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 Dose Escalation Study of Concomitant BIBF 1120 and BIBW 2992 in Patients With Advanced Solid Tumours. (NCT00998296), a na phase 1 study. The primary outcome is Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00998296 |
| Phase | Phase 1 |
| Condition | Neoplasms |
| Allocation | Not applicable (single group) |
| Design model | Single Group |
| Masking | None (open label) |
| Enrollment | 70 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Boehringer Ingelheim |
| Results posted | Yes |
2. Clinical Question
Population
Patients with advanced solid tumours were eligible for this Phase I dose-escalation study. The registry lists neoplasms as the condition and reports enrollment of 70 participants. It does not give further eligibility details in the record.
Intervention
The intervention was concomitant BIBW 2992 and BIBF 1120, identified elsewhere in the record as afatinib and nintedanib. The study explored dose combinations and continuous or intermittent schedules. The record’s primary objective was to determine the combination’s maximum tolerated dose.
Comparator
There was no separate control group: the design is listed as single group, with allocation not applicable and no masking. Dose combinations and schedules appear as cohorts within a dose-escalation study, not as randomized treatment arms suitable for a controlled comparison.
Primary question
During the first treatment cycle, up to 28 days, what maximum tolerated dose of nintedanib plus afatinib could be identified using the percentage of participants who experienced dose-limiting toxicities? The registry describes the intended use of the MTD as informing dosing recommendations for subsequent Phase II trials. It does not report the numerical primary-endpoint result or the decision rule used to define an acceptable toxicity level.
This is a dose-finding question, not a randomized comparison of the combination against another treatment. The main statistical task is to relate dose and schedule to dose-limiting toxicity while accounting for the small, changing cohorts typical of dose escalation. The record gives group-level adverse-event counts, but those counts are not a substitute for the missing primary endpoint result: the registry does not identify which events met the primary endpoint’s dose-limiting-toxicity definition. Nor does it report a comparative estimate of tumour response. The study therefore asks whether dose selection was feasible on the basis of first-cycle toxicity, rather than whether one regimen is superior to a control.
3. Trial Design
The registry describes a completed Phase I dose-escalation study, with a single-group model, allocation listed as not applicable, and no masking. Enrollment was 70. The study start is listed as 2009-10 and primary completion as 2012-12. These dates describe the registry record; they do not establish the timing of individual participant follow-up or when results were analysed.
Participants received BIBW 2992 with BIBF 1120. The intervention and cohort descriptions use the names afatinib and nintedanib, and list multiple dose combinations with continuous or intermittent schedules. The listed adverse-event groups include dose-and-schedule cohorts as well as NSCLC and pancreatic adenocarcinoma categories. The record does not explain how those categories relate to one another, whether they overlap, or whether the tumour categories are separate expansion cohorts. Accordingly, their counts should not be added or treated as independent study arms.
The study’s primary objective was to determine the maximum tolerated dose of the combination. The primary outcome is defined around the percentage of participants experiencing dose-limiting toxicities during the dose-escalation phase, in the first treatment cycle of up to 28 days. The registry also lists outcomes concerning tumour response, adverse events, safety laboratory parameters, drug concentrations, and disease control in an expansion phase. Their presence as planned outcomes does not mean that results are reported for them.
The record does not describe the dose-escalation algorithm, cohort entry rules, dose-limiting-toxicity criteria, planned dose levels, or the stopping rule. It also does not explain how the final MTD was selected from the dose experience. Those details are central to interpreting a Phase I design, and are not reported in the registry record. The design information supports describing the study as dose finding, but not reconstructing the conduct or decision process.
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.
Only the first 6 of 11 groups are shown.
Overall Study
| Stage | Nintedanib 150 mg +Afatinib 30 mg - Continuously | Nintedanib 150 mg +Afatinib 40 mg - Continuously | Nintedanib 200 mg +Afatinib 10 mg - Continuously | Nintedanib 200 mg +Afatinib 20 mg - Continuously | Nintedanib 200 mg +Afatinib 30 mg - Continuously | Nintedanib 200 mg +Afatinib 40 mg - Continuously |
|---|---|---|---|---|---|---|
| STARTED | 6 | 3 | 3 | 3 | 8 | 3 |
| COMPLETED | 6 | 2 | 3 | 3 | 6 | 3 |
| NOT COMPLETED | 0 | 1 | 0 | 0 | 2 | 0 |
Reasons for not completing this period:
| Reason | Nintedanib 150 mg +Afatinib 30 mg - Continuously | Nintedanib 150 mg +Afatinib 40 mg - Continuously | Nintedanib 200 mg +Afatinib 10 mg - Continuously | Nintedanib 200 mg +Afatinib 20 mg - Continuously | Nintedanib 200 mg +Afatinib 30 mg - Continuously | Nintedanib 200 mg +Afatinib 40 mg - Continuously |
|---|---|---|---|---|---|---|
| Progressive disease | 0 | 1 | 0 | 0 | 0 | 0 |
| Dose limiting or dose reducing toxicity | 0 | 0 | 0 | 0 | 1 | 0 |
| Other adverse event | 0 | 0 | 0 | 0 | 1 | 0 |
| Refused to continue taking trial med. | 0 | 0 | 0 | 0 | 0 | 0 |
| Reason other than those specified above | 0 | 0 | 0 | 0 | 0 | 0 |
Analysis population for the primary outcome, as defined in the registry: TS
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: Treated Set (TS): A treated set (TS) was defined consisting of all patients who received at least one dose of nintedanib or afatinib during the study period.
Only the first 6 of 12 groups are shown.
| Characteristic | Unit | Nintedanib 150 mg +Afatinib 30 mg - Continuously | Nintedanib 150 mg +Afatinib 40 mg - Continuously | Nintedanib 200 mg +Afatinib 10 mg - Continuously | Nintedanib 200 mg +Afatinib 20 mg - Continuously | Nintedanib 200 mg +Afatinib 30 mg - Continuously | Nintedanib 200 mg +Afatinib 40 mg - Continuously |
|---|---|---|---|---|---|---|---|
| Participants analysed | 6 | 3 | 3 | 3 | 8 | 3 | |
| Age, Continuous | years | 53.7 (SD 8.1) | 51.7 (SD 1.5) | 46.7 (SD 4.9) | 53.3 (SD 11.0) | 51.5 (SD 9.7) | 44.3 (SD 8.1) |
| Sex: Female, Male: Female | Participants | 3 | 1 | 0 | 1 | 6 | 2 |
| Sex: Female, Male: Male | Participants | 3 | 2 | 3 | 2 | 2 | 1 |
6. Primary Endpoint
The registry lists the primary outcome as Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities, measured over first treatment cycle, up to 28 days.
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | percentage of participants |
| Endpoint classification | Binary Endpoint |
The primary endpoint is the maximum tolerated dose of nintedanib and afatinib, based on the percentage of participants who experienced dose-limiting toxicities during dose escalation. Its stated timeframe is the first treatment cycle, up to 28 days. The registry labels the measurement unit as percentage of participants and the analysis population as TS.
In a dose-finding study, the purpose of this endpoint is to connect a dose combination with early treatment-limiting toxicity. The MTD is intended to inform selection of a dose for later study; the registry specifically describes that purpose as providing a dosing recommendation for subsequent Phase II trials. This makes the endpoint relevant to dose selection, but it is not an efficacy outcome and cannot by itself establish comparative benefit.
General statistical context: a percentage expresses the number of participants meeting an event definition relative to the number assessed. Interpretation depends on a clearly defined event, a clear assessment window, and the number of participants contributing data at each dose. The registry gives the first-cycle window and names dose-limiting toxicity, but does not report the operational criteria for classifying an event as dose limiting or the primary endpoint’s numerical results. It therefore does not permit a reader to identify the selected MTD or judge the precision of the primary estimate. Serious adverse-event counts listed elsewhere are not interchangeable with dose-limiting toxicity: the endpoint definition and event classifications may differ, and the record does not provide a mapping between them.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The posted information supports a description of the trial’s objective and design, but not a numerical conclusion about its primary endpoint. The registry identifies the MTD as the primary outcome and specifies a first-cycle assessment window, yet no percentage of participants with dose-limiting toxicity, dose-specific primary result, or selected MTD is reported in the registry record. The central dose-finding result therefore cannot be evaluated from the information recorded.
The adverse-event figures do give counts of participants affected by serious events in named groups. For example, the Nintedanib 150 mg +Afatinib 30 mg - Continuously group lists 3 affected among 6 at risk; the Nintedanib 200 mg +Afatinib 30 mg - Continuously group lists 7 affected among 8 at risk. These are descriptive group-level observations. They do not establish that a particular regimen caused more toxicity than another, because the groups were not randomized control arms, group sizes differ, and the record does not describe how participants were assigned to dose levels or schedules.
Some listed groups have very small numbers at risk. In small groups, one participant’s outcome can materially affect the observed proportion. General statistical context: estimates from limited samples tend to be imprecise, and confidence intervals can communicate the range of values compatible with the observed data under a stated model. No confidence intervals or other uncertainty estimates for the primary endpoint are reported in the registry record. The listed serious-event percentages should also be read with their own event definitions and denominators in mind; the record does not supply the denominator behind each term percentage.
Interpretation is further limited by the absence of a reported dose-escalation method, DLT criteria, and MTD decision rule. Without those details, the relationship between observed toxicities and the final dose recommendation cannot be reconstructed. The registry also lists response and disease-control outcomes, but does not report their numerical results in the information available for this analysis. Therefore, these data do not establish tumour-response patterns, comparative effectiveness, or the balance of benefits and harms. They document a Phase I dose-escalation effort and selected serious-event counts, while leaving the primary dose-finding result unreported.
9. Statistical Methods Explained
General statistical context: dose-finding studies address a different question from trials designed to compare treatments. Their purpose is commonly to characterize toxicity across candidate doses and identify a dose considered suitable for later investigation. The registry identifies this study’s objective as determining the MTD of the combination, but does not report enough methodological detail to reconstruct how dose escalation proceeded or how the MTD decision was made.
What does a percentage endpoint describe?
The primary endpoint is framed as the percentage of participants experiencing dose-limiting toxicity during the first treatment cycle, up to 28 days. In general, a percentage is a proportion expressed on a percentage scale: it depends on both the event count and the number of participants assessed. The same event count can have different meanings in groups of different sizes, so the denominator matters. The registry record does not report the primary endpoint’s count and denominator by dose, or the final percentage result. The adverse-event summaries should not be substituted for that result because the record does not say that every serious adverse event qualified as a dose-limiting toxicity.
Why does the dose-escalation method matter?
General statistical context: dose-escalation rules determine which participants receive which dose, when escalation or de-escalation occurs, and when enrollment at a dose stops. Different rules can lead to different participant distributions across doses and different ways of estimating a tolerable dose. A reader also needs the DLT definition and the decision threshold: without them, observed events cannot be translated into an MTD decision. The registry record does not report the escalation algorithm, DLT criteria, target toxicity level, or stopping rule. It therefore does not support a judgment about whether a particular method was followed or whether a specific dose met a defined criterion.
How should the safety counts be read?
General statistical context: counts and proportions are descriptive summaries, not automatically causal comparisons. In a nonrandomized dose-escalation design, dose groups can differ in their composition, enrollment timing, and follow-up. The number at risk also varies across the listed groups. A raw comparison between groups cannot isolate a dose effect without suitable design and analysis information. The record lists serious-event counts by several dose-and-schedule groups and tumor categories, but does not explain the relationship between all these categories. They should be interpreted within their own labels rather than combined into an overall comparison.
Uncertainty is especially relevant when groups are small. General statistical context: a confidence interval describes statistical uncertainty around an estimate under the assumptions of the method used. It is not a guarantee that the true value lies within the interval, nor does it address biases caused by study conduct or incomplete reporting. The registry record does not report confidence intervals for the primary endpoint or the adverse-event counts. The displayed counts therefore offer limited precision, and the record does not allow that precision to be quantified with interval estimates.
What can be concluded when analysis details are absent?
The record lists a total enrollment of 70 and labels the primary analysis population TS, but does not explain the population label or give participant counts analysed for the primary endpoint. It reports zero analyses in its analysis listing. That means no analysis results are recorded in that listing; it does not show that investigators conducted no analyses at all. The primary outcome’s numerical result, missing-data handling, and analysis method are not reported in the registry record. Without those details, there is no basis for assessing the endpoint calculation, its uncertainty, or any adjustment for differences in exposure or follow-up.
General statistical context: sample-size planning and observed precision are separate issues. A planning calculation describes how many participants might be needed under stated assumptions; it does not show the power achieved by the participants who enrolled. The record’s planning description refers to an illustration based on an observed effect, two-sided significance level 0.05, equal allocation between two arms, and a normal approximation. It also says that such illustrations give participants per arm except for time-to-event outcomes. Those are planning assumptions, not evidence that this single-group dose-escalation study had a particular observed power. No values from a planning illustration are reported in the registry record for interpretation here, and a two-arm planning framework is not a substitute for this trial’s dose-escalation design.
In short, the endpoint’s intended role is clear, but the statistical evidence needed to evaluate the MTD decision is not present in the registry record. The reported design and event summaries can be described, while the dose-selection process, primary estimate, and its precision remain unresolved.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists multiple outcomes beyond the primary MTD endpoint, including investigator-assessed overall tumour response, adverse events, safety laboratory changes, drug concentrations, objective response and disease control during an expansion phase, and stable disease for at least 12 weeks during that phase. Listing several outcomes creates the general possibility of multiple statistical questions. General statistical context: when many hypotheses are tested, the chance of at least one apparently notable result can increase unless the analysis plan addresses multiplicity. The record does not report a multiplicity strategy, a hierarchy among secondary outcomes, or inferential test results. It is therefore not possible to determine how multiplicity was handled.
Missing-data methods are also not described. The registry does not state how participants who did not complete the first treatment cycle, lacked an assessment, or had incomplete safety or response information were handled. Nor does it report primary-endpoint denominators by dose. These omissions matter because the percentage of participants with an event depends on who is included in the denominator and how incomplete observations are classified.
The primary outcome labels its population as TS, but the meaning of that label and the numbers analysed are not reported in the registry record. The record lists enrollment of 70, but enrollment alone does not establish how many participants contributed to each outcome or dose group. No prespecified statistical analysis plan, analysis populations for the secondary outcomes, or sensitivity analyses are reported. No numerical primary result or inferential analysis is listed. Consequently, the available information does not support an assessment of missing-data bias, multiplicity adjustment, or robustness of the findings. These are reporting gaps, not evidence that the investigators did or did not use particular procedures.
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 |
|---|---|---|---|
| Nintedanib 150 mg +Afatinib 30 mg - Continuously | 3 | 6 | 50.0% |
| Nintedanib 150 mg +Afatinib 40 mg - Continuously | 3 | 3 | 100.0% |
| Nintedanib 200 mg +Afatinib 10 mg - Continuously | 1 | 3 | 33.3% |
| Nintedanib 200 mg +Afatinib 20 mg - Continuosly | 0 | 3 | 0.0% |
| Nintedanib 200 mg +Afatinib 30 mg - Continuously | 7 | 8 | 87.5% |
| Nintedanib 200 mg +Afatinib 40 mg - Continuously | 3 | 3 | 100.0% |
| Nintedanib 150 mg +Afatinib 40 mg - Intermittently | 1 | 7 | 14.3% |
| Nintedanib 200 mg +Afatinib 30 mg - Intermittently | 1 | 6 | 16.7% |
| Nintedanib 200 mg +Afatinib 40 mg - Intermittently | 4 | 6 | 66.7% |
| NSCLC | 7 | 18 | 38.9% |
| Pancreatic Adenocarcinoma | 3 | 7 | 42.9% |
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 |
|---|---|
| Nintedanib 150 mg +Afatinib 30 mg - Continuously | 6 of 6 |
| Nintedanib 150 mg +Afatinib 40 mg - Continuously | 3 of 3 |
| Nintedanib 200 mg +Afatinib 10 mg - Continuously | 3 of 3 |
| Nintedanib 200 mg +Afatinib 20 mg - Continuosly | 3 of 3 |
| Nintedanib 200 mg +Afatinib 30 mg - Continuously | 8 of 8 |
| Nintedanib 200 mg +Afatinib 40 mg - Continuously | 3 of 3 |
Most frequent serious adverse event terms
| Event term | Organ system | Nintedanib 150 mg +Afatinib 30 mg - Continuously | Nintedanib 150 mg +Afatinib 40 mg - Continuously | Nintedanib 200 mg +Afatinib 10 mg - Continuously | Nintedanib 200 mg +Afatinib 20 mg - Continuosly | Nintedanib 200 mg +Afatinib 30 mg - Continuously | Nintedanib 200 mg +Afatinib 40 mg - Continuously |
|---|---|---|---|---|---|---|---|
| Diarrhoea | Gastrointestinal disorders | 2 of 6 | 0 of 3 | 0 of 3 | 0 of 3 | 3 of 8 | 1 of 3 |
| Cholangitis | Hepatobiliary disorders | 0 of 6 | 1 of 3 | 1 of 3 | 0 of 3 | 0 of 8 | 1 of 3 |
| Dehydration | Metabolism and nutrition disorders | 2 of 6 | 0 of 3 | 0 of 3 | 0 of 3 | 1 of 8 | 0 of 3 |
| Haemoptysis | Respiratory, thoracic and mediastinal disorders | 1 of 6 | 0 of 3 | 0 of 3 | 0 of 3 | 1 of 8 | 0 of 3 |
| Pulmonary embolism | Respiratory, thoracic and mediastinal disorders | 1 of 6 | 0 of 3 | 0 of 3 | 0 of 3 | 0 of 8 | 1 of 3 |
| Anaemia | Blood and lymphatic system disorders | 1 of 6 | 0 of 3 | 0 of 3 | 0 of 3 | 0 of 8 | 0 of 3 |
| Vomiting | Gastrointestinal disorders | 0 of 6 | 0 of 3 | 0 of 3 | 0 of 3 | 1 of 8 | 0 of 3 |
| Asthenia | General disorders | 1 of 6 | 0 of 3 | 0 of 3 | 0 of 3 | 0 of 8 | 0 of 3 |
| General physical health deterioration | General disorders | 1 of 6 | 0 of 3 | 0 of 3 | 0 of 3 | 0 of 8 | 0 of 3 |
| Hyperthermia | General disorders | 0 of 6 | 1 of 3 | 0 of 3 | 0 of 3 | 0 of 8 | 0 of 3 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Nintedanib 150 mg +Afatinib 30 mg - Continuously | Nintedanib 150 mg +Afatinib 40 mg - Continuously | Nintedanib 200 mg +Afatinib 10 mg - Continuously | Nintedanib 200 mg +Afatinib 20 mg - Continuosly | Nintedanib 200 mg +Afatinib 30 mg - Continuously | Nintedanib 200 mg +Afatinib 40 mg - Continuously |
|---|---|---|---|---|---|---|---|
| Diarrhoea | Gastrointestinal disorders | 6 of 6 | 3 of 3 | 3 of 3 | 3 of 3 | 8 of 8 | 3 of 3 |
| Asthenia | General disorders | 6 of 6 | 3 of 3 | 2 of 3 | 3 of 3 | 8 of 8 | 3 of 3 |
| Nausea | Gastrointestinal disorders | 4 of 6 | 3 of 3 | 2 of 3 | 3 of 3 | 4 of 8 | 2 of 3 |
| Rhinitis | Infections and infestations | 3 of 6 | 1 of 3 | 3 of 3 | 3 of 3 | 4 of 8 | 2 of 3 |
| Epistaxis | Respiratory, thoracic and mediastinal disorders | 2 of 6 | 2 of 3 | 2 of 3 | 3 of 3 | 5 of 8 | 2 of 3 |
| Vomiting | Gastrointestinal disorders | 1 of 6 | 3 of 3 | 1 of 3 | 2 of 3 | 5 of 8 | 3 of 3 |
| Decreased appetite | Metabolism and nutrition disorders | 3 of 6 | 3 of 3 | 1 of 3 | 2 of 3 | 3 of 8 | 3 of 3 |
| Folliculitis | Infections and infestations | 4 of 6 | 3 of 3 | 0 of 3 | 2 of 3 | 4 of 8 | 1 of 3 |
| Dry mouth | Gastrointestinal disorders | 1 of 6 | 2 of 3 | 2 of 3 | 2 of 3 | 2 of 8 | 2 of 3 |
| Dry skin | Skin and subcutaneous tissue disorders | 1 of 6 | 1 of 3 | 2 of 3 | 2 of 3 | 4 of 8 | 1 of 3 |
Serious events with the highest arm-level rate: diarrhoea (37.5%), hyperthermia (33.3%), oedema peripheral (33.3%), bile duct obstruction (33.3%), cholangitis (33.3%).
The serious adverse-event summary reports, for each listed group, the number at risk and the number affected. For example, Nintedanib 150 mg +Afatinib 30 mg - Continuously lists 6 at risk and 3 affected; Nintedanib 200 mg +Afatinib 30 mg - Continuously lists 8 at risk and 7 affected. Nintedanib 200 mg +Afatinib 20 mg - Continuosly lists 3 at risk and 0 affected. These figures are descriptive counts within the named groups, not adjusted comparisons.
The group labels also include intermittent schedules and tumor categories, including NSCLC and pancreatic adenocarcinoma. The registry does not explain whether these categories overlap with dose groups or how participants were selected for them. The counts should therefore not be summed across labels or read as independent cohorts without further information. A serious event is not necessarily the same as a dose-limiting toxicity: the registry does not give criteria linking serious-event status to the primary endpoint.
The listed serious-event terms include Diarrhoea at 37.5%, and Hyperthermia, Oedema peripheral, Bile duct obstruction, Cholangitis, and Cholecystitis at 33.3% each. The registry record does not give the denominator for these term percentages or explain whether they refer to participants, events, or a particular subgroup. Death counts are not reported in the registry record. These summaries do not establish causation or compare safety against a control group.
12. What the Result Does, and Does Not, Mean
The registry record establishes that this was a completed Phase I dose-escalation study of concomitant nintedanib and afatinib, enrolling 70 participants. It identifies the main objective as determining a maximum tolerated dose using dose-limiting toxicities during the first treatment cycle, up to 28 days. It also provides serious adverse-event counts for named dose-and-schedule groups and tumor categories. These details allow a reader to understand the broad study question and some of the safety reporting.
The record does not report the numerical primary endpoint result, the selected MTD, or the analysis used to reach a dose recommendation. It also does not report the criteria defining a dose-limiting toxicity or the dose-escalation algorithm. The serious-event counts cannot fill those gaps. Without a direct link between event classifications and the DLT endpoint, they do not show which dose met the study’s MTD criterion.
Nor does the record establish that one dose or schedule is safer or more effective than another. The study is listed as single group, without random allocation or masking, and the groups are not described as randomized controls. The registry’s listed response-related outcomes do not include numerical results in the available record. Therefore, no conclusion about comparative tumour response, disease control, or treatment benefit follows from these registry entries.
General statistical context: a result is more informative when its estimate, denominator, uncertainty, outcome definition, and analysis population are all clear. Here, the serious-event summaries are descriptive and the primary endpoint’s result and precision are unreported. The record can identify what investigators set out to assess, but cannot show how precisely the study estimated toxicity at each dose or how the final dose choice followed from the observations. These limitations describe what the registry record contains; they are not evidence that an unreported result was favorable or unfavorable.
13. Why This Trial Matters Statistically
This study is statistically important as an example of a question that differs from the usual treatment-versus-control comparison. In early dose finding, the central task is to learn about toxicity across candidate doses and use that information to guide further investigation. A single-group dose-escalation design is suited to investigating a sequence of dose combinations, but its interpretation depends heavily on the escalation rules, toxicity definitions, and decision criteria.
The registry identifies the intended endpoint and its assessment window, which are essential pieces of a dose-finding question. It also lists serious adverse-event counts across several dose and schedule labels. Those details make clear why the denominator and group structure matter: counts from small, differently sized groups cannot be interpreted as if they came from equal, randomized comparisons. They also show why serious adverse events and dose-limiting toxicities must remain distinct unless the record explicitly defines them as the same classification.
The most important statistical lesson is the difference between a trial objective and a reported result. The objective is to estimate an MTD; however, the primary endpoint result, uncertainty, DLT criteria, escalation algorithm, and MTD decision rule are not reported in the registry record. Without those items, readers cannot assess the dose-selection process or its precision. Listing additional response and safety outcomes does not resolve that gap when numerical results are absent.
General statistical context: transparent reporting of methods and denominators allows independent readers to understand what an estimate means, what assumptions support it, and how uncertain it is. For dose-finding studies, this is especially important because the design determines who receives each dose and how observations influence later enrollment. The available record illustrates both the value of a clearly stated primary question and the limits of interpreting a study when the supporting analysis details and endpoint results are unavailable.
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 main limitation is that the registry record does not report the numerical result for the primary MTD endpoint. It does not state the dose selected as the MTD, the number or percentage of participants with dose-limiting toxicity at each dose, or uncertainty around those estimates. The listed serious adverse-event counts cannot replace these data because the record does not provide a definition linking serious events to dose-limiting toxicity.
Important design details are also absent. The dose-escalation algorithm, planned dose levels, DLT criteria, MTD decision rule, and stopping rule are not reported in the registry record. Without them, the progression from observed toxicity to any dose recommendation cannot be assessed. The record does not explain the relationship between dose-and-schedule categories and tumor categories in the adverse-event listing, so those labels should not be combined or assumed to describe mutually exclusive groups.
The registry does not provide analysis denominators by endpoint, missing-data procedures, participant flow, confidence intervals, or sensitivity analyses. It gives enrollment of 70 but does not show how many participants were analysed for the primary endpoint. The primary population is labelled TS without an explanation in the record. Multiple secondary outcomes are listed, but the statistical plan for their analysis and any multiplicity approach are not reported. Numerical results for those secondary outcomes are also not included in the information.
Finally, the single-group, nonrandomized design does not support a randomized comparison of dose combinations or schedules. The serious-event counts are descriptive and may reflect differences among groups that the registry does not characterize. These limitations constrain interpretation of the registry record; they do not establish what additional information may exist outside it.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Phase I Dose Escalation Study of Concomitant BIBF 1120 and BIBW 2992 in Patients With Advanced Solid Tumours. — NCT00998296.
- Registry record last updated 2015-08-19; status last verified 2015-07.
- Results first posted 2015-02-09.
- 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
NCT00998296 is listed as a completed Phase I dose-escalation study sponsored by Boehringer Ingelheim. It enrolled 70 participants with advanced solid tumours and assessed concomitant BIBW 2992 and BIBF 1120. The design is identified as single group, with allocation not applicable and no masking. The registry lists the study start as 2009-10 and primary completion as 2012-12.
The primary objective was to determine the combination’s maximum tolerated dose based on dose-limiting toxicity during the first treatment cycle, up to 28 days. The primary endpoint’s numerical result and the dose-escalation methods are not reported in the registry record. Serious adverse-event counts are listed for dose-and-schedule groups and tumor categories, but they are descriptive and do not constitute a controlled comparison. The record also lists response, safety, laboratory, and drug-concentration outcomes without reporting numerical results for them in the information.