Fulvestrant, Palbociclib and Erdafitinib in ER+/HER2-/FGFR-amplified Metastatic Breast Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Fulvestrant, Palbociclib and Erdafitinib in ER+/HER2-/FGFR-amplified Metastatic Breast Cancer (NCT03238196), a non-randomized phase 1 study. The primary outcome is Number of Participants With Dose Limiting Toxicities (DLT) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD).

2. Clinical Question

3. Trial Design

This is a phase Ib, open-label, multi-institution trial of fulvestrant, palbociclib and erdafitinib in metastatic breast cancer. The condition is listed as metastatic breast cancer, and the stated target population is ER+/HER2-/FGFR-amplified disease. The registry describes the study model as sequential and allocation as non-randomized. Masking is listed as none.

The record lists Escalation and Expansion groups. The Escalation descriptions include combinations of fulvestrant 500mg, palbociclib 125mg and erdafitinib at 5mg, 6mg or 8mg. The Expansion group is also listed. Fulvestrant is given by intramuscular injection once per month; palbociclib is taken by mouth once daily for 21 days followed by 1 week of rest; and erdafitinib is an oral tablet taken once daily. These descriptions identify the planned regimens, but do not supply group-specific treatment exposure or adherence results.

The trial’s brief summary identifies safety, tolerability and preliminary anti-tumor activity as areas of evaluation. The primary outcome is the number of participants with dose-limiting toxicities in the first cycle, used for determination of the maximum tolerated dose. Listed secondary outcomes include progression-free survival, overall response rate, clinical benefit rate, erdafitinib pharmacokinetic measures and treatment-emergent adverse events. The record lists 13 outcome measures, but does not provide outcome values for most of those measures in the registry record for this analysis.

The registry reports a start date of 2017-08-18, a primary completion date of 2021-04-30 and completed status. The sponsor is Vanderbilt-Ingram Cancer Center. Because the trial is non-randomized and sequential, comparisons between its groups cannot be read as randomized treatment effects. The record does not report a statistical analysis plan or explain how results across the escalation and expansion groups were to be combined.

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: Participants who were treated with Fulvestrant 500mg, Palbociclib 125mg and Erdafitinib in Escalation phase.

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.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Dose Limiting Toxicities (DLT) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD), measured over From the time of randomization up to 4 weeks of treatment (cycle 1), for each patient.

The primary endpoint counts participants who experienced a dose-limiting toxicity during the first treatment cycle. The registry states that this count is used to determine the maximum tolerated dose. The specified population is participants treated with fulvestrant 500mg, palbociclib 125mg and erdafitinib in the Escalation phase. The stated timeframe is up to 4 weeks of treatment for each patient.

In general, a dose-limiting toxicity endpoint is used in early-phase dose-finding research to characterize tolerability at tested dose levels. It provides a focused count of qualifying toxicities over a specified early-treatment period. The endpoint is not itself a measure of tumor response or longer-term safety, and it should not be treated as a comparative estimate of benefit against another treatment.

The registry’s timeframe wording refers to time from randomization, although the trial is listed as non-randomized. This is a wording inconsistency in the record; the registry entries do not explain it. The number of participants with dose-limiting toxicities, the criteria used to classify a toxicity as dose-limiting, and the resulting maximum tolerated dose are not reported in the registry record. Without those details, the primary endpoint’s observed value and its precision cannot be assessed.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count represent?

The primary outcome is a number of participants with a dose-limiting toxicity, rather than a continuous measurement such as a laboratory value. The endpoint counts participants meeting the outcome definition within the stated first-cycle timeframe. The registry describes the endpoint as being used to determine the maximum tolerated dose. The count is not reported in the registry record, and the registry entries do not state the specific criteria used to decide which toxicities qualify as dose-limiting.

For safety outcomes, the registry reports both an at-risk count and an affected-participant count for each group. An at-risk count identifies the group denominator used for that outcome, while the affected count indicates participants recorded as having the event. These counts are descriptive. They do not, by themselves, account for how long participants were followed, whether participants had different treatment exposure, or whether events occurred more than once in the same participant. The record details do not describe these details.

What does non-randomized allocation mean for comparisons?

In general, random allocation is used to make treatment groups more comparable with respect to measured and unmeasured baseline characteristics. Here, the registry lists non-randomized allocation and a sequential model. It also explicitly cautions that the arms are not a like-for-like control comparison. Accordingly, differences in recorded counts across the dose groups should not be interpreted as causal effects of one dose relative to another. Participants in different groups may differ for reasons that cannot be separated from dose using these descriptive data.

The phase Ib designation and Escalation and Expansion labels indicate the study’s early-phase context and group structure, but the registry entries do not describe the operational rules for dose escalation or expansion. They also do not explain how the dose groups were selected, how decisions were made, or whether any participants changed treatment. These details are not reported in the registry record.

How should uncertainty be understood?

In general, a confidence interval gives a range of values compatible with the data under a specified statistical method. It conveys uncertainty around an estimate; it is not a guarantee that the true value lies in that range. No confidence intervals for the primary endpoint or adverse-event counts are reported in the registry entries. The observed counts should not be mistaken for precise estimates of the event frequencies that would occur in other patients or settings.

In general, sparse event data can yield substantial uncertainty, especially when group counts are small. A formal precision assessment would need an appropriate interval method and a clearly specified analysis population. The registry entries do not provide such analyses for these outcomes. No statistical significance test or p-value is reported in the registry record, and none should be inferred from the counts.

What does the record say about analysis?

The registry lists no analysis entries. It does not report a statistical analysis plan, adjustment methods, a primary analysis population, or procedures for handling missing outcome data. These omissions limit the ability to evaluate how the results were intended to be estimated or how robust they might be to alternative analytic choices.

In general, an analysis population defines which participants contribute to a particular outcome analysis. For a first-cycle toxicity endpoint, important details can include who began treatment, who completed or discontinued during the cycle, and how participants without complete observation were handled. Those details are not reported in the registry record. The endpoint description identifies participants treated in the Escalation phase at a named regimen, but does not specify the final analytic denominator.

What can the safety counts establish?

The safety summaries establish the event counts recorded for each listed group, as well as the at-risk counts and deaths. They do not establish that an event was caused by a study drug. The registry entries do not give adjudication details, event timing, duration, severity grading beyond the serious-event categorization, or participant-level overlap between outcome categories. In general, a person may have more than one event, so event terms and participant counts should not be treated as interchangeable without the relevant definitions.

The listed serious-event terms are accompanied by percentages, but the registry entries do not state their denominators or clarify whether percentages refer to participants, events or another basis. That missing context prevents a fuller interpretation of those percentages. The record also does not provide inferential comparisons of the serious-event terms between groups.

What is the role of the listed secondary outcomes?

The registry names progression-free survival, overall response rate, clinical benefit rate, pharmacokinetic measures and treatment-emergent adverse events as secondary outcomes. Naming an outcome does not supply its result or analysis. The registry entries do not provide values, uncertainty estimates or detailed analysis methods for these measures. In general, time-to-event outcomes, response outcomes and pharmacokinetic measures require different definitions and methods; the record’s outcome titles alone do not establish how those methods were applied.

Overall, the available statistical interpretation is limited to the trial structure, endpoint definitions and descriptive safety counts. The registry entries do not support reconstructing an unreported primary endpoint analysis or adding an independent comparison across non-randomized groups.

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("Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5m", "Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 6m", "Fulvestrant 500mg, Palbociclib 125mg and Erdafitin")
n      <- c(3, 6, 4)
events <- c(0, 0, 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  Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5m  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 6m  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Fulvestrant 500mg, Palbociclib 125mg and Erdafitin  4  2  50.0  6.8  93.2  15.0  85.0  14.7  85.3

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 13 outcome measures, including the primary dose-limiting-toxicity endpoint and secondary outcomes covering progression-free survival, response, clinical benefit, pharmacokinetics and treatment-emergent adverse events. It does not report a statistical analysis plan or analysis entries. A multiplicity strategy—such as whether outcomes were prioritized, adjusted or treated as descriptive—is not reported in the registry record.

In general, testing several outcomes can increase the chance of at least one apparently notable result arising by chance when each is treated as a separate confirmatory test. Whether and how that concern applies depends on the intended claims and analysis plan. The registry entries do not establish which outcomes were intended as confirmatory, whether formal hypothesis tests were planned, or whether any adjustment was made. No p-values for the outcomes are reported in the registry record.

Missing-data handling is also not reported in the registry record. The registry entries do not state how participants who discontinued, lacked complete first-cycle observation, or had unavailable assessments were handled. The primary endpoint population is described, but its observed denominator is not given. The record does not report imputation, censoring or sensitivity-analysis procedures.

The analysis populations are not fully specified. The endpoint description names participants treated in the Escalation phase at the stated regimen, but does not identify an analysis set or explain participant inclusion and exclusion rules. The record also does not provide the number analyzed for each secondary outcome. These omissions limit assessment of whether outcome summaries use consistent populations or how missing observations might affect interpretation.

12. 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: sepsis (33.3%), febrile neutropenia (33.3%), alanine aminotransferase increased (25.0%), aspartate aminotransferase increased (25.0%), pulmonary embolism (16.7%).

The registry reports serious adverse event counts and at-risk counts separately for each group. For the 5mg group, these are 1 of 3; for Expansion, 5 of 22; for the 6mg group, 1 of 6; and for the 8mg group, 1 of 4. Other adverse events are reported as 3 of 3, 22 of 22, 6 of 6 and 4 of 4 for those same groups, respectively. Death counts are reported as 2, 3, 6 and 2, respectively.

These are group-specific descriptive summaries. They are not randomized comparisons, and the record cautions that the arms are not a like-for-like control comparison. The death counts do not establish that deaths were caused by treatment; causal attribution is not reported in the registry record. The registry entries also do not specify the follow-up period for these safety summaries, the event grading rules, or whether one participant could contribute to more than one category.

The listed serious-event terms include Sepsis and Febrile neutropenia at 33.3% each; Alanine aminotransferase increased and Aspartate aminotransferase increased at 25.0% each; and Pulmonary embolism and Muscle weakness at 16.7% each. Their denominators and the precise basis of the percentages are not reported in the registry record. They should not be used to compare group risks without that information.

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

The record describes a completed phase Ib study of fulvestrant, palbociclib and erdafitinib in ER+/HER2-/FGFR-amplified metastatic breast cancer. Its primary endpoint was designed to count participants with a dose-limiting toxicity in the first cycle, in connection with determination of the maximum tolerated dose. The endpoint result and resulting maximum tolerated dose are not reported in the registry record. Therefore, the primary outcome cannot be interpreted in the registry record.

The registry’s safety summaries provide counts for serious adverse events, other adverse events and deaths across the listed groups. These counts describe what the record reports for those groups, but do not demonstrate that any event was caused by a study drug. Nor do they establish a comparative safety effect between doses: allocation was non-randomized, the study model was sequential, and the record cautions that the arms are not like-for-like controls.

The study’s brief summary identifies preliminary anti-tumor activity as an area of evaluation, and the record names progression-free survival, overall response rate and clinical benefit rate among secondary outcomes. Their results are not reported in the registry record for this analysis. No conclusion about response or disease control should be drawn from the outcome names alone.

More broadly, the posted information does not include confidence intervals, statistical tests or a stated analysis plan. The counts consequently have no reported statistical precision measures, and they cannot establish how well the observed results would generalize beyond the study. The enrollment figure is not a substitute for the number analyzed for a particular endpoint. The record does not report endpoint-specific analysis denominators.

In general, early-phase non-randomized studies can describe tolerability and inform further investigation, but they do not provide the same basis for treatment-effect comparisons as randomized trials. The registry entries support describing the design and the recorded safety counts, while leaving the primary outcome, many secondary results and key analytic details unresolved.

14. Why This Trial Matters Statistically

This trial is statistically notable for the distinction between a dose-finding endpoint and a comparative treatment-effect question. The primary outcome is a count of participants with dose-limiting toxicity during the first cycle, used in determining the maximum tolerated dose. That is a different objective from estimating whether the regimen improves an outcome relative to a control. The registry lists no randomized comparator, so the groups should not be read as arms in a controlled efficacy comparison.

The design also makes clear why group labels and dose levels alone do not establish comparability. The registry describes sequential, non-randomized allocation and explicitly warns that the groups are not like-for-like controls. Descriptive differences in recorded adverse events cannot be assigned to dose without a design and analysis that support that interpretation.

The registry further illustrates the difference between an outcome being named and a result being available. It lists a primary toxicity outcome and a range of secondary endpoints, yet the primary endpoint value is not reported in the registry record. The safety counts are present, but lack accompanying precision estimates and key analysis details. Statistical interpretation depends not only on a study’s questions, but on the outcome definitions, analysis populations, uncertainty measures and methods reported alongside the results.

For clinical researchers, the record is a useful reminder to distinguish planned endpoint purpose from observed evidence. Early-phase safety counts can be informative as descriptions, while remaining insufficient for causal comparisons or broad claims. Missing analysis details do not prove that analyses were not performed; they mean that those details are not reported in the registry record and cannot be evaluated from it.

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 primary limitation is that the registry does not report the primary endpoint result: the number of participants with a dose-limiting toxicity in the first cycle. It also does not report the maximum tolerated dose determined from that endpoint. The description gives the endpoint’s purpose and population, but not its observed denominator, qualifying-toxicity criteria or result.

The study is non-randomized and sequential, and the record cautions that its groups are not like-for-like controls. Comparisons of event counts between the dose groups are therefore descriptive, not causal. The registry entries do not describe baseline characteristics, treatment exposure, follow-up duration by group or group-selection rules, all of which would affect interpretation of between-group differences.

The timeframe wording for the primary outcome refers to time from randomization, although allocation is listed as non-randomized. The record does not explain this inconsistency. Safety reporting also lacks event timing, detailed severity grading, causal attribution, and clarification of the denominators used for the listed serious-event percentages. The relationship between participants and multiple recorded events is not described.

The registry lists 13 outcome measures but no analysis entries. It does not report the statistical analysis plan, confidence intervals, p-values, missing-data methods, analysis populations or multiplicity procedures. Secondary outcome names are listed without results in the registry record. These limitations leave both the primary endpoint and much of the planned outcome profile unevaluable from the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Fulvestrant, Palbociclib and Erdafitinib in ER+/HER2-/FGFR-amplified Metastatic Breast Cancer — NCT03238196.
• Registry record last updated 2024-11-14; status last verified 2024-10.
• Results first posted 2023-02-16.
• 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 NCT03238196, a completed, open-label, multi-institution phase Ib trial of fulvestrant, palbociclib and erdafitinib in ER+/HER2-/FGFR-amplified metastatic breast cancer. Allocation is non-randomized, the model is sequential and masking is none. The listed enrollment is 35.

The primary endpoint is the number of participants with dose-limiting toxicities in the first cycle, for determination of the maximum tolerated dose. The endpoint result and maximum tolerated dose are not reported in the registry record. Listed secondary outcomes include progression-free survival, response, clinical benefit, erdafitinib pharmacokinetic measures and treatment-emergent adverse events.

Group-specific counts are reported for serious adverse events, other adverse events and deaths. Because the groups are not randomized comparators, these figures are descriptive rather than comparative treatment-effect estimates. The registry does not report a statistical analysis plan, confidence intervals or missing-data procedures in the registry record.