Combination of BKM120 and Bevacizumab in Refractory Solid Tumors and Relapsed/Refractory Glioblastoma Multiforme: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Combination of BKM120 and Bevacizumab in Refractory Solid Tumors and Relapsed/Refractory Glioblastoma Multiforme (NCT01349660), a na phase 1, phase 2 study. The primary outcome is Number of Phase I Patients Receiving 60mg or 80mg BKM120 Experiencing a Dose-Limiting Toxicity (DLT) to Determine the Optimal Dosage.

2. Clinical Question

The broader study aim was to evaluate the feasibility and efficacy of the combination in relapsed or refractory glioblastoma. Listed secondary outcomes include overall response, median overall survival, and safety and tolerability. Numerical results for response and survival are not reported in the registry record, so this record does not establish the size or precision of any efficacy effect.

3. Trial Design

This completed study had phase I and phase II portions and a total enrollment of 88. The registry lists December 2011 as the start and December 2016 as the primary completion. The sponsor was SCRI Development Innovations, LLC.

Phase I addressed dose selection in patients with refractory solid tumors. Participants received BKM120 orally once daily at 60 mg or 80 mg, alongside bevacizumab 10 mg/kg intravenously every 2 weeks. The dose-limiting toxicity assessment covered the first treatment cycle, up to 28 days. The registry states that the optimal BKM120 dose was determined to be 60 mg once daily, with bevacizumab on Day 1 and Day 15 of each 28 day cycle.

Phase II focused on eligible patients with recurrent or progressive glioblastoma after first-line combined modality therapy. It used 60 mg BKM120, the dose selected in phase I, with bevacizumab 10 mg/kg every 2 weeks. Limited pharmacokinetic sampling was planned for phase II participants; the registry summary says this was to assess BKM120 pharmacokinetics during concurrent bevacizumab administration.

The design is listed as single-group, with no masking and no randomized allocation. Accordingly, the phase I dose levels are not a randomized comparison, and phase II has no listed concurrent control group. Differences between people treated at different doses or with different prior bevacizumab experience would not, by themselves, establish a causal treatment difference. The registry does not report further details of the allocation process or a 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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Includes all Phase I patients receiving assigned study dosing.

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: Patients that received at least one dose of study treatment

6. Primary Endpoint

The registry lists the primary outcome as Number of Phase I Patients Receiving 60mg or 80mg BKM120 Experiencing a Dose-Limiting Toxicity (DLT) to Determine the Optimal Dosage, measured over Collected from day of first dose to the end of the first treatment cycle, up to 28 days.

The primary endpoint counts phase I participants who experienced a dose-limiting toxicity (DLT) while receiving assigned study dosing. The assessment window ran from the first dose through the end of the first treatment cycle, up to 28 days. DLTs were assessed using NCI CTCAE v4.03. The endpoint is a count of participants, rather than a measure of tumor response or survival.

Dose finding uses early safety and tolerability information to select a dose for further study. In this record, the stated decision rule was to select a BKM120 dose at which no more than 1 of 6 patients experienced a DLT in Cycle 1. The registry reports that 60 mg was selected for combination with bevacizumab. It does not report the number of DLTs observed at either dose level, so the reported dose selection cannot be independently checked against the stated rule using the posted primary endpoint results.

The endpoint is limited to the defined assessment period and toxicity criteria. It does not summarize all possible adverse events over the entire study, and it does not measure efficacy. The registry identifies all phase I patients receiving assigned study dosing as the primary endpoint population. Additional details about exclusions or missing endpoint assessments are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical interpretation depends on the question each measure can answer. The primary phase I outcome is a participant count: the number experiencing a DLT within a defined assessment window. It is not a continuous measurement and should not be read as a tumor-response rate or as a summary of all toxicity during the study. The registry states that NCI CTCAE v4.03 was used to assess DLTs in Cycle 1. It also gives the dose-selection rule and states that 60 mg was selected, but the observed DLT counts are not reported in the registry record.

What a count can show

A count describes how many participants in a group met the specified event definition. Its interpretation depends on the denominator, the event definition, and the period during which events were assessed. Counts from small groups can be unstable: a change in the outcome of one participant can materially change the descriptive picture. This is a general statistical point, not a claim about an unreported DLT result in this study.

For phase I, the decision rule refers to 6 patients at a dose level and to the first 28 day cycle. The posted record identifies 60 mg as the selected dose, but does not give the DLT counts by dose. It is therefore not possible to reproduce the rule-based decision from the endpoint counts in the record. The count data also would not, by themselves, quantify the uncertainty around the underlying probability of a DLT; that would require an estimate and an uncertainty interval, neither of which is reported.

Confidence intervals and precision

In general, a confidence interval describes the uncertainty around an estimated quantity under the assumptions of a statistical method. A narrow interval indicates greater precision than a wide interval, while an interval that includes a range of plausible values does not establish that any one value is certain. No confidence interval for the primary endpoint, response, or survival is reported in the registry record. Without estimates and their uncertainty, the numerical precision of the principal outcomes cannot be assessed from this record.

The secondary outcomes include overall response, defined in the outcome title as complete or partial response, and median overall survival. Overall response is a binary outcome for each participant under the applicable response criteria; it is usually summarized using counts or proportions. Median survival describes the time by which half of the analyzed population has experienced the event, with interpretation dependent on follow-up and censoring. These are general descriptions of the statistical concepts. The registry record does not state numerical values for response or survival, nor does it provide enough information to assess censoring, follow-up completeness, or the criteria used for response assessment.

Single-group design and comparisons

Because this is a single-group study with no randomized allocation listed, the results are primarily descriptive. Randomization is a general method for balancing measured and unmeasured participant characteristics across treatment groups; without a randomized comparator, observed differences cannot be attributed to treatment with the same protection against confounding. Phase I dose levels are part of dose selection, not control arms. The phase II outcome listings distinguish participants by prior bevacizumab experience, but such subgroups are not randomized comparisons. Differences between them may reflect differences in their clinical histories or other characteristics not reported in the registry record.

For a binary outcome, a comparison can be expressed as an absolute difference or a relative measure, but each requires outcome data and a defined comparison. No such efficacy estimates are reported. No recalculated unadjusted comparisons are reported in the registry record. There is therefore no sponsor analysis to compare against a recalculation, and no numerical comparison should be inferred from the group descriptions alone.

Planning illustrations

Any sample-size planning illustration based on an observed effect is not an observed trial result and is not observed power. In general, such an illustration asks how many participants might be needed to detect a chosen fraction of an estimated effect under stated assumptions. Its output depends on the effect estimate and assumptions, so it should not be interpreted as the number enrolled or as proof that the study could or could not detect an effect. The registry record does not report a sample-size justification or a trial-specific sample-size analysis plan. No numeric planning result is stated in the registry record.

The planning assumptions described for illustrations include a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the target effect set as a stated fraction of an observed effect. Such assumptions are general planning choices; they do not establish that the original trial used them. The trial's own statistical plan is not reported in the registry record. The study itself was single-group, so an illustration based on equal allocation between two arms should not be mistaken for the actual trial design.

What can and cannot be inferred

Descriptive safety counts can document how many participants had recorded events in the listed groups. They do not establish that one dose caused more events than another, especially without randomization and a reported comparative analysis. Similarly, the selection of 60 mg records the study's stated dose decision, but not a quantified probability of toxicity or evidence about efficacy. General statistical interpretation should distinguish the recorded decision, the observed counts, and estimates with uncertainty; only the dose decision and safety counts are numerically stated in this record.

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 Dose Level 1 (60 mg BKM120, 10mg/kg Bevaci", "Phase I Dose Level 2 (80 mg BKM120, 10mg/kg Bevaci")
n      <- c(6, 6)
events <- c(0, 3)
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 Dose Level 1 (60 mg BKM120, 10mg/kg Bevaci  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Phase I Dose Level 2 (80 mg BKM120, 10mg/kg Bevaci  6  3  50.0  11.8  88.2  18.8  81.2  18.4  81.6

11. Multiplicity, Missing Data and Analysis Populations

The registry lists several outcomes, including the phase I DLT count, phase II overall response, median overall survival, and safety and tolerability outcomes. It also lists response and survival separately for participants with prior bevacizumab and those who were bevacizumab naive. When multiple outcomes or subgroups are examined, the chance of obtaining an apparently notable result by chance can increase. General methods for addressing multiplicity include prespecifying a primary hypothesis or adjusting inference across multiple tests. The registry record does not report a multiplicity strategy, hierarchy of secondary outcomes, or statistical analysis plan.

The record lists no analyses. Numerical phase II response and survival results are not reported in the registry record. It is therefore not possible to determine how many analyses were conducted, whether subgroup analyses were prespecified, or whether any adjustments were applied. The presence of listed outcomes alone does not show how they were analyzed.

Missing-data handling is also not reported in the registry record. The primary endpoint population is described as all phase I patients receiving assigned study dosing, but the record does not state whether all participants had complete DLT assessments or how missing assessments were handled. For the phase II outcomes, the record does not describe exclusions, censoring rules, follow-up completeness, or the analysis population beyond the outcome listings. In general, missing outcome information can affect both the estimated result and its uncertainty, depending on why data are missing and how the analysis treats them. Those details are not available, so no particular missing-data assumption should be attributed to the investigators.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: seizure (16.7%), pneumonia (16.7%), cellulitis (16.7%), diarrhea (16.7%), enteritis (16.7%).

The registry reports serious adverse events and other adverse events as participant counts in three groups. In phase I at the 60 mg BKM dose level with bevacizumab, serious adverse events were reported for 3 of 6 participants and other adverse events for 6 of 6. At the 80 mg BKM120 dose level with bevacizumab, the corresponding counts were 2 of 6 and 6 of 6. In phase II at 60 mg with bevacizumab, the counts were 27 of 76 for serious adverse events and 75 of 76 for other adverse events.

These counts describe the participants recorded as affected in each group; they do not show event severity beyond the separate serious-event classification, duration, recurrence, or timing. The listed serious-event terms include Seizure, Pneumonia, Cellulitis, Diarrhea, Enteritis, and Urinary Tract Infection, each reported as 16.7%. The record does not provide enough detail to determine whether participants experienced more than one event or how the terms relate to the participant counts. Deaths are not reported in the registry record.

The groups are not randomized control groups, and the phase I groups are dose levels in a dose-finding study. The counts should therefore be read descriptively, not as evidence of a difference caused by dose or treatment.

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

The registry record supports several limited conclusions about what the study did. It evaluated BKM120 with bevacizumab in phase I and phase II, identified 60 mg as the selected BKM120 dose, and reported adverse-event counts for the listed groups. The phase I primary endpoint was designed to inform dose selection using DLTs during the first treatment cycle. The phase II portion was intended for eligible participants with recurrent or progressive glioblastoma after first-line combined modality therapy.

The record does not report the DLT counts underlying the dose decision. It also does not provide numerical overall response or median overall survival results. Without those estimates and measures of uncertainty, the magnitude and precision of efficacy outcomes cannot be evaluated. A statement that a dose was selected is not itself a measure of tumor response or survival, and it does not establish how outcomes compare with another treatment or with outcomes outside the study.

The single-group design is another important boundary. Without a randomized comparator, the study can describe outcomes among its enrolled participants but cannot isolate the effect of the combination from other explanations. The phase I dose levels and phase II subgroup listings do not provide randomized treatment contrasts. The adverse-event counts are useful descriptive information, but they do not demonstrate a causal difference between groups.

These limitations do not erase the descriptive information the record contains. They clarify what can be said with confidence from the posted data and what remains unquantified. The registry's stated dose selection and safety counts can be described as reported; efficacy, comparative benefit, and the precision of the main outcomes cannot be inferred from the absent numerical results.

14. Why This Trial Matters Statistically

This study illustrates how phase I dose finding and phase II outcome assessment answer different statistical questions within a single trial. The phase I portion used a defined early toxicity window and a stated rule to select a BKM120 dose for combination treatment. The phase II portion then evaluated the regimen in a specified population with relapsed or refractory glioblastoma. Separating these aims matters: a dose-selection decision is not an efficacy estimate, and a selected dose does not replace reporting the underlying toxicity counts.

The record also demonstrates why outcome definitions and denominators are essential. A participant count is interpretable only in relation to the group and assessment period; the safety results give group sizes and affected-participant counts, while the primary DLT counts are absent. Without the underlying DLT observations, the stated phase I rule cannot be checked directly from the posted endpoint data.

Finally, the single-group design sets a clear limit on causal inference. It can provide descriptive information about participants treated in the study, but it does not supply the randomized comparison needed to separate treatment effects from other factors. The record's lack of numerical response and survival results further limits assessment of phase II outcomes. Taken together, these features show why transparent outcome reporting, uncertainty estimates, analysis populations, and a prespecified statistical plan are important for evaluating clinical trial evidence.

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.

Several trial-specific limitations affect interpretation. First, the registry reports that 60 mg BKM120 was selected but does not give the DLT counts at the phase I dose levels. The primary endpoint's stated rule therefore cannot be checked against the observed counts in the registry record.

Second, numerical phase II results for overall response and median overall survival are not reported in the registry record. The record does not provide estimates, confidence intervals, or statistical tests for these outcomes. It also does not describe follow-up completeness, censoring, response assessment details, or analysis populations for the phase II outcomes.

Third, the study is listed as single-group and unmasked, without randomized allocation or a separate comparator. The phase I dose levels and prior-bevacizumab subgroups should not be treated as randomized contrasts. Differences in outcomes across such groups may reflect participant characteristics or histories as well as treatment exposure.

Finally, the registry does not report a trial-specific sample-size justification, detailed statistical analysis plan, multiplicity approach, or missing-data methods. Serious adverse-event counts are available, but the record does not provide event-level timing, recurrence, or participant-level context. These omissions restrict assessment of precision, bias, and the strength of comparisons that can be made from the posted results.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Combination of BKM120 and Bevacizumab in Refractory Solid Tumors and Relapsed/Refractory Glioblastoma Multiforme — NCT01349660.
• Registry record last updated 2020-06-17; status last verified 2020-06.
• Results first posted 2018-01-31.
• 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

NCT01349660 is a completed phase I/II, single-group study of BKM120 with bevacizumab in refractory solid tumors and relapsed or refractory glioblastoma multiforme. The phase I portion evaluated 60 mg and 80 mg BKM120 dose levels with bevacizumab; the registry reports that 60 mg was selected. Phase II used 60 mg BKM120 with bevacizumab in eligible patients with recurrent or progressive glioblastoma after first-line combined modality therapy.

The primary outcome counted phase I participants with a DLT during the first treatment cycle. The observed DLT counts are not reported in the registry record. Secondary outcomes include overall response, median overall survival, and safety. Numerical response and survival results are not reported. The registry gives serious and other adverse-event counts for the phase I dose groups and phase II group, but the study has no randomized comparator listed. The record does not report a detailed statistical analysis plan, multiplicity strategy, or missing-data methods.