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 Phase I Study of Ipilimumab Combined With Whole Brain Radiation Therapy or Radiosurgery for Melanoma (NCT01703507), a non-randomized phase 1 study. The primary outcome is Maximum Tolerated Dose (MTD) of Ipilimumab.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01703507 |
| Phase | Phase 1 |
| Condition | Recurrent Melanoma, Stage IV Melanoma, Tumors Metastatic to Brain |
| Allocation | Non-Randomized |
| Design model | Parallel |
| Masking | None (open label) |
| Enrollment | 17 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Sidney Kimmel Comprehensive Cancer Center at Thomas Jefferson University |
| Results posted | Yes |
2. Clinical Question
Population
Patients with melanoma and brain metastases; the registry lists recurrent melanoma, stage IV melanoma, and tumors metastatic to brain among the conditions. The record reports enrollment of 17.
Intervention
Ipilimumab combined with radiation. Arm A received ipilimumab with whole brain radiation therapy (WBRT); Arm B received ipilimumab with stereotactic radiosurgery (SRS).
Comparator
The two treatment arms are described, but the study was non-randomized and had no masking. Neither arm is a randomized control for the other, so their outcomes should not be read as a like-for-like treatment comparison.
Primary question
What maximum tolerated dose (MTD) of ipilimumab was identified when combined with WBRT or SRS? The endpoint is defined by the last dose studied or the previous dose, based on clinical judgment of toxicity at the last dose. The registry record does not report the MTD result.
3. Trial Design
This completed phase I study examined ipilimumab in combination with either WBRT or SRS in patients with melanoma and brain metastases. Its stated primary endpoint was the maximum tolerated dose of ipilimumab when combined with either radiation approach. The study was non-randomized, used a parallel model, and had no masking. These design features matter when interpreting the arms: the registry record does not describe a randomized comparison, and the arms are not a like-for-like control comparison.
Arm A combined ipilimumab with WBRT. The regimen description says ipilimumab was given intravenously over 90 minutes once in weeks 1, 4, 7, and 10, with WBRT five days a week in weeks 1–2. Arm B combined ipilimumab with SRS. Ipilimumab was given as in Arm A, and SRS was delivered on day 1 in week 1. These are different radiation approaches and schedules, so arm membership represents more than a simple treatment assignment that can be compared as if randomized.
The record reports enrollment of 17 and gives study dates of 2012-11-09 for start and 2015-05-20 for primary completion. The sponsor is Sidney Kimmel Comprehensive Cancer Center at Thomas Jefferson University. The registry lists secondary outcomes concerning new brain metastases, extracranial response, overall survival, progression-free survival, and adverse events. The record lists six outcome measures but no analyses. Details of a statistical analysis plan, randomization procedure, allocation concealment, or interim analyses 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.
Overall Study
| Stage | Arm A (Ipilimumab and Whole Brain Radiation Therapy) | Arm B (Ipilimumab and Stereotactic Radiosurgery) |
|---|---|---|
| STARTED | 6 | 11 |
| COMPLETED | 5 | 11 |
| NOT COMPLETED | 1 | 0 |
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 | Arm A (Ipilimumab and Whole Brain Radiation Therapy) | Arm B (Ipilimumab and Stereotactic Radiosurgery) | Total |
|---|---|---|---|---|
| Participants analysed | 6 | 11 | 17 | |
| Age, Categorical: <=18 years | Participants | 0 | 0 | 0 |
| Age, Categorical: Between 18 and 65 years | Participants | 1 | 8 | 9 |
| Age, Categorical: >=65 years | Participants | 5 | 3 | 8 |
| Sex: Female, Male: Female | Participants | 2 | 3 | 5 |
| Sex: Female, Male: Male | Participants | 4 | 8 | 12 |
| Ethnicity (NIH/OMB): Hispanic or Latino | Participants | 0 | 0 | 0 |
| Ethnicity (NIH/OMB): Not Hispanic or Latino | Participants | 6 | 11 | 17 |
| Ethnicity (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Asian | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Black or African American | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): White | Participants | 6 | 11 | 17 |
| Race (NIH/OMB): More than one race | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 |
| Region of Enrollment: United States | participants | 6 | 11 | 17 |
6. Primary Endpoint
The registry lists the primary outcome as Maximum Tolerated Dose (MTD) of Ipilimumab, measured over 30 days following the completion of radiation therapy.
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | mg/kg |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint is the maximum tolerated dose of ipilimumab when combined with WBRT or SRS. The record specifies the unit as mg/kg and gives a timeframe of 30 days following completion of radiation therapy. Its definition is not a numerical summary such as an average: it is the last dose studied or the previous dose, selected on the basis of clinical judgment about the toxicity seen at the last dose.
In general, an MTD endpoint is used in early-phase research to characterize a dose in relation to tolerability. This differs from an endpoint designed to estimate whether a treatment improves a clinical outcome relative to a control. The toxicity-based definition makes clinical judgment part of the endpoint rule; the registry record does not describe a formal algorithm, toxicity grading criteria, or dose-selection analysis beyond the stated definition.
The endpoint title and definition are reported, but no MTD value, dose-level results, or associated uncertainty estimate is reported in the registry record. Consequently, the posted information does not establish which dose met the study’s MTD definition or how precisely that dose was estimated. The endpoint timeframe also should not be interpreted as describing longer-term toxicity; the record identifies the specified assessment window but does not give additional timing details for the primary endpoint.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record describes a phase I dose and toxicity study, not a randomized efficacy comparison. Its primary question concerns the maximum tolerated dose of ipilimumab in combination with WBRT or SRS. Although the endpoint definition is stated, its result is not reported in the record. No numerical primary outcome, dose-level findings, or uncertainty interval is available for interpretation.
The record names several secondary outcomes: the rate of developing new brain metastases in each arm, extracranial disease response, overall survival, progression-free survival, and adverse and serious adverse events. Their presence as planned or listed outcomes does not by itself establish their results. Apart from the adverse-event counts and the listed serious-event term, numerical outcome findings are not reported in the record. In particular, the registry information does not provide numerical results for response, survival, progression, or new brain metastases.
The study is explicitly non-randomized. Therefore, differences between the arms, if encountered in other summaries, cannot be interpreted as an unbiased causal contrast on the basis of this design description alone. Treatment assignment could be associated with characteristics or clinical decisions that also relate to outcomes; the record does not report enough information to assess or adjust for such factors. The radiation regimens also differ, so the arms represent distinct treatment combinations rather than a single intervention contrasted with a control.
The reported safety counts are descriptive. Arm A lists five participants at risk for serious adverse events and one affected; Arm B lists 11 at risk and four affected. The record also lists other adverse events for two participants in Arm A and four in Arm B. These counts do not, on their own, establish whether an event was caused by ipilimumab, radiation, the combination, or the underlying illness. The registry does not describe event-level attribution or provide enough detail to characterize duration, severity grades, or overlap between event categories.
The registry lists enrollment of 17, while the safety risk sets are reported separately by arm. These figures describe different record fields, and the registry information does not explain their relationship. No analysis records are listed. Statistical significance, adjusted estimates, confidence intervals, and handling of missing outcomes are not reported in the registry record. The results therefore support a limited description of study design and posted safety counts, not a conclusion about comparative efficacy or a definitive dose effect.
9. Statistical Methods Explained
The study is labeled phase I and has a dose-finding primary endpoint. In general, early-phase dose studies focus on describing dose and toxicity rather than estimating a treatment effect against a randomized control. Here, the registry defines the MTD as the last dose studied or the previous dose, depending on clinical judgment about toxicity at the last dose. That definition indicates that judgment is part of the endpoint, but does not specify the decision procedure, toxicity thresholds, or detailed dose-escalation rules. Those details are not reported in the registry record.
What does the non-randomized design imply?
Random allocation is intended to make treatment groups comparable on average with respect to both measured and unmeasured baseline characteristics. In a non-randomized study, that protection is absent. Differences between arms can reflect treatment, patient characteristics, clinical choices, or other factors. This study also compares different combinations of ipilimumab and radiation schedules. Accordingly, the arm descriptions are useful for understanding what was studied, but do not turn the arms into a randomized treatment-versus-control comparison.
The parallel model means the record describes separate arms rather than a crossover in which participants switch treatments. No masking was used. In general, masking can reduce some forms of measurement or decision bias, while its absence means that participants or study personnel may know the assigned approach. The registry record does not detail who assessed toxicity or outcomes, or whether any outcome assessments were independently reviewed.
How should the MTD definition be understood?
MTD is a dose-selection concept tied to tolerability. The endpoint is not an estimate of average symptom burden or a measure of tumor response. The record’s definition relies on the dose studied and clinical judgment about toxicity at that dose. Because the dose-level observations and selected dose are not reported, readers cannot reconstruct the MTD decision or assess its precision from the registry record. A confidence interval would ordinarily express uncertainty around an estimate; no confidence interval for the MTD is reported.
What do the safety counts describe?
The adverse-event entries give counts of participants at risk and counts affected for serious and other adverse events within each arm. These are descriptive summaries. Counts do not convey the timing, duration, severity grading, recurrence, or causal attribution of individual events. Nor do they show whether a participant with a serious event also appears in the other-adverse-event count. That overlap and the event-level details are not reported in the registry record. General statistical comparisons of event rates require clearly defined populations, follow-up, and event rules; the posted information does not document a comparative analysis.
The registry also lists diarrhea at 36.4% among the top serious-event terms. This term-level percentage should be read as the record presents it; the registry information does not state an arm-specific breakdown alongside that entry. It should not be used to infer a count, denominator, or causal relationship that the record does not explicitly report.
What information is missing for statistical assessment?
The record lists six outcome measures and no analyses. It does not report an analysis plan, model specifications, adjustment variables, confidence intervals, or hypothesis-test results. It also does not describe how missing data, censoring, or analysis populations were handled. For time-to-event outcomes such as overall survival or progression-free survival, general methods may account for differing follow-up and censoring, but the method used in this study is not reported in the registry record.
The registry’s sample-size assumptions describe planning illustrations based on a two-sided significance level of 0.05, equal allocation, a normal approximation, and detection of a stated fraction of the observed effect. The record states that time-to-event illustrations use a total event count and other illustrations use participants per arm. Such illustrations are planning calculations, not observed power and not evidence that a study had a particular probability of detecting an effect. The numerical illustration results are not reported in the registry information, and the record does not state that these assumptions were the trial’s original design justification.
In general, over-dispersion occurs when variability in count data exceeds what a simple statistical model assumes. It can make standard errors too small if ignored. The registry record does not identify a count model or report an over-dispersion assessment, so no claim about its use or relevance in the trial’s analyses can be made. More broadly, statistical methods should be interpreted in light of the question, outcome definition, and analysis population; those details are not reported for the listed secondary endpoints.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists multiple secondary outcomes, including new brain metastases, extracranial response, overall survival, progression-free survival, and adverse events. When many outcomes are examined, the chance of at least one apparently notable finding can increase. General approaches to multiplicity include designating a primary analysis, adjusting inference across selected comparisons, or treating secondary results as exploratory. The registry record does not report a multiplicity strategy or clarify which secondary outcomes, if any, were subject to formal hypothesis testing.
Missing-data handling is also not reported in the registry record. For outcomes with incomplete follow-up, the amount and pattern of missingness can affect interpretation. For time-to-event outcomes, censoring is a specific form of incomplete event information; the record does not describe censoring rules, follow-up completeness, or any analysis method for these endpoints. It also does not describe imputation or sensitivity analyses.
The record does not specify analysis populations, such as which participants were included in each endpoint analysis or whether participants were analyzed according to an assigned treatment category. It reports enrollment of 17, but that number alone does not identify the population used for each outcome. The safety risk sets are listed separately for the arms, and their relationship to the overall enrollment is not explained in the registry record.
No analyses are listed. As a result, the registry does not provide adjusted or unadjusted estimates, inferential tests, or uncertainty intervals for the listed clinical outcomes. The absence of this information should not be mistaken for evidence that no missing data or multiplicity concerns existed; their handling is simply not reported in the registry record.
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 |
|---|---|---|---|
| Arm A (Ipilimumab and Whole Brain Radiation Therapy) | 1 | 5 | 20.0% |
| Arm B (Ipilimumab and Stereotactic Radiosurgery) | 4 | 11 | 36.4% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Arm A (Ipilimumab and Whole Brain Radiation Therapy) | 3 of 5 |
| Arm B (Ipilimumab and Stereotactic Radiosurgery) | 3 of 11 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Arm A (Ipilimumab and Whole Brain Radiation Therapy) | 2 of 5 |
| Arm B (Ipilimumab and Stereotactic Radiosurgery) | 4 of 11 |
Most frequent serious adverse event terms
| Event term | Organ system | Arm A (Ipilimumab and Whole Brain Radiation Therapy) | Arm B (Ipilimumab and Stereotactic Radiosurgery) |
|---|---|---|---|
| diarrhea | Gastrointestinal disorders | 1 of 5 | 4 of 11 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Arm A (Ipilimumab and Whole Brain Radiation Therapy) | Arm B (Ipilimumab and Stereotactic Radiosurgery) |
|---|---|---|---|
| headache | General disorders | 2 of 5 | 4 of 11 |
| Diarrhea | Gastrointestinal disorders | 2 of 5 | 3 of 11 |
| Changes in Hearing | Ear and labyrinth disorders | 2 of 5 | 1 of 11 |
| Anoerexia | Metabolism and nutrition disorders | 2 of 5 | 1 of 11 |
| fatigue | General disorders | 1 of 5 | 1 of 11 |
| hypertension | Vascular disorders | 2 of 5 | 0 of 11 |
| Alopecia | General disorders | 2 of 5 | 0 of 11 |
| Anemia | Blood and lymphatic system disorders | 1 of 5 | 1 of 11 |
| hot flashes | General disorders | 1 of 5 | 0 of 11 |
| Constipation | Gastrointestinal disorders | 1 of 5 | 0 of 11 |
Serious events with the highest arm-level rate: diarrhea (36.4%).
For Arm A, the record lists five participants at risk for serious adverse events and one affected. It lists five at risk for other adverse events and two affected. For Arm B, it lists 11 participants at risk for serious adverse events and four affected; for other adverse events, it lists 11 at risk and four affected. These are the counts as recorded for each arm, not estimates of causal risk attributable to a particular component of treatment.
The registry lists diarrhea at 36.4% among the top serious-event terms. The record does not give an arm-specific value with that term in the available information. It also does not report event-level timing, duration, severity grades, attribution, or whether participants could contribute to more than one category. Those omissions limit how much can be inferred from the counts.
Deaths are listed as three in Arm A and three in Arm B. The record does not state the causes or attribute these deaths to study treatment. These descriptive entries should not be treated as evidence of a treatment effect or as a comparative safety test. The registry does not report a statistical analysis of adverse events or an uncertainty estimate for these counts.
12. What the Result Does, and Does Not, Mean
The study addresses a phase I question about the maximum tolerated dose of ipilimumab combined with WBRT or SRS in patients with melanoma and brain metastases. The registry provides the endpoint definition and treatment schedules, but not the selected MTD or its uncertainty. Therefore, the posted information does not allow a reader to identify the dose determined by the study or assess the evidence behind such a determination.
The record’s non-randomized design also constrains what can be said about the two treatment arms. The study does not establish a like-for-like comparison between WBRT and SRS, nor does it estimate a randomized treatment effect. The radiation approaches differ, and assignment was not randomized. Any differences in outcomes across arms could reflect factors other than the treatment combination.
Although the registry names outcomes related to brain metastases, extracranial response, survival, progression, and adverse events, numerical results for those clinical outcomes are not reported in the registry record. The adverse-event counts and deaths are descriptive entries; without event details, attribution, and comparative analyses, they do not establish that a treatment caused or prevented an outcome.
In general, statistical uncertainty is important because a point estimate alone may be compatible with a broad range of underlying values. The registry does not report confidence intervals or other uncertainty estimates for the primary or secondary outcomes. Nor does it report how missing data, multiple outcomes, or analysis populations were handled. The evidence available in the record is therefore limited to study characteristics, endpoint definitions, and the stated safety counts. It does not support conclusions about efficacy, comparative safety, or the precision of an MTD estimate.
13. Why This Trial Matters Statistically
This study is statistically informative as an example of how a phase I question differs from an efficacy comparison. Its primary endpoint concerns a toxicity-based dose decision, defined using clinical judgment about the last dose studied. That kind of endpoint asks what dose is considered tolerable under the study’s definition; it is not the same as asking whether one treatment improves survival or tumor response compared with another.
The non-randomized design is also central to interpretation. The registry presents two parallel treatment arms but does not establish them as comparable groups for causal inference. This is particularly important because the arms pair ipilimumab with different radiation approaches and schedules. The distinction between treatment description and treatment-effect estimation is a basic statistical issue that applies well beyond this study.
The record illustrates why endpoint definitions and analysis details matter. It names a primary endpoint, provides a timeframe, and lists secondary outcomes, yet the MTD result and analyses are not reported. Without outcome estimates, uncertainty intervals, and details on analysis populations or missing data, readers cannot evaluate precision or reproduce an inferential claim. The reported safety counts can be described, but they cannot replace a prespecified comparative analysis.
Finally, the registry’s planning assumptions should be kept separate from observed evidence. General sample-size illustrations are calculations about hypothetical design requirements under stated assumptions. They are not observed power and do not demonstrate that a treatment effect was present. In this record, the distinction reinforces a broader lesson: design descriptions, outcome definitions, and numerical findings answer different questions, and none should be substituted for another.
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.
The registry record does not report the primary MTD result, dose-level observations, or uncertainty around the dose decision. Although it gives a toxicity-based definition and an assessment timeframe of 30 days following completion of radiation therapy, it does not describe toxicity grading criteria, detailed dose-selection rules, or the clinical judgment process beyond that definition. This prevents independent assessment of the primary endpoint.
The non-randomized design limits comparisons between arms. The record does not provide baseline characteristics, reasons for treatment allocation, or adjustment methods that might help assess comparability. The arms also use different radiation approaches and schedules. Any numerical contrast between them would therefore need careful qualification, and the registry does not report a comparative analysis.
Outcome reporting is incomplete in the available record. The registry names secondary endpoints but does not report numerical results for those outcomes or list analyses. It does not describe analysis populations, missing-data procedures, censoring rules, multiplicity handling, or confidence intervals. No conclusions about the precision or statistical significance of secondary findings can be drawn from the listed outcomes alone.
The safety entries lack detail about event timing, duration, grade, attribution, overlap, and causes of death. The registry lists an overall enrollment of 17 and separate arm-specific safety risk sets, but does not explain the relationship between these counts. This limits interpretation of denominators and completeness. These are limitations of what the registry record reports; they do not establish how the investigators handled these issues outside the record.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Phase I Study of Ipilimumab Combined With Whole Brain Radiation Therapy or Radiosurgery for Melanoma — NCT01703507.
- Registry record last updated 2025-05-16; status last verified 2025-05.
- Results first posted 2019-08-19.
- 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 describes a completed phase I, non-randomized, parallel study of ipilimumab combined with WBRT or SRS in patients with melanoma and brain metastases. Enrollment is listed as 17. Arm A received ipilimumab with WBRT, and Arm B received ipilimumab with SRS.
The primary endpoint is the maximum tolerated dose of ipilimumab, defined using the last dose studied or the previous dose based on clinical judgment of toxicity. Its timeframe is 30 days following completion of radiation therapy. The MTD result is not reported in the registry record. The record lists six outcome measures and no analyses.
Safety entries report serious and other adverse-event counts by arm, as well as three deaths in each arm. Diarrhea is listed at 36.4% among the top serious-event terms. The registry does not report causal attribution, detailed event characteristics, or comparative safety analyses. Numerical results for the named response, progression, brain-metastasis, and survival outcomes are not reported in the registry record.