This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Lapatinib in Combination With Radiation Therapy in Patients With Brain Metastases From HER2-Positive Breast Cancer (NCT00470847), a na phase 1 study. The primary outcome is The Maximum Tolerated Dose of Lapatinib When Combined With Cranial Radiation in Patients With CNS Metastases From HER2-positive Breast Cancer..
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00470847 |
| Phase | Phase 1 |
| Condition | Breast Cancer, Brain Metastases |
| Allocation | Not applicable (single group) |
| Design model | Single Group |
| Masking | None (open label) |
| Enrollment | 35 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Nancy Lin, MD |
| Results posted | Yes |
2. Clinical Question
Population
Patients with HER2-positive breast cancer and central nervous system metastases. The registry record describes brain metastases as the condition of interest. It lists enrollment as 35, but does not provide further eligibility details or a description of the analyzed population.
Intervention
Lapatinib before and during whole brain radiation therapy, followed by Herceptin 4mg/kg IV weekly. The brief summary says some participants may also have stereotactic radiosurgery depending on their cancer, but the registry does not specify how that possibility was applied in the study.
Comparator
There was no separate control group. The registry describes a single-group study, with allocation listed as NA and masking as none. Dose levels appear in the safety information, but these are not a randomized, like-for-like comparator.
Primary question
What is the maximum tolerated dose of lapatinib when combined with cranial radiation in patients with HER2-positive breast cancer and central nervous system metastases? The endpoint is a dose-finding safety measure, not a comparative estimate of treatment benefit.
The study is registered as phase I and completed. Its stated purpose was to examine the safety of combining lapatinib with radiation in people whose breast cancer had spread to the brain. The rationale in the brief summary is that lapatinib might affect cancer-cell growth and might make cancer cells more sensitive to radiation. Those statements describe the study rationale, not a finding from this trial.
The treatment description specifies lapatinib before and during whole brain radiation therapy, with Herceptin afterward. The summary also mentions possible stereotactic radiosurgery, depending on the participant’s cancer. The registry record does not report which participants received that procedure or the criteria used to select it. Because treatment could include more than one component, an outcome cannot be attributed to lapatinib alone from this single-group design.
3. Trial Design
This was a phase I, single-group study with no masking. Allocation is recorded as NA, and there is no separate control arm. The registered enrollment is 35. The registry describes a treatment sequence of lapatinib before and during whole brain radiation therapy, followed by Herceptin 4mg/kg IV weekly. The brief summary also notes that some participants may have stereotactic radiosurgery depending on their cancer.
The primary objective was to identify the maximum tolerated dose of lapatinib when combined with cranial radiation. That objective is consistent with dose-finding rather than a randomized comparison of treatments. Dose Level 1, Dose Level 2, and Dose Level 3 appear in the serious-adverse-event information, but the registry record does not report the dose assigned to each level, the sequence in which levels were studied, or the rules used to move between levels.
The registry lists five secondary outcomes: progression-free survival, objective response rate in central nervous system sites, the percentage of participants whose first progression was in central nervous system sites, the percentage whose first progression was at non-central nervous system sites, and overall survival. These outcomes could describe disease course, response, and the location of progression, but registered outcome names alone do not establish the analysis methods or findings.
The study start is recorded as 2007-04, and primary completion as 2009-12. Its status is completed. The registry record does not report a randomization procedure, a masking procedure beyond no masking, a statistical analysis plan, eligibility criteria in detail, or participant flow through treatment and follow-up. A separate comparator-based interpretation is not supported by this design.
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
| Stage | Lapatinib,Whole Brain Radiation,Herceptin |
|---|---|
| STARTED | 35 |
| COMPLETED | 34 |
| NOT COMPLETED | 1 |
Reasons for not completing this period:
| Reason | Lapatinib,Whole Brain Radiation,Herceptin |
|---|---|
| Pt still receiving treatment | 1 |
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.
| Characteristic | Unit | Lapatinib,Whole Brain Radiation,Herceptin |
|---|---|---|
| Participants analysed | 35 | |
| Age, Customized: Between 30 and 78 | participants | 35 |
| Sex: Female, Male: Female | Participants | 35 |
| Sex: Female, Male: Male | Participants | 0 |
| Region of Enrollment: United States | participants | 35 |
6. Primary Endpoint
The registry lists the primary outcome as The Maximum Tolerated Dose of Lapatinib When Combined With Cranial Radiation in Patients With CNS Metastases From HER2-positive Breast Cancer., measured over 5 Years.
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | milligrams |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint is the maximum tolerated dose of lapatinib when combined with cranial radiation in patients with central nervous system metastases from HER2-positive breast cancer. The registry describes this as a number measured in milligrams and defines maximum tolerated dose as the highest dose that does not cause unacceptable side effects. The listed timeframe is 5 Years.
In general, dose-finding studies use a maximum tolerated dose endpoint to guide selection of a dose for further study. It represents a tolerability boundary under the conditions of the study, rather than a measure of whether treatment improves survival, reduces disease, or is superior to another treatment. The endpoint therefore matches the phase I safety question, while the secondary outcomes address response and disease progression.
The registry record does not report the maximum tolerated dose result, the dose levels in milligrams, the definition of an unacceptable side effect used for decision-making, or the dose-escalation rules. It also does not explain how the 5 Years timeframe relates to the dose-finding outcome. Without those details and the endpoint result, the primary question can be described but not answered from the registry record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The central statistical point is that this is a dose-finding study without a control group. Its primary question concerns the dose of lapatinib that could be combined with cranial radiation without unacceptable side effects. The registry record states the endpoint and its general definition, but does not report the dose identified. Thus, the record does not give a numerical primary result to interpret.
The registry’s single-group design is important. Observations at different dose levels may help characterize tolerability in the enrolled participants, but the record does not describe dose assignment or escalation rules. These levels should not be read as randomized treatment arms. Without a concurrent control group, changes in response, progression, or survival cannot be interpreted as a treatment effect relative to an alternative. This is especially relevant because the treatment description includes radiation and Herceptin as well as lapatinib, and the brief summary mentions possible stereotactic radiosurgery.
The registry lists progression-free survival, objective response rate in central nervous system sites, first site of progression, and overall survival as secondary outcomes. These outcome names identify questions the study planned to assess; they are not results. The registry record does not report numerical estimates, uncertainty intervals, event counts for these outcomes, or analysis methods. Consequently, no conclusion about the size or precision of any secondary outcome estimate can be drawn from the record.
Safety information is reported by dose level. For Dose Level 2, the registry lists 27 as at risk and 8 as serious-event affected. For Dose Level 1, it lists 3 as at risk and 0 as serious-event affected. For Dose Level 3, it lists 5 as at risk and 0 as serious-event affected. The corresponding other-event affected counts are 27, 3, and 5. These are descriptive registry counts; the record does not supply the event definitions, observation periods, or a comparison adjusted for differences between dose levels. In particular, the counts do not establish that one dose level is safer than another.
The registry also lists serious adverse-event terms and percentages, including diarrhea, pulmonary embolus, and vomiting at 7.4%, and hypoxia and sinusitis at 3.7%. The denominator and the method used to assign these percentages are not reported in the registry record. The percentages should therefore be treated as the registry’s descriptive figures, not as independently interpretable risks or comparative estimates.
Overall, the available record describes the design, treatment, intended outcomes, and selected safety counts, but does not report the primary dose-finding result or statistical analyses. No efficacy conclusion or comparative safety conclusion follows from the posted information. The study’s stated question and its observed results must be kept distinct: the former is documented, while the latter is not reported for the primary endpoint.
9. Statistical Methods Explained
The design determines what statistical interpretation is possible. This is a phase I single-group study, not a randomized comparison. The registry lists no masking and allocation as NA. Those design features mean there is no separate control group against which to estimate a treatment contrast. The dose-level safety counts are descriptive; the record does not identify them as randomized groups or report an analysis comparing them.
What does a maximum tolerated dose measure?
The primary outcome is the maximum tolerated dose of lapatinib combined with cranial radiation. In general, dose-finding asks how tolerability varies across dose levels and identifies a dose under a prespecified safety rule. The registry gives a general definition: the highest dose that does not cause unacceptable side effects. However, the operational definition of unacceptable side effects and the dose-escalation algorithm are not reported in the registry record. Without those rules, a reader cannot reconstruct how the dose decision would have been made.
The endpoint is recorded as a number in milligrams. The result itself, including the selected dose, is not reported in the registry record. The listed timeframe is 5 Years, but the record does not clarify how that timeframe applies to a dose-finding endpoint. It would be inappropriate to infer a dose or a decision rule from the safety counts alone.
Why does the single-group design matter?
In general, a randomized control group helps separate a treatment contrast from differences in patient characteristics, clinical course, and other care. A single-group study does not make that comparison. Here, the registered treatment sequence includes lapatinib, whole brain radiation, and subsequent Herceptin; the brief summary also mentions possible stereotactic radiosurgery. Because these components are not isolated through a control comparison, observed outcomes cannot be assigned to lapatinib alone.
Dose levels can still be informative in a dose-finding context, but interpreting them requires details about how participants entered each level, what triggered dose changes, and how toxicity was assessed. Those details are not reported in the registry record. The available counts therefore do not support a causal comparison between levels.
What can be learned from the secondary outcomes?
The registry lists progression-free survival, objective response rate in central nervous system sites, first site of progression, and overall survival. In general, these outcomes capture different aspects of disease course. A response rate concerns tumor response under a specified assessment method; progression-free survival concerns time until a defined progression event or other endpoint event; and overall survival concerns time until death. The registry record does not report the definitions, assessment schedules, censoring rules, analysis populations, estimates, or uncertainty for these measures.
It also lists the percentage of participants whose first progression was in central nervous system sites and the percentage whose first progression was at non-central nervous system sites. Those are location-specific outcomes, and interpretation depends on how progression was evaluated and how participants without observed progression were handled. These details are not reported in the registry record. Outcome labels alone cannot show the frequency, timing, or precision of the results.
How should uncertainty be understood?
In general, an estimate describes the observed result in a study, while a confidence interval describes a range of values compatible with the data under the statistical model. Wider intervals indicate less precision; narrower intervals indicate greater precision, conditional on the assumptions used. No confidence intervals or other precision measures for the registered clinical outcomes are reported in the registry record. With no such estimates, the magnitude and precision of the outcomes cannot be assessed.
A significance level is a threshold used in a planned statistical test. General descriptions of sample-size planning associated with the posted results use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect described as a fraction of the observed effect. These assumptions do not describe the trial’s single-group design and do not establish that a two-arm test was performed. The registry record does not report a sample-size justification for this phase I study or a statistical plan matching those planning assumptions. Planning illustrations are not observed power and do not substitute for a result.
Why can counts at risk differ by dose level?
The registry reports different at-risk counts for Dose Level 1, Dose Level 2, and Dose Level 3. In general, small or unequal groups can make descriptive percentages unstable and comparisons imprecise. Dose-finding studies may enroll different numbers at different levels, but the design details for this trial are not reported in the registry record. No new percentages or comparative estimates should be calculated from the posted counts without a justified analysis plan and clear definitions.
More generally, adverse events can be counted by participant, by event, or by severity, and the meaning depends on the registry’s definitions. The record gives serious-event affected counts and other-event affected counts but does not fully describe the counting rules or follow-up. This limits interpretation of both frequency and risk.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists five secondary outcomes alongside the primary dose-finding outcome and reports six outcome measures. Examining multiple outcomes raises a general multiplicity issue: when many statistical tests are conducted, the chance of at least one apparently notable result can increase. Methods such as prespecified outcome hierarchies or multiplicity adjustments can address that issue, but the registry record does not report whether any such approach was planned or used.
The registry reports zero analyses. It does not provide outcome estimates, hypothesis tests, confidence intervals, analysis populations, or a statistical analysis plan. As a result, there is no reported inferential analysis to evaluate for multiplicity, and there is no basis for assuming either that adjustment was performed or that it was unnecessary.
Missing data handling is not reported in the registry record. The record does not describe missing outcome assessments, loss to follow-up, censoring rules, or any imputation approach. For time-to-event outcomes such as progression-free survival and overall survival, general interpretation depends on definitions of events and censoring; those details are not reported. For response and progression-location outcomes, the handling of unevaluable participants is also not reported.
The analysis population is not reported in the registry record. It is therefore unclear which participants were included in each planned outcome analysis or how the registry’s enrolled participants relate to those analyses. These omissions limit reproducibility and prevent assessment of whether the reported safety counts and any intended secondary analyses used consistent populations.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Dose Level 2 | 8 | 27 | 29.6% |
| Dose Level 1 | 0 | 3 | 0.0% |
| Dose Level 3 | 0 | 5 | 0.0% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Dose Level 2 | 27 of 27 |
| Dose Level 1 | 3 of 3 |
| Dose Level 3 | 5 of 5 |
Most frequent serious adverse event terms
| Event term | Organ system | Dose Level 2 | Dose Level 1 | Dose Level 3 |
|---|---|---|---|---|
| Diarrhea | Gastrointestinal disorders | 2 of 27 | 0 of 3 | 0 of 5 |
| Pulmonary Embolus | Respiratory, thoracic and mediastinal disorders | 2 of 27 | 0 of 3 | 0 of 5 |
| Vomiting | Gastrointestinal disorders | 2 of 27 | 0 of 3 | 0 of 5 |
| Hypoxia | Respiratory, thoracic and mediastinal disorders | 1 of 27 | 0 of 3 | 0 of 5 |
| Sinusitis | Respiratory, thoracic and mediastinal disorders | 1 of 27 | 0 of 3 | 0 of 5 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Dose Level 2 | Dose Level 1 | Dose Level 3 |
|---|---|---|---|---|
| Fatigue | General disorders | 21 of 27 | 3 of 3 | 5 of 5 |
| Diarrhea | Gastrointestinal disorders | 21 of 27 | 3 of 3 | 4 of 5 |
| Nausea | Gastrointestinal disorders | 18 of 27 | 2 of 3 | 4 of 5 |
| Rash-Acneiform | Skin and subcutaneous tissue disorders | 16 of 27 | 2 of 3 | 3 of 5 |
| Vomiting | Gastrointestinal disorders | 14 of 27 | 2 of 3 | 2 of 5 |
| AST/ALT alkaline phosphatase | Hepatobiliary disorders | 13 of 27 | 2 of 3 | 3 of 5 |
| Headache | Nervous system disorders | 14 of 27 | 1 of 3 | 2 of 5 |
| Anorexia | Gastrointestinal disorders | 14 of 27 | 0 of 3 | 2 of 5 |
| Lymphocytes/leukocytes | Blood and lymphatic system disorders | 11 of 27 | 2 of 3 | 3 of 5 |
| Hyperglycemia | Endocrine disorders | 10 of 27 | 2 of 3 | 3 of 5 |
Serious events with the highest arm-level rate: diarrhea (7.4%), pulmonary embolus (7.4%), vomiting (7.4%), hypoxia (3.7%), sinusitis (3.7%).
The serious adverse-event information is listed by dose level. For Dose Level 2, the registry records 27 at risk and 8 serious-event affected. For Dose Level 1, it records 3 at risk and 0 serious-event affected. For Dose Level 3, it records 5 at risk and 0 serious-event affected. These counts are descriptive and should not be treated as evidence from randomized comparisons.
The registry also records other-event affected counts of 27 for Dose Level 2, 3 for Dose Level 1, and 5 for Dose Level 3. The record does not explain the precise definitions or counting rules behind these categories, or specify the observation period for each count. It is not reported whether counts refer to participants with at least one event or to event occurrences, so the figures should be read as registry entries rather than reconstructed risks.
Serious adverse-event terms include diarrhea, pulmonary embolus, and vomiting, each listed at 7.4%, and hypoxia and sinusitis, each listed at 3.7%. The denominator and method for these percentages are not reported in the registry record. They are not comparative estimates, and should not be used to infer a difference between dose levels or to rank the overall safety of treatments. The primary maximum tolerated dose result is also not reported.
12. What the Result Does, and Does Not, Mean
The registry record establishes that a phase I single-group study examined lapatinib in combination with cranial radiation for patients with HER2-positive breast cancer and central nervous system metastases. Its primary question was dose finding: identify the maximum tolerated dose, defined in general terms as the highest dose that does not cause unacceptable side effects. The study is marked completed, but the primary dose result is not reported in the registry record.
The posted safety information gives counts by dose level and selected serious adverse-event terms and percentages. These figures describe entries in the registry; they do not show a controlled comparison. The dose levels are not described as randomized arms, and the record does not report their dose amounts or the rules used to assign participants. Differences in the counts cannot be interpreted as evidence that one level or treatment is safer than another.
The registry lists secondary outcomes related to response, progression, and survival, but provides no results for them. The outcome names do not establish that the intervention improved response or changed progression or survival. Likewise, the study’s rationale—that lapatinib might affect cancer-cell growth or sensitivity to radiation—is not a trial finding.
The treatment included more than lapatinib: the registered description specifies whole brain radiation and subsequent Herceptin, and the brief summary mentions possible stereotactic radiosurgery. A single-group study with these components cannot isolate the contribution of lapatinib from the other care described. No comparison with radiation alone, another dose, or another treatment is reported.
Accordingly, the record supports a description of the intended safety question and the available event counts, but not a conclusion about treatment benefit, comparative safety, or the selected maximum tolerated dose. Statistical interpretation is constrained by the absence of endpoint results, uncertainty measures, analysis methods, and detailed safety definitions.
13. Why This Trial Matters Statistically
This study illustrates why the design and endpoint should be read together. The primary endpoint is a maximum tolerated dose, a dose-finding safety measure suited to a phase I question. It is not the same as an estimate of treatment benefit, and it does not by itself answer whether a treatment improves survival or response. Keeping those questions separate prevents a safety-focused study from being interpreted as a comparative efficacy trial.
The single-group design also matters. There is no control group, and allocation is recorded as NA. Dose levels are listed in the safety data, but the registry does not describe them as randomized. This means the record supports descriptive interpretation of the posted counts, not a like-for-like comparison between treatments. It also highlights why dose assignment and escalation rules are important details in a dose-finding study.
The treatment description includes lapatinib, whole brain radiation, and subsequent Herceptin, with possible stereotactic radiosurgery mentioned in the brief summary. This multi-component care makes attribution particularly difficult without a control design that separates treatment effects. Registry outcomes such as response, progression, and survival remain distinct from the primary tolerability question.
Finally, the record shows the value of reporting complete statistical details. A maximum tolerated dose result, the operational toxicity definition, dose-level rules, outcome estimates, uncertainty, and analysis populations would make the findings easier to assess. In their absence, the registered purpose and selected safety counts can be described, but the primary question cannot be resolved from the registry record.
14. 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.
Important design details for interpreting a dose-finding study are not reported in the registry record. These include the dose in milligrams associated with each level, the order of dose assignment, the escalation or de-escalation rules, and the criteria defining unacceptable side effects. The maximum tolerated dose result is not reported, so the principal study question cannot be answered from the available record.
The single-group design provides no control-based treatment contrast. The registered treatment description includes lapatinib, whole brain radiation, and subsequent Herceptin; the brief summary also mentions possible stereotactic radiosurgery. The record does not specify which participants received stereotactic radiosurgery or provide a way to separate the contributions of treatment components. Comparisons among the dose-level counts would also be difficult to interpret because their assignment and follow-up are not described.
Further limitations concern outcome reporting. Although secondary outcomes are named, their definitions, assessment schedules, estimates, precision, and analysis methods are not reported in the registry record. Missing-data procedures, censoring rules, and analysis populations are also not reported. The serious adverse-event percentages have no stated denominator, and the safety categories’ counting rules and observation periods are not described.
The registry lists the primary endpoint timeframe as 5 Years but does not explain its relationship to dose finding. It also does not report a statistical analysis plan or sample-size justification for the trial. These gaps restrict reproducibility and make it impossible to assess the precision of the intended clinical outcomes.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Lapatinib in Combination With Radiation Therapy in Patients With Brain Metastases From HER2-Positive Breast Cancer — NCT00470847.
- Registry record last updated 2014-05-22; status last verified 2014-04.
- Results first posted 2014-01-20.
- 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.
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18. Record Summary
The registry record describes a completed phase I, single-group study of lapatinib combined with cranial radiation in patients with HER2-positive breast cancer and central nervous system metastases. The treatment description specifies lapatinib before and during whole brain radiation therapy, followed by Herceptin 4mg/kg IV weekly. The brief summary mentions possible stereotactic radiosurgery.
The primary outcome is the maximum tolerated dose in milligrams, defined as the highest dose that does not cause unacceptable side effects. Its listed timeframe is 5 Years. The dose result is not reported in the registry record. Secondary outcomes include progression-free survival, central nervous system response and progression measures, and overall survival, but outcome results and analysis methods are not reported.
Serious-event counts are listed for Dose Level 1, Dose Level 2, and Dose Level 3, along with selected event terms and percentages. The record has no control group, reports no analyses, and does not provide the statistical details needed to interpret the primary result or make comparative conclusions.