RO4929097 and Whole-Brain Radiation Therapy or Stereotactic Radiosurgery in Treating Patients With Brain Metastases From Breast Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for RO4929097 and Whole-Brain Radiation Therapy or Stereotactic Radiosurgery in Treating Patients With Brain Metastases From Breast Cancer (NCT01217411), a randomized phase 1, phase 2 study. The primary outcome is Response Rate (Complete or Partial Response).

2. Clinical Question

3. Trial Design

The study is registered as a phase I/II trial with randomized allocation, no masking, and a parallel-group model. Its official title describes two phase I studies in patients with brain metastases from any primary histology, followed by a randomized phase 2 study of RO4929097 combined with central nervous system radiotherapy in patients with estrogen receptor-negative breast cancer brain metastases. The brief description also refers to comparison with radiotherapy alone.

The treatment plan paired the radiotherapy approach with the number of brain lesions. Patients with at least 4 lesions were assigned WBRT, while patients with 3 or fewer lesions were assigned SRS. The described comparison was radiotherapy alone versus radiotherapy with RO4929097. The arm descriptions name Arm I as WBRT or SRS and Arm II as WBRT or SRS with RO4929097. However, the adverse-event group labels describe Phase 1 Arm I as WBRT plus RO4929097 and Phase 1 Arm II as SRS plus RO4929097. This mismatch makes the labels difficult to reconcile and limits certainty about the precise treatment represented by each safety group.

The registry lists enrollment of 5 and reports phase I arm sizes of 3.0 and 2.0. The record is marked terminated. It lists a start date of 2010-10-01 and a primary completion date of 2011-11-30. The reason for termination is not reported in the registry record. Although the registration describes a planned randomized phase 2 component, the posted arm results are labelled phase I, and the record does not report phase 2 comparison results.

The trial included cognitive assessment and laboratory biomarker analysis among its interventions. The registry record does not report further details of these procedures or their results. Nor does it report the randomization method, allocation concealment, or a detailed statistical analysis plan.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: Study terminated early due to low accrual and discontinuation of investigational study drug.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Analysis was not available due to small number of patients on the study.

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: 5 participants were enrolled/treated at the 5 mg (starting dose) study drug.

6. Primary Endpoint

The registry lists the primary outcome as Response Rate (Complete or Partial Response), measured over 12 weeks.

The primary endpoint is response rate, defined as the number of participants with complete or partial response, assessed at 12 weeks. It is a binary clinical outcome at the participant level: each participant is classified according to whether their disease meets the response definition. The registry describes complete response as disappearance of all lesions. Partial response requires at least a 50% decrease in the sum of the bidimensional products of lesions, relative to baseline.

The response categories are interpreted alongside progressive disease and stable disease. Progressive disease includes an increase greater than 25% in the sum of lesion bidimensional products, progression of a treated lesion that is not a target lesion, or the appearance of new lesions meeting the stated size criterion. Stable disease is neither sufficient shrinkage for partial response nor sufficient increase for progressive disease, using the smallest sum of lesion bidimensional products as the reference.

A response endpoint is used to describe whether measurable disease has decreased or disappeared according to prespecified criteria. It can provide a direct summary of tumor response at a defined assessment time, but it does not by itself describe response duration, survival, quality of life, or the balance of benefits and harms. The registry limits evaluability to participants with measurable disease at baseline who received at least 6 weeks of therapy and had disease re-evaluated. The registry record does not report the response assessment results in a form that supports a reliable comparison between the treatment groups.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The outcome is binary because each evaluable participant is classified as having complete or partial response, or not meeting either response category. A count of participants with an event can be useful as a direct description, but a treatment comparison generally also needs the corresponding denominator and a clear account of which participants were included. For this trial, the posted primary outcome is a response count at 12 weeks. The registry record does not provide an estimable comparison between the two arms.

What does a confidence interval communicate?

In general, a confidence interval describes the uncertainty around an estimated quantity under a statistical model and repeated-sampling framework. For a binary outcome, an interval around a response proportion or a between-group contrast helps show how compatible the data are with a range of possible values. A narrow interval indicates greater precision than a wide interval. It is not a guarantee that the true value lies inside the interval, and it does not resolve limitations in the study design or outcome data. The registry record does not report confidence intervals for the primary comparison.

Why is a treatment contrast not available?

A between-group comparison requires interpretable outcome information for each group. The posted record identifies phase I arms and gives arm values, but marks the binary comparison as missing or not estimable. Without a valid, comparable response estimate for both groups, a contrast cannot be interpreted as an estimate of the treatment effect. A numerical difference should not be reconstructed from the arm entries: the record does not establish that those values are response counts suitable for such a calculation, and it does not report a comparison estimate.

How should planning calculations be read?

In general, power calculations for a future study use assumptions about the effect to detect, the significance level, the allocation between groups, and a statistical approximation. The registry's planning description states a two-sided significance level of 0.05, equal allocation, and a normal approximation, with planning based on a stated fraction of the observed effect. These are planning illustrations, not evidence about the chance that this completed or terminated trial detected an effect. They are not observed power. For time-to-event outcomes, the stated convention is a total event count; for other outcomes, the convention is participants per arm. The primary outcome in this record is binary, and its two-arm comparison is not estimable, so planning figures based on an observed effect should be interpreted with particular caution.

Statistical power is a property of a design under assumed conditions, not a retrospective score that can establish whether a treatment effect exists. A nonsignificant or unavailable comparison does not demonstrate equivalence, and a planning illustration does not supply evidence of efficacy. The registry record does not report the original sample-size justification or a detailed statistical analysis plan, so the assumptions used in any planning illustration should not be mistaken for the trial's protocol.

What does the endpoint definition add?

The registry defines response using changes in lesion measurements and includes complete response, partial response, progressive disease, and stable disease categories. Such definitions help make outcome classification more consistent by specifying what constitutes a sufficiently large decrease or increase. The record also conditions response evaluability on baseline measurable disease, receipt of at least 6 weeks of therapy, and reassessment of disease. These criteria explain who can contribute to the response endpoint, but the registry record does not report how many participants met each criterion or how any unevaluable participants were handled in the analysis.

In general, endpoint classification can be affected by measurement variation, timing of reassessment, and missing evaluations. Those considerations matter because participants without an assessment cannot automatically be classified as responders or nonresponders unless the analysis rules specify how to treat them. The registry record does not report rules for missing response assessments or details of the assessment process.

Why does the treatment grouping matter?

The described study compares radiotherapy alone with radiotherapy plus RO4929097, using lesion count to guide the radiotherapy type. The posted adverse-event group labels, however, identify both groups as receiving RO4929097. This discrepancy means the treatment contrast cannot be confidently reconstructed from the group labels. In general, a valid comparison depends on knowing which intervention each participant received and whether outcomes are attributed to the intended groups. The registry record does not report enough detail to resolve the labeling mismatch.

These methodological explanations are general statistical guidance. The specific limitation for this trial is that the registry record does not provide an estimable primary two-arm result, and it does not report the analysis details needed to recover one.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Phase I Arm I", "Phase 1 Arm II")
n      <- c(3, 2)
events <- c(3, 2)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Phase I Arm I  3  3  100.0  29.2  100.0  43.9  100.0  39.8  99.4
ARM  Phase 1 Arm II  2  2  100.0  15.8  100.0  34.2  100.0  29.2  99.2

11. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises when a study tests or interprets multiple outcomes, time points, or treatment comparisons. In general, making many statistical tests can increase the chance of at least one apparently notable result, so a protocol may specify a primary outcome and methods for controlling or interpreting multiple comparisons. The registry identifies response rate at 12 weeks as the primary endpoint and lists 3 outcome measures overall, but it does not provide details of the other measures in the posted record. No secondary outcomes are posted, and the record lists no analyses. Whether multiplicity adjustments were planned or used is not reported in the registry record.

The response analysis is restricted to participants with measurable disease at baseline who received at least 6 weeks of therapy and had disease re-evaluated. This is an evaluability definition, not a complete description of the analysis population. The registry record does not report the number who met each criterion, the number with missing assessments, or how missing data were handled. It also does not report an intention-to-treat analysis, a per-protocol analysis, or another named analysis population.

These omissions matter because excluding participants without an evaluable assessment can affect interpretation if missingness is related to prognosis, treatment exposure, or response. That is a general concern, not evidence that such bias occurred in this trial. The record also does not report whether outcome assessments were independently reviewed or how disagreements were resolved. The reason for trial termination and its effect on planned analyses are not reported in the registry record.

12. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: hyperglycemia (50.0%), hyponatremia (50.0%), anemia (33.3%), anorexia (33.3%), death nos (33.3%).

The adverse-event record lists serious and other events separately, with counts of participants at risk and affected in each group. The group labelled Phase 1 Arm I (WBRT + R04929097) lists 3 at risk and 1 affected for serious events, and 3 at risk and 3 affected for other events. The group labelled Phase 1 Arm II (SRS + RO4929097) lists 2 at risk and 1 affected for serious events, and 2 at risk and 2 affected for other events. These are descriptive counts, not adjusted comparisons.

The listed serious-event terms include hyperglycemia and hyponatremia at 50.0% each, and anemia, anorexia, Death NOS, and dyspnea at 33.3% each. The registry does not give enough information alongside these terms to establish how they are distributed between groups or whether a participant could contribute more than one term. The percentages should not be added together: event categories may overlap, and the record does not say they represent mutually exclusive participants.

The group labels require caution because both name RO4929097, unlike the described comparison of radiotherapy alone with radiotherapy plus RO4929097. Death counts are not reported in the registry record. These safety entries do not establish comparative risk or causation.

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

The posted results establish that the registry contains phase I arm entries and adverse-event counts, and that the study status is terminated. They do not establish a reliable comparative response estimate for the planned strategies. The primary endpoint is clearly defined as complete or partial response at 12 weeks, but the registry record marks the two-arm binary comparison as not estimable and does not report confidence intervals or a hypothesis test.

The arm values are counts, not evidence by themselves of the size or precision of a treatment effect. The record's reported group sizes are small, and the primary outcome entries do not allow a valid comparison to be interpreted. Even if an observed count appears different between groups, counts without a clearly specified outcome denominator and an estimable contrast cannot show how large or uncertain the difference is.

Nor does the record establish that the two treatment strategies are equivalent. Failure to report an estimable comparison is not evidence that outcomes were the same. The registry also does not report survival, response duration, or posted secondary outcome results. The available response endpoint therefore cannot answer every question about clinical course or longer-term outcomes.

The safety counts describe events recorded in groups whose labels do not align cleanly with the stated treatment plan. They should not be used to attribute events to a particular treatment strategy or to infer causation. The record's reported adverse-event terms provide descriptive information, but do not support a complete comparative safety assessment.

In short, these results document a limited set of registry entries from a terminated trial. They do not provide a precise estimate of whether adding RO4929097 changed response or safety relative to radiotherapy alone. The reason for termination, the completeness of planned phase 2 work, and the handling of missing outcome assessments are not reported in the registry record.

14. Why This Trial Matters Statistically

This trial raises several statistical issues that matter in clinical research. First, a prespecified primary endpoint needs to be accompanied by interpretable group-specific results and a valid comparison. Naming response at 12 weeks is not enough if the posted record does not make the two-arm result estimable. Readers need to know the relevant outcome counts, denominators, analysis population, and uncertainty around the contrast to judge what the data can support.

Second, a small study can be useful for early-stage investigation, but its results may be imprecise. This is a general statistical point: when the amount of information is limited, estimates can be sensitive to individual observations. Planning calculations are not a substitute for observed evidence, and a sample-size illustration based on an observed effect does not demonstrate that a study had adequate power or that an effect is real.

Third, consistency in treatment labels is essential. The trial description distinguishes radiotherapy alone from radiotherapy plus RO4929097, while the adverse-event group labels name the drug in both groups. A discrepancy of this kind can make treatment attribution and comparison uncertain. Clear participant flow and arm-specific outcome reporting are needed to connect the planned design to the analyses.

Finally, the response endpoint depends on evaluability, including baseline measurable disease and reassessment after treatment. Reporting the numbers meeting these criteria and the handling of missing assessments would help readers understand which participants informed the outcome. The registry record does not report these details. Together, these points illustrate why transparent reporting of analysis populations, missing data, treatment allocation, and uncertainty is central to interpreting clinical trial results.

15. Limitations

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

The registry record has several trial-specific limitations for interpreting the posted results. It is marked terminated, but the reason for termination is not reported in the registry record. The record does not explain whether the planned randomized phase 2 study proceeded as intended or how termination affected follow-up and analysis. The posted arm outcomes are labelled phase I, and no phase 2 comparison result is reported.

The primary endpoint is defined, but the two-arm binary comparison is marked as missing or not estimable. The registry does not report response proportions, confidence intervals, a p-value, or a clear analysis population. It also does not report how many participants met the baseline measurability and follow-up requirements, how missing assessments were handled, or whether any participants were excluded from the response analysis.

There is a mismatch between the arm descriptions and adverse-event group labels. The design description includes radiotherapy alone as a comparator, whereas both adverse-event group labels include RO4929097. This limits confidence in assigning the safety counts to the intended comparison. The registry also does not report a reason for this mismatch.

Enrollment is listed as 5, with phase I arm sizes of 3.0 and 2.0. The small reported groups limit the amount of information available for estimating response or comparing safety. The record does not report a sample-size justification, detailed analysis plan, multiplicity approach, randomization method, or allocation concealment. These omissions restrict assessment of the design and analysis, but do not establish that any particular method was or was not used.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: RO4929097 and Whole-Brain Radiation Therapy or Stereotactic Radiosurgery in Treating Patients With Brain Metastases From Breast Cancer — NCT01217411.
• Registry record last updated 2024-11-19; status last verified 2024-10.
• Results first posted 2015-02-06.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

The registry describes a randomized, parallel phase I/II study of RO4929097 with WBRT or SRS for brain metastases, with a planned comparison against radiotherapy alone. The radiotherapy approach was based on lesion count. The primary outcome was the number of participants with complete or partial response at 12 weeks. The study is marked terminated, with enrollment of 5 and phase I arm sizes of 3.0 and 2.0.

The posted record does not provide an estimable two-arm response comparison, and no analyses or secondary results are listed. Adverse-event counts are reported, but group labels do not align fully with the treatment description. The reason for termination, missing-data handling, and the status of the planned phase 2 comparison are not reported in the registry record.