single hazard ratio can conceal important features of the underlying survival curves.
10. Understanding the Registry's Phase III Endpoint
The distinction between a registered endpoint and an analyzed endpoint is especially important for IPATunity150. The registry identifies PFS as a Phase III primary endpoint with a follow-up period of up to approximately 36 months. The study, however, was terminated before initiation of Phase III.
| Element | Statistical meaning |
|---|---|
| Endpoint | Progression-free survival |
| Event | First investigator-determined progression according to RECIST v1.1 or death from any cause |
| Starting point | Randomization in Phase III |
| Planned observation period | Up to approximately 36 months |
| Analysis status | No posted statistical analysis for the endpoint |
| Study status | Terminated before initiation of Phase III |
This distinction prevents a common statistical error: treating the existence of a prespecified endpoint as evidence that the corresponding endpoint was successfully evaluated. An endpoint can be formally registered without generating a completed efficacy comparison when the study does not reach the stage at which that endpoint is intended to be assessed.
11. What the Study Design Does and Does Not Establish
Randomization
Randomized allocation provides the structural basis for a comparative treatment analysis by reducing systematic allocation differences between study groups.
Parallel design
Participants were assigned to parallel treatment arms rather than being exposed sequentially to both randomized treatment strategies.
Triple masking
The registry classifies the study as triple masked, a design feature intended to reduce the influence of treatment knowledge on relevant aspects of trial conduct and assessment.
Termination
The study's termination before Phase III means the planned Phase III efficacy question did not proceed to its intended analysis stage.
12. Why the Sample Size Matters Statistically
The study enrolled 20 participants. Sample size affects the amount of information available for estimating treatment effects and the precision of statistical estimates. With a small randomized study, a treatment-effect estimate can be highly sensitive to individual observations, particularly for time-to-event endpoints where a relatively small number of events may determine much of the available information.
For a mature PFS analysis, investigators would ordinarily need enough qualifying progression or death events to provide the planned information for the treatment comparison. Enrollment by itself does not establish that sufficient event information exists.
The IPATunity150 record illustrates why a registered Phase III endpoint and a completed Phase III statistical analysis are different concepts. The registry's stated reason for termination specifically indicates that Phase III was not initiated and that the corresponding primary efficacy, secondary efficacy, safety and pharmacokinetic outcome measures were not assessed or analyzed.
13. Limitations
- Early termination: the study was terminated before initiation of Phase III as a result of the sponsor's decision.
- No Phase III efficacy analysis: the registry states that primary efficacy and secondary efficacy outcome measures for Phase III were not assessed or analyzed.
- No Phase III safety analysis: the registry states that Phase III safety outcome measures were not assessed or analyzed.
- No Phase III pharmacokinetic analysis: the registry states that Phase III pharmacokinetic outcome measures were not assessed or analyzed.
- Limited safety information: the posted serious-adverse-event information identifies 4 affected participants among 20 at risk in the Phase Ib ipatasertib combination arm, without providing a corresponding comparative safety result in the record summarized here.
- Endpoint-stage distinction: the registered PFS endpoint belongs to the planned Phase III component, so it should not be treated as a completed Phase I efficacy result.
- Precision: the enrollment of 20 provides a limited amount of statistical information compared with the larger samples typically required for mature confirmatory time-to-event analyses.
14. Why This Trial Matters Statistically
IPATunity150 is a useful teaching example because it shows that statistical analysis begins with understanding the relationship between study design, endpoint definition, analysis stage, and the information actually available for inference. A registry can contain a detailed prospective endpoint while the corresponding analysis remains unperformed because the study stops before that phase begins.
| Statistical concept | How it appears in IPATunity150 |
|---|---|
| Randomization | The study uses randomized allocation. |
| Parallel design | The trial has 2 parallel arms. |
| Masking | The registry classifies the study as triple masked. |
| Time-to-event analysis | The registered Phase III endpoint is progression-free survival. |
| RECIST-based endpoint | Progression is defined using investigator assessment according to RECIST v1.1. |
| Censoring | Would be relevant to a conventional PFS analysis because participants can remain event-free at the end of observation. |
| Hazard ratio | Would ordinarily provide a relative treatment-effect measure in a Cox analysis of PFS. |
| Kaplan-Meier estimation | Would ordinarily describe the PFS distribution over time. |
| Early termination | The planned Phase III analysis did not proceed because Phase III was never initiated. |
| Analysis availability | The registry contains no posted statistical analyses for the registered primary endpoint. |
15. Clinical Interpretation vs Statistical Interpretation
Statistical interpretation
The registered Phase III PFS endpoint is a time-to-event outcome that would ordinarily support Kaplan-Meier estimation and comparative modeling of progression or death. The registry does not provide a completed statistical analysis for that endpoint.
Clinical interpretation
The study evaluated an ipatasertib-containing regimen against a placebo-containing regimen in the specified breast cancer population, but the registry states that Phase III was not initiated and its efficacy endpoints were not assessed or analyzed.
16. Statistical Interpretation of an Unanalyzed Endpoint
The registered PFS endpoint clearly defines the event and its time origin: randomization in Phase III followed by the first investigator-determined progression according to RECIST v1.1 or death from any cause.
If a completed PFS analysis had produced a hazard ratio, the estimate would summarize the relative instantaneous rate of progression or death between randomized groups under the selected survival model. A confidence interval would quantify statistical uncertainty around that estimate.
For any future or hypothetical formal comparison, a p-value would address evidence against a specified null hypothesis under the statistical testing framework. It would not quantify the magnitude of a treatment effect. Effect size, confidence interval, and clinically relevant absolute measures answer different questions.
Because the study was terminated before Phase III was initiated, the planned Phase III PFS question did not progress to its intended efficacy analysis. The absence of a completed comparison is therefore a feature of the study's development path rather than evidence for or against either treatment strategy.
17. Record-Level Interpretation of Termination
The registry states that the study was terminated before initiation of Phase III as per the sponsor's decision. It further states that, as a result, no primary efficacy and secondary efficacy, safety and pharmacokinetic outcome measures were assessed or analyzed and no data was collected for Phase III.
This is an important distinction in evidence interpretation. A randomized design can establish the intended framework for comparison, but randomization alone does not produce an estimate of treatment effect. The estimate comes from the subsequent observation, endpoint adjudication, statistical analysis, and uncertainty quantification.
18. Sources
- ClinicalTrials.gov: NCT04060862 — IPATunity150.
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19. Record Summary
IPATunity150 was a randomized, triple-masked, parallel phase 1 study of ipatasertib plus palbociclib and fulvestrant versus placebo plus palbociclib and fulvestrant in hormone receptor positive and HER2 negative locally advanced unresectable or metastatic breast cancer. The study enrolled 20 participants and was terminated before initiation of Phase III. Its registered Phase III primary endpoint was progression-free survival, defined from randomization to the first occurrence of investigator-determined progression according to RECIST v1.1 or death from any cause, with a planned time frame of up to approximately 36 months.
The principal statistical lesson is the distinction between a registered endpoint and a completed analysis. PFS is naturally analyzed with time-to-event methods such as Kaplan-Meier estimation, log-rank comparison, and Cox modeling, but those methods require observed endpoint data. The registry states that the planned Phase III efficacy, secondary efficacy, safety and pharmacokinetic outcome measures were not assessed or analyzed because Phase III was not initiated.