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 Study of the Combination of Vorinostat and Radiation Therapy for the Treatment of Patients With Brain Metastases (NCT00838929), a non-randomized phase 1 study. The primary outcome is Maximum Tolerated Dose (MTD) and Recommended Phase II Dose (RP2D) of Vorinostat and Radiotherapy in Patients With Brain Metastases..
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00838929 |
| Phase | Phase 1 |
| Condition | Brain Metastases |
| Allocation | Non-Randomized |
| Design model | Single Group |
| 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 brain metastases were eligible for the study. The registry record describes a multi-center study and records enrollment of 17 participants. Further eligibility details and characteristics of the enrolled population are not reported in the registry record.
Intervention
The intervention combined oral vorinostat with radiation therapy. The registry describes treatment in sequential dose cohorts, with vorinostat dose levels of 200 mg, 300 mg, and 400 mg, and lower dose levels designated for de-escalation if toxicity occurred.
Comparator
There was no randomized comparator group. The design is recorded as non-randomized and single-group, with participants treated in dose cohorts. Those cohorts represent different dose levels, not a like-for-like control comparison.
Primary question
The primary question was what maximum tolerated dose and recommended Phase II dose of vorinostat could be identified when combined with radiotherapy in patients with brain metastases. The registry outcome describes dose determination in relation to dose-limiting toxicity. The final MTD and RP2D are not reported in the registry record.
This is a dose-finding question, not a randomized test of whether the combination is better than another treatment. The study description also says that anti-tumor activity would be assessed, but the listed primary outcome concerns dose selection. No comparative estimate of anti-tumor activity is reported in the registry record. The study is listed as Phase I, completed, and open-label. Its stated treatment period was 3 weeks, with the primary outcome timeframe also mentioning assessment during treatment, on the last day of treatment, and at follow-up every 3 months.
3. Trial Design
The registry identifies this as a Phase I, multi-center, open-label, non-randomized, single-group study. Enrollment is recorded as 17, and the study status is completed. The record lists a start of 2009-03 and primary completion of 2012-01. These registry entries describe the study record; they do not establish when individual participants entered or completed treatment.
Participants were assigned to sequential dose cohorts rather than randomized between treatments. The listed cohorts received vorinostat at 200 mg, 300 mg, or 400 mg with radiation. The outcome description also names dose levels of 50 mg and 100 mg for use in de-escalation if toxicity occurred, and identifies 200 mg as the initial starting dose. The brief description says that cohorts would be treated at sequentially rising doses and outlines rules for escalation or de-escalation based on dose-limiting toxicity. These are protocol descriptions, not evidence that every listed dose level was reached or that a particular dose was established as the MTD.
The record states that the MTD would be one dose below a dose associated with dose-limiting toxicity under its stated rule. However, the final MTD and recommended Phase II dose are not reported in the registry record. The registry also does not report the number of participants treated at the 50 mg or 100 mg levels, or whether either level was used.
Because there was no randomized control arm, comparisons across cohorts should not be interpreted as randomized treatment effects. Cohort dose levels were part of dose finding, and participants at different dose levels may not be exchangeable. The allocation method, masking, and model fields support this reading: allocation is non-randomized, masking is none, and the model is single-group.
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 | Vorinostat (200 mg) and Radiation | Vorinostat (300 mg) and Radiation | Vorinostat (400 mg) and Radiation |
|---|---|---|---|
| STARTED | 3 | 8 | 6 |
| COMPLETED | 3 | 5 | 5 |
| NOT COMPLETED | 0 | 3 | 1 |
Reasons for not completing this period:
| Reason | Vorinostat (200 mg) and Radiation | Vorinostat (300 mg) and Radiation | Vorinostat (400 mg) and Radiation |
|---|---|---|---|
| Protocol Violation | 0 | 1 | 0 |
| Disease progression | 0 | 2 | 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 | Vorinostat (200 mg) and Radiation | Vorinostat (300 mg) and Radiation | Vorinostat (400 mg) and Radiation | Total |
|---|---|---|---|---|---|
| Participants analysed | 3 | 8 | 6 | 17 | |
| Age, Categorical: <=18 years | Participants | 0 | 0 | 0 | 0 |
| Age, Categorical: Between 18 and 65 years | Participants | 0 | 5 | 5 | 10 |
| Age, Categorical: >=65 years | Participants | 3 | 3 | 1 | 7 |
| Sex: Female, Male: Female | Participants | 1 | 5 | 3 | 9 |
| Sex: Female, Male: Male | Participants | 2 | 3 | 3 | 8 |
| Region of Enrollment: United States | participants | 3 | 8 | 6 | 17 |
6. Primary Endpoint
The registry lists the primary outcome as Maximum Tolerated Dose (MTD) and Recommended Phase II Dose (RP2D) of Vorinostat and Radiotherapy in Patients With Brain Metastases., measured over Weekly during treatment On Last day of treatment (30 days after last drug dose) Follow-up (every 3 months).
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | mg |
| Endpoint classification | not reduced to a single comparison |
The primary outcome is titled as the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of vorinostat and radiotherapy for patients with brain metastases. It is recorded as a numeric outcome measured in mg. The description explains that the MTD is determined in relation to dose-limiting toxicity and describes dose levels from 50 mg through 400 mg. The timeframe includes weekly assessment during treatment, assessment on the last day of treatment, and follow-up every 3 months.
Dose-finding endpoints are used in early-phase studies to guide selection of a dose for later research. In general, escalating exposure can help characterize tolerability, while rules based on dose-limiting toxicity provide a structured basis for decisions about escalation or de-escalation. This is a general description of dose-finding logic, not a claim about what happened in this study.
The registry record does not report the observed MTD, the selected RP2D, or participant-level dose-limiting toxicity results by dose. Although one primary outcome measure is listed, the outcome result itself is not reported in the registry record. Therefore, the endpoint definition explains what the study sought to determine, but does not establish what dose was selected or how precisely that determination was supported.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The posted registry information describes a dose-finding study of vorinostat combined with radiation therapy, not a controlled efficacy comparison. The primary objective was to determine the MTD and RP2D. Although the study is marked completed, the registry record does not report the primary outcome value. It therefore does not identify a final tolerated dose or a recommended dose for later-phase study.
The adverse-event records show participants at risk and participants affected for serious and other adverse events within the listed dose cohorts. For serious adverse events, the 200 mg cohort lists 3 at risk and 1 affected; the 300 mg cohort lists 7 at risk and 3 affected; and the 400 mg cohort lists 6 at risk and 3 affected. For other adverse events, the corresponding records list 3 at risk and 2 affected, 7 at risk and 6 affected, and 6 at risk and 3 affected. These are cohort-specific registry counts. They do not provide a complete account of event timing, severity beyond the serious/other classification, attribution to treatment, or the number of events per affected participant.
The registry lists serious-event terms that include increase in amylase at 33.3%, death at 33.3%, pulmonary embolism at 16.7%, hypotension at 14.3%, renal failure at 14.3%, and ulceration - Grade 3 at 14.3%. Those percentages should be read as the registry’s reported term figures, not as a basis for comparing dose cohorts: the record does not attach these percentages to specific cohorts in the term list. The group-level deaths field is null for each listed cohort, while death also appears in the serious-event term list. The registry record does not reconcile those entries or provide further detail about the death term.
No efficacy estimate, comparative treatment effect, confidence interval, or inferential test is reported for the primary outcome. The record lists zero analysis entries. That means the registry has no analysis record to interpret; it does not by itself establish whether analyses were or were not performed outside the registry. Without the primary outcome result and a reported analysis, the posted information supports a description of the design and recorded safety counts, but not a conclusion about which dose was selected or the anti-tumor activity of the combination.
Because the cohorts are non-randomized and differ by dose, apparent differences in counts cannot establish that dose caused a difference in risk. Cohort size, participant characteristics, observation time, and dose-limiting toxicity rules can affect the interpretation. The registry record does not report enough detail to adjust for those considerations or to make a causal comparison.
9. Statistical Methods Explained
What does the design permit?
This is recorded as a non-randomized, single-group study with no masking. In general, randomization helps balance measured and unmeasured characteristics between comparison groups, while masking can reduce some forms of assessment or reporting bias. Neither feature is part of the recorded design. The dose cohorts therefore serve the purpose of dose escalation and tolerability assessment, rather than as randomized control groups for estimating a treatment effect.
In general, a dose-finding design evaluates tolerability as dose changes and uses prespecified decision rules to guide escalation or de-escalation. The registry summary describes a cohort-based rule involving dose-limiting toxicity and gives dose levels of 50 mg, 100 mg, 200 mg, 300 mg, and 400 mg. It says 200 mg was the initial starting dose and that the lower levels were for de-escalation if toxicity occurred. The registry does not report whether all these levels were used, the final dose decisions, or the complete results of the dose-limiting toxicity assessments.
What does a dose-limiting toxicity rule tell the reader?
In general, dose-limiting toxicity rules translate observed tolerability into a dose-selection decision. Such a rule is a design convention; it is not itself a result. The study description says that escalation would proceed depending on whether dose-limiting toxicities occurred, and defines the MTD in relation to a dose at which toxicity met a specified threshold. The record does not report the observed toxicity pattern needed to apply that rule, nor does it report the selected MTD or RP2D. It would therefore be inappropriate to infer the chosen dose from the listed cohort doses or from the adverse-event counts alone.
How should the event counts be read?
The registry’s safety entries distinguish participants at risk from participants affected for serious and other adverse events. These counts describe the reported cohort records. They are not an estimate of comparative risk across randomized arms, because there are no randomized arms. In general, event counts are most interpretable when the record also clarifies event definitions, time at risk, severity, attribution, repeated events, and participant-level follow-up. Those details are not reported in the registry record for these entries. The serious-event term percentages are listed separately and are not linked to specific dose cohorts in the term list, so they should not be treated as dose-specific rates.
What is not available for statistical inference?
The registry lists one primary outcome measure, but no numerical result for that measure. It records zero analysis entries. No confidence interval, standard error, p-value, or model-based estimate for the MTD or RP2D is reported in the registry record. Without an outcome estimate and its uncertainty, the precision of dose selection cannot be assessed from the posted information.
In general, a confidence interval expresses the range of values compatible with an estimate under the assumptions of the statistical method. It helps distinguish an estimate that is precise from one with substantial uncertainty. No confidence interval is reported for this study’s primary endpoint, and none can be inferred from the cohort counts alone. Similarly, a p-value addresses compatibility of data with a specified statistical model or null hypothesis; it does not by itself measure clinical importance. The registry does not report a hypothesis test for the primary dose-finding outcome.
General statistical methods for comparisons between treatment groups are not directly applicable as causal analyses because there is no randomized comparator. Differences across dose cohorts could reflect factors other than dose, and the registry provides no adjustment model or comparative analysis to address such factors. The study’s principal statistical task is described as dose selection, but the final decision and its supporting analysis are not reported.
What do the missing analysis details mean?
The statistical analysis plan is not reported in the registry record. This includes details such as planned estimands, methods for handling incomplete observations, analysis populations, and any planned sensitivity analyses. These elements should not be reconstructed from general practice or from the brief design description. The registry’s lack of analysis entries is a limit on what can be interpreted from this record, rather than evidence that no analysis took place.
In general, over-dispersion matters when observed variability exceeds what a chosen probability model expects; failing to account for it can make uncertainty appear too small. The registry does not report a model for the primary endpoint or provide data that would support a model-based assessment of dispersion. A discussion of over-dispersion is therefore only general and does not describe an analysis performed in this study.
Likewise, sample-size planning cannot be evaluated from this record. Enrollment is recorded as 17, but the registry does not report a sample-size justification or statistical power calculation for the dose-finding objective. Enrollment should not be treated as evidence of adequate power, and there is no basis in the registry record for an observed-power calculation. The posted information supports careful description of the design and the recorded counts, but not additional inferential calculations.
10. Multiplicity, Missing Data and Analysis Populations
The registry record does not report a statistical analysis plan, a multiplicity strategy, or any planned hierarchy of hypotheses. The primary outcome is dose determination, and the study description also mentions assessment of anti-tumor activity. However, no inferential results for anti-tumor activity are reported, and the record does not explain how multiple outcomes, dose levels, or safety assessments were to be handled statistically. It would be inappropriate to assume that a correction or testing strategy was used.
Missing-data rules and analysis populations are not reported in the registry record. The record does not explain how participants who stopped treatment, missed assessments, or lacked follow-up would be handled, or whether analyses used all enrolled participants, treated participants, or another defined population. The adverse-event entries include at-risk counts for each listed cohort, but those counts alone do not specify the analysis population for the primary outcome or the handling of incomplete follow-up.
In general, multiplicity arises when several outcomes, comparisons, or repeated tests are considered; without an analysis plan, the implications for false-positive findings cannot be assessed. In general, missing-data methods matter because results can depend on whether missingness is related to participant characteristics or outcomes. These are general statistical considerations, not methods documented for this study.
The registry lists zero analysis entries and does not report a primary endpoint result. Thus, the posted record does not allow assessment of multiplicity control, missing-data handling, or population-specific analyses. This absence should be distinguished from proof that no such procedures were carried out outside the registry.
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 |
|---|---|---|---|
| Vorinostat (200 mg) and Radiation | 1 | 3 | 33.3% |
| Vorinostat (300 mg) and Radiation | 3 | 7 | 42.9% |
| Vorinostat (400 mg) and Radiation | 3 | 6 | 50.0% |
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 |
|---|---|
| Vorinostat (200 mg) and Radiation | 2 of 3 |
| Vorinostat (300 mg) and Radiation | 6 of 7 |
| Vorinostat (400 mg) and Radiation | 3 of 6 |
Most frequent serious adverse event terms
| Event term | Organ system | Vorinostat (200 mg) and Radiation | Vorinostat (300 mg) and Radiation | Vorinostat (400 mg) and Radiation |
|---|---|---|---|---|
| Death | Nervous system disorders | 0 of 3 | 0 of 7 | 2 of 6 |
| Pulmonary embolism | Vascular disorders | 0 of 3 | 1 of 7 | 1 of 6 |
| Increase in amylase | Gastrointestinal disorders | 1 of 3 | 0 of 7 | 0 of 6 |
| Hypotension | Vascular disorders | 0 of 3 | 1 of 7 | 0 of 6 |
| Renal failure | Renal and urinary disorders | 0 of 3 | 1 of 7 | 0 of 6 |
| Ulceration - Grade 3 | Skin and subcutaneous tissue disorders | 0 of 3 | 1 of 7 | 0 of 6 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Vorinostat (200 mg) and Radiation | Vorinostat (300 mg) and Radiation | Vorinostat (400 mg) and Radiation |
|---|---|---|---|---|
| Low hemoglobin | Blood and lymphatic system disorders | 0 of 3 | 2 of 7 | 2 of 6 |
| Fatigue | General disorders | 1 of 3 | 0 of 7 | 2 of 6 |
| Rash/desquamation | Skin and subcutaneous tissue disorders | 1 of 3 | 0 of 7 | 1 of 6 |
| Oral pain | General disorders | 1 of 3 | 1 of 7 | 0 of 6 |
| Nausea | General disorders | 0 of 3 | 1 of 7 | 1 of 6 |
| Hyperglycemia | General disorders | 0 of 3 | 1 of 7 | 1 of 6 |
| Neutropenia | Blood and lymphatic system disorders | 1 of 3 | 0 of 7 | 1 of 6 |
| Low platelets | Blood and lymphatic system disorders | 0 of 3 | 0 of 7 | 2 of 6 |
| Ulceration - Grade 2 | General disorders | 1 of 3 | 0 of 7 | 0 of 6 |
| Vomiting | General disorders | 0 of 3 | 1 of 7 | 0 of 6 |
Serious events with the highest arm-level rate: increase in amylase (33.3%), death (33.3%), pulmonary embolism (16.7%), hypotension (14.3%), renal failure (14.3%).
The serious adverse-event entries list participants at risk and participants affected separately for each dose cohort. The 200 mg cohort records 3 at risk and 1 affected; the 300 mg cohort records 7 at risk and 3 affected; and the 400 mg cohort records 6 at risk and 3 affected. For other adverse events, the same cohorts record 3 at risk and 2 affected, 7 at risk and 6 affected, and 6 at risk and 3 affected, respectively. These figures are registry counts, not randomized comparisons.
The serious-event term list reports increase in amylase at 33.3%, death at 33.3%, pulmonary embolism at 16.7%, hypotension at 14.3%, renal failure at 14.3%, and ulceration - Grade 3 at 14.3%. The record does not link these term percentages to individual cohorts in the term list, so they should not be read as rates for a particular dose. The death count field is null for each cohort, even though death appears as a serious-event term. Further clarification is not reported in the registry record.
In general, event counts and term percentages can differ in meaning depending on whether they refer to participants, events, or a subset of reported terms. The registry does not provide enough detail to resolve those distinctions fully. These data do not establish causation, comparative safety, or the timing and duration of events.
12. What the Result Does, and Does Not, Mean
The record shows that a Phase I dose-finding study was conducted using vorinostat with radiation therapy in patients with brain metastases. It specifies sequential dose cohorts and describes a toxicity-based approach to dose escalation and selection. It also records serious and other adverse-event counts within the listed cohorts. These details characterize the study design and the safety information entered in the registry.
The central endpoint was the MTD and RP2D, but neither selected dose nor a numerical primary outcome result is reported in the registry record. As a result, the posted data do not establish what dose was recommended for a later study or how certain that choice was. The description that anti-tumor activity would be assessed is not accompanied by a reported efficacy result. The registry therefore does not support a conclusion about anti-tumor activity or a treatment effect.
The cohort counts should not be used to claim that one dose was safer or more hazardous than another. The design was not randomized, and the registry does not report a controlled comparison or adjustment for differences between cohorts. Counts also do not convey the full event history, including timing, attribution, recurrence, or duration. The serious-event term percentages lack cohort attribution in the term list, and the death entries are not reconciled with the null group-level death fields.
In general, early-phase dose-finding studies answer a different question from trials designed to compare clinical outcomes between treatment strategies. Their principal role is to inform dose selection and characterize tolerability under the study conditions. That general distinction does not fill in the absent dose-selection result for this trial. The registry record supplies evidence of the planned objective and some safety reporting, but leaves the primary result and its statistical uncertainty unreported.
13. Why This Trial Matters Statistically
This trial is statistically informative as an example of the difference between dose finding and treatment comparison. Its non-randomized, single-group design uses sequential dose cohorts to address a tolerability and dose-selection question. It does not provide randomized evidence comparing the combination with another treatment. Recognizing that distinction helps prevent dose-cohort counts from being interpreted as controlled treatment effects.
The record also illustrates why an outcome definition is not the same as an outcome result. The primary endpoint is clearly described as determining the MTD and RP2D, with toxicity-based dose rules and a stated assessment timeframe. Yet the registry does not report the final dose or the data used to reach it. Without those elements, readers cannot evaluate the endpoint result, its precision, or the consistency of the dose decision with the described rule.
Safety reporting requires similar care. Counts are presented by cohort, while serious-event term percentages are listed separately without cohort linkage in the term list. The death term and null group-level death fields are not reconciled. These details show how different registry fields can answer different questions and why clear denominators, definitions, and event-level context matter for statistical interpretation.
Finally, the record contains no analysis entries and does not report its statistical analysis plan, missing-data methods, or analysis populations. That absence limits reproducibility and prevents readers from assessing the inferential framework. It is not evidence that analyses were not conducted outside the registry. The statistical lesson is to separate what the registry documents—the design, intended endpoint, and recorded safety counts—from what remains unreported: the primary dose result and the analyses supporting it.
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 primary limitation for interpretation is that the registry record does not report the primary outcome result. The final MTD and RP2D, dose-limiting toxicity results, and the rationale for the selected dose are not available in the record. Although the study is marked completed, completion status does not substitute for outcome reporting.
The listed dose cohorts are non-randomized and do not provide a like-for-like control comparison. Participant numbers differ across the cohort safety entries, and the record does not provide participant characteristics by cohort or an adjusted analysis. The counts therefore cannot establish that dose caused any observed difference. The registry also does not state whether every dose level in the endpoint description was used, including the levels designated for de-escalation.
Safety information is limited to summary counts and a list of serious-event terms with percentages. The term list does not link those percentages to dose cohorts, and the group-level death fields are null while death appears in the term list. Event timing, attribution, recurrent events, duration, and detailed severity information are not reported in the registry record. The counts alone do not resolve these issues.
The record does not report a statistical analysis plan, sample-size justification, multiplicity strategy, missing-data rules, analysis populations, or uncertainty estimates for the primary endpoint. No analysis entries are listed. Consequently, readers cannot assess the planned inferential methods or the precision of the dose determination from this record. These limits concern the information available in the registry record and do not establish what documentation or analyses may exist elsewhere.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Study of the Combination of Vorinostat and Radiation Therapy for the Treatment of Patients With Brain Metastases — NCT00838929.
- Registry record last updated 2025-05-04; status last verified 2025-05.
- Results first posted 2013-11-01.
- 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, open-label, non-randomized, single-group study of vorinostat combined with radiation therapy in patients with brain metastases. Enrollment is recorded as 17. The study used sequential dose cohorts, with listed cohorts at 200 mg, 300 mg, and 400 mg; the endpoint description also identifies 50 mg and 100 mg levels for de-escalation if toxicity occurred.
The primary outcome was the MTD and RP2D, assessed in relation to dose-limiting toxicity. The registry record does not report the selected dose or a numerical primary outcome result. It records serious and other adverse-event counts by cohort and lists serious-event terms with percentages, but does not provide cohort attribution for those term percentages. The analysis plan, missing-data methods, and analysis populations are not reported, and the record lists zero analysis entries. The posted information supports a description of the design and recorded safety summaries, but not a conclusion about the selected dose or treatment effect.