Study Of Palbociclib Combined With Chemotherapy In Pediatric Patients With Recurrent/Refractory Solid Tumors: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study Of Palbociclib Combined With Chemotherapy In Pediatric Patients With Recurrent/Refractory Solid Tumors (NCT03709680), a randomized phase 2 study. The primary outcome is Phase 1, Dose Escalation/Dose Determination Cohorts: Number of Participants With Dose Limiting Toxicities (DLTs).

2. Clinical Question

3. Trial Design

The registry describes a phase 1/2 study with randomized allocation, no masking, and a sequential model. It lists an enrollment of 128 and a completed status. The recorded start was 2019-05-24, and the primary completion date was 2024-08-26. Those registry-level details do not establish how many participants contributed to any particular outcome: the outcome populations differ by phase, cohort, and analysis.

Phase 1 included dose escalation cohorts using palbociclib with temozolomide and irinotecan at 55 mg/m^2, 75 mg/m^2, or 95 mg/m^2, as well as a dose determination cohort using palbociclib 75 mg/m^2 with topotecan and cyclophosphamide. A neuroblastoma-specific cohort and dose expansion cohorts are also described in the registry, but the primary DLT result listed for this analysis is limited to the dose escalation and dose determination cohorts.

Phase 2 compared palbociclib 75 mg/m^2 plus irinotecan and temozolomide with irinotecan and temozolomide alone. The posted phase 2 outcomes include investigator-assessed response rate and progression-free survival, and event-free survival assessed by a blinded independent review committee. The registry characterizes the trial as randomized, but details of the randomization procedure, allocation ratio, and concealment are not reported in the registry record. Masking is listed as none; that does not mean the independent review committee was necessarily unblinded, because the EFS outcome is explicitly described as BIRC-assessed.

Across the entire study, the registry lists palbociclib, temozolomide, irinotecan, topotecan, and cyclophosphamide as interventions. The record’s phase-specific objectives matter when interpreting results: the phase 1 primary endpoint is a safety and dose-finding measure, while the phase 2 secondary results address comparative disease outcomes. A detailed account of the protocol’s analysis plan is 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.

Before assignment: A total of 128 participants were enrolled (Phase 1: 60, TSC: 5 and Phase 2: 63).

Only the first 6 of 9 groups are shown.

Phase-1(Escalation-Expansion):Treatment

Reasons for not completing this period:

Phase-1(Escalation-Expansion): Follow-up

Reasons for not completing this period:

TSC: Treatment

Reasons for not completing this period:

TSC: Follow-up

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: DLT evaluable set included all enrolled participants who received at least one dose of study drug and did not have major treatment deviations during the first cycle of treatment (unless the treatment deviation was due to a DLT or other treatment-related toxicity and was replaced as needed to permit maximum tolerated dose estimation).

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: Baseline data are reported for FAS. "Number(no.) Analyzed"=no. of participants(ppts) included in FAS for Phase(P)1, TSC, P2 independently. Per protocol, two ppts with recurrent/refractory neuroblastoma (NB)from P1 were counted toward additional 5 ppts enrolled in NB TSC, for a total of 7 ppts required for Stage 1. To provide complete FAS of each cohort, these ppts are included in "No. Analyzed" counts for both P1 \& TSC. To avoid duplicate counting, "N" for "P 1 + TSC" includes only unique ppts.

6. Primary Endpoint

The registry lists the primary outcome as Phase 1, Dose Escalation/Dose Determination Cohorts: Number of Participants With Dose Limiting Toxicities (DLTs), measured over Cycle 1 (21 days).

The primary endpoint counts participants with dose-limiting toxicities (DLTs) in the phase 1 dose escalation and dose determination cohorts. The stated timeframe is Cycle 1 (21 days). The registry defines a DLT as an adverse event occurring in the first treatment cycle, attributable to at least one agent in the combination, and meeting study-specific criteria set by the sponsor. Adverse events were graded according to CTCAE version 4.03.

A count is useful in early dose-finding because the question is whether toxicity at a tested regimen meets prespecified criteria that may inform dose selection. This endpoint is not a general count of all adverse events: it depends on timing, attribution, severity or other sponsor-defined criteria, and evaluation rules. The registry also describes a DLT-evaluable set that includes enrolled participants who received at least one dose and did not have major treatment deviations during the first cycle, with exceptions related to DLT or other treatment-related toxicity. The remainder of that population description is incomplete in the registry record, so further details should not be inferred.

In the posted dose escalation and dose determination results, DLT counts were 0 of 4 at palbociclib 55 mg/m^2 with temozolomide and irinotecan, 0 of 6 at 75 mg/m^2 with that chemotherapy, 2 of 6 at 95 mg/m^2 with that chemotherapy, and 1 of 6 at 75 mg/m^2 with topotecan and cyclophosphamide. These observations describe the listed cohorts; they do not by themselves establish a maximum tolerated dose or characterize the full safety profile.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Several different statistical summaries appear in the registry results. They answer related but non-identical questions, so interpretation depends on distinguishing an observed count or median from a between-group comparison. The registry record gives a primary phase 1 toxicity endpoint and phase 2 time-to-event and response outcomes.

What does a confidence interval describe?

In general, a confidence interval describes the uncertainty around an estimated quantity under the assumptions of the analysis. It is not a range containing a guaranteed proportion of individual outcomes, and it does not measure the probability that a particular treatment effect is true. A wide interval indicates that the data are compatible with a broad range of values. For the phase 2 comparisons, the intervals are wide; the data therefore do not pin down the comparative effects precisely.

For response rate, each group has a percentage estimate and a 95% confidence interval. The reported comparison is an odds ratio with its own 95% confidence interval. An odds ratio compares odds, not percentages directly. The posted odds ratio was 0.882, with a 95% confidence interval of 0.151 to 6.350. The interval spans values below and above 1, which is the null value for an odds ratio. The group percentages and the odds ratio are different summaries and should not be treated as interchangeable.

The unadjusted recalculation reports a risk difference, which expresses the difference between the two observed response proportions on the probability scale. It is 0.015, with a 95% confidence interval from -0.186 to 0.216. This is a simple, unadjusted re-analysis of the posted summary counts, whereas the registry’s reported analysis uses the Cochran-Mantel-Haenszel method. The reported sponsor analysis is the primary registry comparison to cite; the recalculation provides a separate descriptive view and is not an adjusted substitute.

How should the time-to-event results be read?

Event-free survival and progression-free survival are time-to-event outcomes. A median is the time by which the estimated event-free or progression-free survival curve reaches its midpoint. It is not the mean follow-up time, and it does not state that every participant had an event at that time. The posted median EFS values were 1.54 months and 4.14 months; the PFS medians were 1.54 months and 4.4 months. The definitions of the event and the assessment method differ: EFS was assessed by a blinded independent review committee, while PFS was based on investigator assessment.

A hazard ratio summarizes the relative event rate over time under the analysis model; it is not a ratio of the medians. The registry reports a hazard ratio of 1.54 for EFS and 2.03 for PFS, both with 95% confidence intervals that include 1. The direction of a hazard ratio depends on the group ordering used in the comparison, so the estimate should be read with its stated treatment-group comparison. The registry reports log-rank methods for these outcomes. Details about model diagnostics, proportional-hazards assessment, censoring procedures, or any additional covariate adjustment are not reported in the registry record.

What does a p-value contribute?

In general, a p-value describes how incompatible the observed data are with a specified null hypothesis under the analysis assumptions. It is not the probability that the null hypothesis is true, and it does not quantify the size or clinical importance of an effect. The reported p-values were 0.877 for EFS, 0.583 for response rate, and 0.962 for PFS. These values do not establish that the groups are equivalent; equivalence would require a defined margin and an appropriate analysis, neither of which is reported in the registry record.

Why do planning illustrations differ from observed results?

The planning illustrations use the observed effect as an input and show hypothetical sample-size or event requirements under stated assumptions. For the response comparison, the stated assumptions are a two-sided significance level of 0.05, equal allocation, and a normal approximation; the illustrated effect is a stated fraction of the observed effect. For time-to-event outcomes, the illustrations report total events using a Schoenfeld approach. These are planning illustrations, not observed power and not evidence that the trial was designed around those requirements. The registry record does not report the trial’s own sample-size justification.

For response, the illustrations give participants per arm for 80% and 90% power under each stated effect fraction. For EFS and PFS, the corresponding illustrations give total event counts. Because the observed phase 2 estimates are uncertain, illustrations based on those estimates are themselves sensitive to the observed effect and assumptions. They should be interpreted as hypothetical planning scenarios, not as confirmation of a treatment effect or as an account of the trial’s original design.

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 1, Dose Escalation Cohort 1: Palbociclib 55 ", "Phase 1, Dose Escalation Cohort 2: Palbociclib 75 ", "Phase 1, Dose Escalation Cohort 3: Palbociclib 95 ", "Phase 1, Dose Determination Cohort: Palbociclib 75")
n      <- c(4, 6, 6, 6)
events <- c(0, 0, 2, 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  Phase 1, Dose Escalation Cohort 1: Palbociclib 55   4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2
ARM  Phase 1, Dose Escalation Cohort 2: Palbociclib 75   6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Phase 1, Dose Escalation Cohort 3: Palbociclib 95   6  2  33.3  4.3  77.7  9.7  70.0  9.9  71.0
ARM  Phase 1, Dose Determination Cohort: Palbociclib 75  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9

11. Multiplicity, Missing Data and Analysis Populations

The registry record does not report whether the phase 2 secondary outcomes were tested under a prespecified hierarchy, whether multiplicity adjustments were used, or how the family of hypotheses was defined. The reported p-values should therefore be read as results of their named analyses, not as evidence that the overall set of secondary comparisons was controlled for multiple testing. In general, multiplicity matters when many outcomes or comparisons are examined because the chance of at least one apparently notable result can increase.

Missing-data methods are not reported in the registry record. The registry entries available do not describe how participants with incomplete follow-up, missing assessments, or unevaluable responses were handled. They also do not describe censoring rules in detail for EFS or PFS. These omissions limit assessment of whether missingness could affect the estimates; they do not establish that missing data occurred or that any particular method was used.

The primary endpoint is defined for a DLT-evaluable set, described as enrolled participants who received at least one dose and did not have major treatment deviations during the first cycle, with stated exceptions related to DLT or other treatment-related toxicity. The population description is truncated in the registry record. The full evaluability rules, any replacement procedures beyond the partial description, and the number excluded from the primary analysis are not reported in the registry record. The phase 2 outcome counts vary by analysis, and the registry does not give a full accounting of all randomized participants, exclusions, or analysis populations in the registry record.

The registry lists randomized allocation and no masking, but does not report the randomization method, allocation ratio, concealment details, or whether analyses followed intention-to-treat principles. It does not report a protocol-level statistical analysis plan, interim-analysis procedures, or a sample-size justification. Those details are important for judging prespecification and potential bias, but should not be inferred from the posted estimates alone.

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: febrile neutropenia (30.0%), malignant neoplasm progression (25.0%), shock (25.0%), atrial fibrillation (16.7%), pericardial effusion (16.7%).

The registry reports serious adverse event counts and other adverse event counts for several phase 1 and phase 2 groups. These are group-specific figures, and the cohort definitions differ across the record. For example, the phase 2 palbociclib combination group lists 15 participants with serious adverse events among 41 at risk, while the irinotecan and temozolomide group lists 4 among 21 at risk. The record also reports other adverse events and deaths for those groups. These counts should be read as posted for each group, not combined into a trial-wide total.

A serious adverse event is not necessarily caused by study treatment. The registry’s serious-event figures do not by themselves establish causation, comparative risk, or the timing and duration of events. The record’s listed top serious-event terms include febrile neutropenia at 30.0%, malignant neoplasm progression at 25.0%, shock at 25.0%, atrial fibrillation at 16.7%, pericardial effusion at 16.7%, and chest pain at 16.7%. The registry entries available do not clarify the denominator or group aggregation underlying those term percentages, so they should not be interpreted as rates for a particular arm.

Death counts are reported, but the registry entries available do not specify the cause or attribution for each death. Accordingly, the adverse event summaries describe reported safety events; they do not alone support a causal or comparative conclusion.

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

The results establish what was recorded for the specified phase 1 and phase 2 analyses. In phase 1, the posted DLT counts vary across dose escalation and dose determination cohorts during Cycle 1 (21 days). In phase 2, the registry reports response and time-to-event estimates with broad confidence intervals. These are descriptive and comparative statistical findings, not a complete account of every clinical outcome or participant experience.

The primary endpoint is an early-cycle safety and dose-determination measure. It is not designed to show whether one phase 2 regimen improves disease outcomes relative to the comparator. Conversely, phase 2 efficacy estimates do not determine the maximum tolerated dose. The questions should remain distinct when interpreting the study.

The phase 2 confidence intervals are compatible with a range of comparative effects, including values on either side of the null value for the reported comparison measures. A non-significant p-value does not prove equivalence, absence of an effect, or equal outcomes. The registry does not report an equivalence or noninferiority margin, and the estimates are not precise enough to support a narrow conclusion about the size of any difference.

The posted results also do not establish that the treatments caused every reported adverse event or death. Safety summaries require attention to each group’s definition, the event type, and whether attribution was assessed. The registry record alone does not supply enough detail to make those causal judgments.

In general, clinical interpretation also depends on the population enrolled, outcome definitions, follow-up, and the analysis plan. The registry identifies a young population with recurrent or refractory solid tumors and a phase 2 focus on Ewing sarcoma, but the registry entries available do not provide detailed eligibility criteria, participant characteristics, or a complete account of follow-up and missingness. The results therefore should be understood within the specific cohorts and analyses reported, rather than generalized to all young people with solid tumors or all chemotherapy regimens.

14. Why This Trial Matters Statistically

This study is statistically informative because it combines an early-phase dose-finding objective with a randomized phase 2 comparison. Those components answer different questions and require different interpretations. The phase 1 DLT counts describe early toxicity under specific cohort regimens; the phase 2 outcomes estimate comparative disease endpoints. Keeping that distinction clear prevents a safety count from being mistaken for an efficacy result or an efficacy estimate from being treated as a dose-finding conclusion.

The phase 2 results also illustrate why point estimates need to be read with their uncertainty. The posted confidence intervals are broad for response and time-to-event comparisons. A single estimate or p-value cannot capture that uncertainty, and the reported values do not establish equivalence. The trial record therefore supports careful description of observed results, rather than a definitive interpretation of the comparative effect.

Another statistical issue is the difference between sponsor-reported analyses and simple recalculation from posted summary data. The response outcome has a sponsor-reported Cochran-Mantel-Haenszel odds ratio and a separate unadjusted risk-difference recalculation. These statistics use different scales and methods. Their distinction is important: a recalculation can provide a transparent descriptive check, but it does not replace the analysis specified and reported by the sponsor.

Finally, planning illustrations are not retrospective evidence of power. They depend on assumptions and on the observed effect used as their input. Without the trial’s own design justification and statistical analysis plan, the illustrations cannot show whether the study was adequately planned for a prespecified effect. The record’s limitations in reporting multiplicity, missing-data handling, and analysis populations further constrain confirmatory interpretation. Together, these features make the study a useful case for separating endpoint purpose, analysis method, precision, and reporting completeness.

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 limitations specific to this record affect interpretation. The trial spans phase 1 dose escalation and dose determination, expansion cohorts, a neuroblastoma-specific cohort, and a randomized phase 2 comparison. The primary DLT result covers only the phase 1 dose escalation and dose determination cohorts, while the efficacy comparisons concern phase 2. A single overall interpretation would obscure those differences in cohorts and objectives.

The phase 2 groups have limited posted analysis counts: the response and time-to-event results list 35 for the palbociclib combination and 19 for chemotherapy alone for the relevant outcomes, with some endpoint-specific differences in the displayed counts. Confidence intervals are broad. The registry entries available do not provide a participant flow account that would explain the relationship among the registry’s overall enrollment, randomization, and each analysis population.

The registry lists no masking, but gives limited detail about randomization and outcome assessment. EFS is specifically attributed to blinded independent review committee assessment; investigator assessment is specified for response and PFS. The record does not report additional details about assessment procedures, adjudication, or potential sources of measurement variation.

The primary DLT-evaluable population description is incomplete, and missing-data handling, censoring detail, multiplicity control, interim analyses, and the protocol’s statistical plan are not reported in the registry record. The adverse event figures include multiple differently defined cohorts, and the record’s top serious-event percentages lack a clearly specified denominator in the registry record. These reporting limits make it difficult to assess comparability or reconstruct the full analysis pathway. They should be treated as information gaps, not evidence that a particular bias or analytic problem occurred.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study Of Palbociclib Combined With Chemotherapy In Pediatric Patients With Recurrent/Refractory Solid Tumors — NCT03709680.
• Registry record last updated 2026-10-07; status last verified 2026-09.
• Results first posted 2026-10-07.
• 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 NCT03709680, a completed randomized, unmasked phase 1/2 study sponsored by Pfizer. Its title concerns palbociclib combined with chemotherapy in pediatric patients with recurrent or refractory solid tumors. The listed enrollment is 128; the recorded study start is 2019-05-24, and primary completion is dated 2024-08-26.

The phase 1 primary endpoint was the number of participants with DLTs during Cycle 1 (21 days) in dose escalation and dose determination cohorts. Posted cohort counts were 0 of 4, 0 of 6, 2 of 6, and 1 of 6. Phase 2 compared palbociclib with irinotecan and temozolomide against irinotecan and temozolomide alone in Ewing sarcoma, with posted EFS, response-rate, and PFS results. The reported comparisons are imprecise, and the registry record does not report a complete statistical plan, multiplicity strategy, or missing-data approach. The phase 1 safety endpoint and phase 2 efficacy outcomes should be interpreted as distinct analyses.