Phase 2a Study of ZW25 in Combination With Palbociclib Plus Fulvestrant: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase 2a Study of ZW25 in Combination With Palbociclib Plus Fulvestrant (NCT04224272), a na phase 2 study. The primary outcome is Number of Participants With Dose-Limiting Toxicities.

2. Clinical Question

Statistically, this is a safety-focused question about an observed count in the study population, not a comparative estimate of benefit. The study also lists anti-tumor activity among its aims and includes outcomes such as objective response rate, duration of response, disease control rate, and progression-free survival. However, the posted registry information does not give their numerical results. The available record therefore supports describing the study’s question, design, and posted safety figures, but not drawing conclusions about comparative efficacy or the size and precision of an anti-tumor effect.

3. Trial Design

This completed Phase 2a study was open-label, multicenter, and conducted in 2 parts with a sequential model. The registry lists enrollment of 51 participants and allocation as NA. It describes one treatment combination: ZW25 (zanidatamab) with palbociclib and fulvestrant. No randomized control group or separate comparator is described. The sponsor is Jazz Pharmaceuticals.

The stated regimen was intravenous ZW25 at 20 mg/kg every 2 weeks, oral palbociclib at 125 mg once daily from Days 1 to 21, and intramuscular fulvestrant at 500 mg every 2 weeks for 3 doses: Cycle 1 Days 1 and 15 and Cycle 2 Day 1. Each cycle is described as 28 days. The registry’s primary endpoint assesses dose-limiting toxicities from Cycle 1 Day 1 to Day 28. The treatment schedule and endpoint window are details about the registered study; the record does not provide a fuller account of how sequential decisions between the study parts were made.

The study began on 2020-06-10, reached primary completion on 2023-04-28, and is listed as completed. Its stated aims were to investigate safety, tolerability, and anti-tumor activity in patients with locally advanced (unresectable) and/or metastatic HER2-positive, hormone receptor-positive breast cancer. The registry lists 13 outcome measures, including safety, pharmacokinetic, immunogenicity, response, and time-to-event outcomes. No numerical results for the primary endpoint or those secondary outcomes are included in the available results information.

Because this is not a randomized comparison, the observed outcomes describe participants receiving the combination. Differences from other populations or treatments cannot be attributed to the regimen using this design alone. Details such as eligibility criteria beyond the broad disease description, study-part transition rules, and the statistical plan are not reported in the registry record.

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.

Part 1 - Dose Finding

Reasons for not completing this period:

Part 2 - Dose Expansion

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Dose-limiting toxicities were assessed in participants with available data in the Safety Analysis Set.

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: The baseline demographic characteristics were assessed in the Safety Analysis Set.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Dose-Limiting Toxicities, measured over Cycle 1 Day 1 to Day 28 (each cycle is 28 days).

The primary endpoint is the number of participants with dose-limiting toxicities. It is a participant count, assessed over Cycle 1 Day 1 to Day 28. The registry says that a qualifying event must occur following administration of ZW25, palbociclib, and fulvestrant and must meet criteria specified in the protocol. Events are defined using NCI CTCAE version 5.0. The endpoint population is participants with available data in the Safety Analysis Set.

Early safety studies commonly use a dose-limiting toxicity endpoint to characterize serious tolerability concerns during a defined treatment window. General statistical context: a count conveys how many participants meet a specified event definition, while its interpretation also depends on the number assessed and the completeness of their outcome data. A count alone does not describe event timing, severity beyond the definition, or whether an event was caused by treatment.

The registry record does not report the primary endpoint count, the number of participants with available endpoint data, or an interval estimate. Therefore, the endpoint’s observed frequency and its precision cannot be evaluated from the posted results. The listed safety counts elsewhere in the record should not be treated as a substitute for this primary endpoint: dose-limiting toxicities have a specific definition and time window, while the broader adverse-event summaries cover different categories.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies the primary outcome as a participant count. This type of outcome records whether each assessed participant did or did not meet the endpoint definition during the specified period, and the main summary is the number meeting the definition. For interpretation, the count needs a clearly defined denominator: the relevant participants assessed for the outcome. The registry states that dose-limiting toxicities were assessed in participants with available data in the Safety Analysis Set, but the number with available primary-endpoint data is not reported in the registry record.

What does the primary endpoint count?

The outcome is not a count of all adverse events. It counts participants with dose-limiting toxicities that occur following administration of the combination and meet protocol criteria. The stated assessment window is Cycle 1 Day 1 to Day 28, and the classification references NCI CTCAE version 5.0. Thus, a participant’s event must meet the study’s specified definition and timing to contribute to this endpoint. The detailed protocol criteria themselves are not reported in the registry record.

General statistical context: binary outcomes are often described by the number of participants with an event and the number assessed. A proportion can help communicate frequency, and an interval estimate can convey uncertainty. These summaries do not imply causation, and their interpretation depends on the event definition, the population assessed, and completeness of follow-up. No primary-endpoint count, proportion, or interval estimate is reported in the registry record, so none can be interpreted for this trial.

What does the design allow?

The study is open-label and has allocation listed as NA; it is described as a 2-part sequential study. The record presents a regimen rather than randomized treatment groups. General statistical context: random allocation can help balance known and unknown prognostic factors between groups, while a concurrent comparator can support estimation of a treatment contrast. Without such a comparator, outcomes can be described for the participants who received the combination, but treatment-related differences cannot be isolated through a randomized comparison. The registry does not describe a statistical model or a comparative analysis plan.

The sequential description does not, by itself, specify the rules governing decisions or transitions between parts. Information about stopping boundaries, interim analyses, or how data from the parts were combined is not reported in the registry record. These methods should not be inferred from the word “sequential.”

How should safety counts be read?

The adverse-event summary lists participants at risk and participants affected for serious and other adverse-event categories. The record lists 51 at risk for serious events and 9 affected; for other events it lists 51 at risk and 51 affected. It separately lists 27 deaths. These are counts, not comparative effects, and they should be read with the category labels and their definitions in mind. The record does not report whether events were judged related to treatment. General statistical context: multiple events may occur in one participant, so a count of participants affected is not necessarily a count of total event occurrences.

Several serious-event terms are reported at 2.0% each. The registry information does not give confidence intervals for these percentages. General statistical context: uncommon events can be estimated imprecisely in a study of limited size, and an interval would make that uncertainty more visible. No such interval is reported for these terms.

What can sample-size calculations tell us?

The stated planning illustration uses a two-sided significance level of 0.05, equal allocation between 2 arms, and a normal approximation. It frames the effect to detect as a stated fraction of an observed effect. For time-to-event outcomes, the illustration is described in terms of total events; for other outcomes, it is described as participants per arm. The registry notes that these calculations are illustrations based on an observed effect, not the trial’s own design.

General statistical context: a planning calculation depends on assumptions about the target effect, variability or event rate, significance level, and design. It is not evidence that a study was designed with those assumptions, and it does not describe the certainty of an observed result. In particular, an illustration using equal allocation between 2 arms does not describe the registered study’s allocation, which is listed as NA. The protocol’s sample-size justification and the assumptions used to plan the trial are not reported in the registry record. No sample-size illustration should be interpreted as observed power.

The registry lists 13 outcome measures and 0 analyses. This indicates that no analysis entries are listed in the registry information; it does not establish what analyses were conducted outside that record. Statistical methods for estimating outcomes, handling repeated measures, adjusting for covariates, or conducting subgroup analyses are not reported in the registry record. No p-value or confidence interval for the primary endpoint is available to interpret.

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("ZW25 (Zanidatamab) + Palbociclib + Fulvestrant")
n      <- c(8)
events <- c(1)
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  ZW25 (Zanidatamab) + Palbociclib + Fulvestrant  8  1  12.5  0.3  52.7  2.2  47.1  2.8  48.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 13 outcome measures, spanning adverse events, ZW25 concentrations, anti-drug antibodies, response outcomes, and progression-free survival. Having multiple outcomes raises a general statistical issue: when many hypotheses are tested, the chance of at least one apparently notable result can increase. Methods such as prespecifying a primary outcome or adjusting for multiple testing can address that issue, but the registry does not describe whether or how multiplicity was handled. A testing hierarchy and any adjustment procedure are not reported in the registry record.

The registry identifies dose-limiting toxicities as the primary endpoint, but it does not provide a numerical result or analysis entry. It lists 0 analyses. This describes the analysis entries in the registry record; it does not show whether analyses were performed elsewhere. The analysis population for the primary endpoint is described as participants with available data in the Safety Analysis Set. Further details about population definitions for the other outcomes are not reported in the registry record.

Information about missing outcome data, exclusions from analyses, imputation, censoring rules, and sensitivity analyses is not reported in the registry record. These details matter because incomplete observation can affect the number analyzed and the interpretation of outcome summaries. For progression-free survival, for example, the handling of censoring and event definitions would be important to interpretation, but those methods are not reported in the registry record. No assumption about missingness or follow-up should be inferred from the fact that the study is listed as completed.

General statistical context: a complete analysis description connects the prespecified question to the population, outcome definition, estimator, uncertainty measure, and handling of missing data and multiplicity. The available registry information does not establish those analysis choices beyond the stated primary outcome definition and Safety Analysis Set description.

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: duodenal ulcer (2.0%), gastric ulcer (2.0%), small intestinal obstruction (2.0%), covid-19 (2.0%), covid-19 pneumonia (2.0%).

The adverse-event summary lists 51 participants at risk for serious adverse events and 9 affected. For other adverse events, it lists 51 at risk and 51 affected. The same record lists 27 deaths. These counts should be read as descriptive entries for the study group, not as comparisons with another treatment. The record does not state whether the events or deaths were considered related to the study drugs.

The listed serious-event terms are duodenal ulcer, gastric ulcer, small intestinal obstruction, COVID-19, COVID-19 pneumonia, and psoas abscess, each reported at 2.0%. A term’s appearance in the list does not establish that treatment caused it. The record does not provide event timing, participant-level overlap among terms, or interval estimates for these percentages. General statistical context: a participant can experience more than one type of event, so categories may not represent distinct people when added together. The figures also describe adverse-event categories, not the primary dose-limiting toxicity endpoint; the endpoint’s count is not reported in the registry record.

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

The record establishes that a completed Phase 2a study evaluated zanidatamab with palbociclib and fulvestrant in participants with HER2-positive, hormone receptor-positive advanced breast cancer. It records the regimen, the primary dose-limiting toxicity question, and descriptive adverse-event counts. Those details help clarify what was studied and which safety information was posted.

The record does not report the number of participants meeting the primary dose-limiting toxicity definition. It also does not provide numerical results for the listed anti-tumor outcomes, including objective response rate, duration of response, disease control rate, and progression-free survival. The stated study aim to investigate anti-tumor activity should not be mistaken for a reported efficacy result. The safety counts do not fill that gap, because they address different outcomes.

There is no randomized comparator in the registered design. Therefore, the observed outcomes cannot establish how the combination compares with another treatment, and they cannot by themselves identify the cause of an event or outcome. The posted deaths and adverse events are not evidence of treatment causation. Nor does the record provide uncertainty intervals that would show the precision of the listed safety frequencies.

General statistical context: a study’s result is interpreted in relation to its endpoint definition, analysis population, follow-up, design, and uncertainty. A descriptive count can be informative about what was recorded among participants, but it is not automatically a causal effect estimate. Missing analysis details and absent numerical primary and efficacy results limit the conclusions that can be drawn from the registry record. The record supports a description of the study and its posted safety summary, not a definitive comparative judgment about benefit or harm.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of how a safety-focused early-phase study can be described without a randomized control group. Its primary question is a count of participants with protocol-defined dose-limiting toxicities during a specified early treatment window. That makes the definition, assessment period, and analysis population central to interpretation. Here, the registry identifies those elements but does not report the primary count or the number with available endpoint data.

The design also illustrates why descriptive safety results and comparative effects are different quantities. The record reports affected-participant counts and serious-event terms, but no concurrent control group is described. Such counts document what was recorded among participants receiving the combination; they do not estimate an excess risk attributable to treatment. General statistical context: a comparative estimate requires a meaningful reference group and a method that accounts for the design.

The record lists a broad set of secondary outcomes, including safety, pharmacokinetic, immunogenicity, response, and progression measures. That breadth makes transparent reporting of analysis populations, missing data handling, and multiplicity methods important. Those details are not reported in the registry record. The listing of multiple outcomes does not itself establish that each was analyzed or that a particular result was favorable.

Finally, planning illustrations and the actual trial design answer different questions. The registry’s stated illustration uses equal allocation between 2 arms, while this study has allocation listed as NA and no comparator arm is described. Keeping those concepts separate prevents a planning scenario from being mistaken for the study’s protocol or for evidence of observed precision. The record offers useful design and safety context, while leaving key outcome and analysis information unavailable.

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 most consequential limitation for interpreting the primary endpoint is that its numerical result is not reported in the registry record. The primary endpoint population is described as participants with available data in the Safety Analysis Set, but the number assessed is also not reported. Without the event count and denominator, the primary safety frequency and its precision cannot be evaluated.

The study is open-label, allocation is listed as NA, and no comparator arm is described. These design features mean the posted outcomes are descriptive rather than randomized comparative estimates. The registry does not provide numerical results for the secondary response and progression outcomes, so the stated interest in anti-tumor activity cannot be assessed from the posted results.

The adverse-event summary includes counts and selected serious-event terms, but the registry does not report causal attribution, participant-level overlap, event timing, or interval estimates for the listed percentages. The record lists 27 deaths without providing further context about their relationship to treatment. These omissions limit interpretation of the safety entries and do not permit causal conclusions.

Further limitations arise from unreported methods. The protocol’s dose-limiting toxicity criteria, statistical analysis plan, interim analysis procedures, sample-size justification, missing-data approach, censoring rules, multiplicity handling, and sensitivity analyses are not reported in the registry record. The registry lists 0 analyses, which indicates no analysis entries are listed there but does not establish what was conducted elsewhere. The record also does not describe how the sequential parts informed one another. These gaps constrain assessment of prespecification and analytic robustness.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Phase 2a Study of ZW25 in Combination With Palbociclib Plus Fulvestrant — NCT04224272.
• Registry record last updated 2026-09-24; status last verified 2026-08.
• Results first posted 2024-08-14.
• 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

NCT04224272 is a completed, open-label, multicenter Phase 2a study of ZW25 (zanidatamab) with palbociclib and fulvestrant in HER2-positive, hormone receptor-positive advanced breast cancer. The registered model is sequential, the study has 2 parts, and enrollment is 51. The primary endpoint is the number of participants with dose-limiting toxicities from Cycle 1 Day 1 to Day 28, assessed among participants with available data in the Safety Analysis Set.

The adverse-event summary lists 9 participants affected by serious adverse events among 51 at risk, 51 affected by other adverse events among 51 at risk, and 27 deaths. Six serious-event terms are each listed at 2.0%. The primary endpoint result and numerical secondary outcome results are not reported in the registry record. No randomized comparator is described, and the registry lists 0 analyses. Accordingly, the available information supports a descriptive account of the study and posted safety counts, but not a comparative estimate or a complete statistical assessment of the trial outcomes.