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 Evaluating Neratinib In Combination With Temsirolimus In Subjects With Solid Tumors (NCT00838539), a non-randomized phase 1 study. The primary outcome is Probability of Dose-Limiting Toxicity (DLT).
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00838539 |
| Phase | Phase 1 |
| Condition | Neoplasms, Malignant Carcinoma |
| Allocation | Non-Randomized |
| Design model | Sequential |
| Masking | None (open label) |
| Enrollment | 63 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Puma Biotechnology, Inc. |
| Results posted | Yes |
2. Clinical Question
Population
People with solid tumors were eligible for the study. The registry lists Neoplasms and Malignant Carcinoma among the conditions. The primary endpoint population was described as subjects evaluable for maximum tolerated dose contour estimation: those experiencing a dose-limiting toxicity within the first 28 days, regardless of doses received, or those receiving at least 21 doses of neratinib and at least 2 doses of temsirolimus during that period. The description of the second criterion is incomplete in the registry record, and other eligibility details are not reported in the registry record.
Intervention
The intervention was neratinib taken orally each day together with temsirolimus given intravenously once weekly. The listed dose levels varied the doses of both drugs: neratinib doses ranged across 120 mg, 160 mg, 200 mg and 240 mg, while temsirolimus doses ranged across 15 mg, 25 mg, 50 mg and 75 mg. Treatment was described as continuing for as long as tolerated and while the disease under study did not worsen.
Comparator
There was no randomized control group. The allocation was non-randomized and the model was sequential, with participants assigned to combination dose levels. These dose-level groups are not like-for-like randomized comparisons: differences between them cannot be attributed to dose alone from this design. The registry does not report a separate placebo or standard-treatment comparator.
Primary question
The stated primary purpose was to identify the maximum tolerated dose or doses of neratinib in combination with temsirolimus. The primary endpoint was the probability of dose-limiting toxicity from the first dose through day 28. The study also planned a preliminary evaluation of efficacy and assessment of pharmacokinetic parameters. The registry record does not report the primary endpoint results, an estimated maximum tolerated dose, or results for those additional objectives.
3. Trial Design
This was a phase 1 study of neratinib in combination with temsirolimus in subjects with solid tumors. It was non-randomized, unmasked, and described as sequential. The registry records enrollment of 63. The study began in 2009-04, had primary completion in 2011-06, and is listed as completed. Puma Biotechnology, Inc. is the sponsor.
The design assigned participants to combination dose levels rather than randomly allocating them to a treatment and control group. The listed levels changed the neratinib and temsirolimus doses in a sequence: neratinib was listed at 120 mg, 160 mg, 200 mg and 240 mg; temsirolimus was listed at 15 mg, 25 mg, 50 mg and 75 mg, with not every combination represented. Neratinib was described as daily oral treatment and temsirolimus as weekly intravenous treatment. Both were to continue as long as tolerated and while the disease under study did not worsen.
The study's stated main aim was dose finding, specifically identifying maximum tolerated dose or doses for the combination. Preliminary efficacy and pharmacokinetic assessment were also described as objectives. This design differs from a randomized efficacy trial: it does not establish a like-for-like treatment contrast, and sequential assignment can make the dose groups differ in ways other than the doses they received. The registry record does not report the exact dose-escalation algorithm, stopping rules, decision thresholds, or the rationale for the chosen dose levels. It also does not report a detailed sample-size justification.
The enrollment figure describes the overall study, not necessarily the number contributing to each endpoint or dose group. The registry record does not report endpoint-specific analysis populations or participant flow across dose levels. The dose-level adverse-event records give group counts for safety summaries, but those records do not establish the number of participants included in each efficacy, pharmacokinetic, or primary endpoint analysis.
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 12 groups are shown.
Overall Study
| Stage | N120 + T15 | N120 + T25 | N120 + T50 | N120 + T75 | N160 + T15 | N160 + T25 |
|---|---|---|---|---|---|---|
| STARTED | 3 | 6 | 5 | 4 | 6 | 4 |
| Received Treatment | 3 | 5 | 5 | 4 | 4 | 4 |
| COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 |
| NOT COMPLETED | 3 | 6 | 5 | 4 | 6 | 4 |
Reasons for not completing this period:
| Reason | N120 + T15 | N120 + T25 | N120 + T50 | N120 + T75 | N160 + T15 | N160 + T25 |
|---|---|---|---|---|---|---|
| Disease Progression | 2 | 4 | 3 | 2 | 4 | 2 |
| Adverse Event | 1 | 1 | 1 | 1 | 2 | 1 |
| Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 | 0 |
| Death | 0 | 0 | 0 | 0 | 0 | 0 |
| Physician Decision | 0 | 0 | 0 | 0 | 0 | 0 |
| Clinical Progression | 0 | 0 | 0 | 0 | 0 | 0 |
| Symptomatic Deterioration | 0 | 0 | 1 | 1 | 0 | 1 |
Analysis population for the primary outcome, as defined in the registry: Evaluable subjects for the Maximum Tolerated Dose (MTD) contour estimation were those who either experienced a DLT within the first 28 days, regardless of the number of doses of treatment received, or received at least 21 doses of neratinib and at least 2 doses of Temsirolimus in the first 28 days of treatment.
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.
Only the first 6 of 13 groups are shown.
| Characteristic | Unit | N120 + T15 | N120 + T25 | N120 + T50 | N120 + T75 | N160 + T15 | N160 + T25 |
|---|---|---|---|---|---|---|---|
| Participants analysed | 3 | 5 | 5 | 4 | 4 | 4 | |
| Age, Categorical: <=18 years | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Age, Categorical: Between 18 and 65 years | Participants | 2 | 4 | 4 | 4 | 4 | 4 |
| Age, Categorical: >=65 years | Participants | 1 | 1 | 1 | 0 | 0 | 0 |
| Age, Continuous | years | 50.00 (SD 26.15) | 58.60 (SD 10.26) | 43.00 (SD 16.40) | 49.50 (SD 7.94) | 49.75 (SD 4.79) | 49.75 (SD 5.68) |
| Sex: Female, Male: Female | Participants | 1 | 3 | 1 | 4 | 3 | 4 |
| Sex: Female, Male: Male | Participants | 2 | 2 | 4 | 0 | 1 | 0 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): Asian | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): Black or African American | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): White | Participants | 1 | 3 | 2 | 1 | 1 | 3 |
| Race (NIH/OMB): More than one race | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 2 | 2 | 3 | 3 | 3 | 1 |
6. Primary Endpoint
The registry lists the primary outcome as Probability of Dose-Limiting Toxicity (DLT), measured over From first dose date to day 28.
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | percent probability |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint is titled Probability of Dose-Limiting Toxicity (DLT), with a timeframe from the first dose date to day 28. The registry describes a DLT as a dose-limiting adverse event related to neratinib plus temsirolimus. The stated examples include Grade 3 or higher nonhematologic toxicity, except neutropenia, and Grade 3 or higher diarrhea lasting >2 days despite optimal antidiarrheal therapy. The definition ends with “etc.”, so the full set of qualifying events is not reported in the registry record.
In general, a dose-limiting toxicity endpoint is used in early-phase dose-finding research to identify treatment levels at which clinically important toxicities occur during a defined observation period. The aim is to inform dose selection for further study, rather than to provide a definitive comparison of efficacy against a control. A probability is meaningful only alongside its estimate, the number of evaluable participants, and the method used to estimate it. The registry record states the endpoint and timeframe but does not report an estimate, uncertainty interval, or detailed estimation method.
The registry also describes the population considered evaluable for maximum tolerated dose contour estimation. It includes participants with a DLT during the first 28 days regardless of how many doses they received, or participants who received at least 21 doses of neratinib and at least 2 doses of temsirolimus in that period. The description is incomplete at its end, so whether additional conditions applied is not reported in the registry record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry states a dose-finding objective and specifies dose-limiting toxicity during the first 28 days as the primary endpoint. It does not report the primary endpoint result. Consequently, the posted record does not establish the estimated probability of DLT at any dose level, identify a maximum tolerated dose, or show the precision of any such estimate. The number of registered participants alone cannot substitute for endpoint results or endpoint-specific analysis counts.
The study included multiple neratinib and temsirolimus combinations. Because dose assignment was sequential and non-randomized, the groups should not be read as randomized treatment arms. Comparisons across dose levels may be affected by how participants entered the sequence, by the number of participants at each level, and by other differences in their clinical circumstances. The registry record does not describe the allocation decisions or adjustment methods, so no adjusted comparison can be interpreted from the record.
Safety summaries list serious adverse event counts and counts for other adverse events by dose-level group. These are descriptive counts, not estimates of comparative risk. A serious event is not automatically a dose-limiting toxicity: the primary endpoint has its own definition, relationship criterion, grading threshold, and 28-day window. The registry does not report enough detail to map every serious event to the primary endpoint, or to determine whether the listed adverse events occurred within that endpoint's timeframe.
The registry lists Best Overall Response, Clinical Benefit Rate, Objective Response Rate and Area Under the Curve Tau as secondary outcomes. It does not report their results, definitions, analysis populations, or uncertainty. The study's brief summary mentions preliminary efficacy and pharmacokinetic assessment, but that statement is a description of intent, not evidence of observed outcomes. No result should be inferred from the fact that those outcomes were planned.
The safety data include differing numbers at risk across dose-level groups, so raw counts cannot be treated as directly comparable without considering denominators and follow-up. Percentages listed for selected serious adverse event terms also lack sufficient detail in the registry record about their denominators and analysis population. The record does not report a statistical analysis or uncertainty estimates. The appropriate reading is therefore descriptive: it documents planned objectives and posted safety counts, but does not provide a complete inferential account of dose-related toxicity or efficacy.
9. Statistical Methods Explained
What does a sequential, non-randomized design imply?
In general, sequential dose-finding studies assign participants to dose levels in an order that can depend on the study's progression. This is distinct from random allocation, which uses chance to create treatment groups intended to be comparable. Here, the registry describes the model as sequential and allocation as non-randomized, but does not report the precise assignment algorithm. It is therefore not possible to reconstruct from the record how decisions to move between dose levels were made.
In general, the absence of randomization limits causal comparisons between groups. If toxicity counts differ across dose levels, that pattern alone does not show that dose caused the difference. The groups may differ in participant characteristics, their position in the sequence, or other factors. A dose-finding design can still be useful for describing tolerability and informing later research, but interpretation depends on its specified decision rules and complete outcome reporting. Those rules and the primary endpoint results are not reported in the registry record.
What does a DLT probability represent?
In general, a probability expresses the chance of an event in a defined population and time window. For this study, the named event was a qualifying dose-limiting toxicity related to the combination, and the stated window ran from the first dose through day 28. The registry gives elements of the DLT definition, including toxicity grade and exceptions, but the definition is not fully stated. A probability estimate would require a specified approach to use observed DLT outcomes and define who contributes to estimation. The registry does not report an estimate or its method.
In general, an uncertainty interval around an estimate communicates how compatible a range of values is with the observed data and the model used. Wider intervals indicate less precision, while narrower intervals indicate greater precision under that model. No interval or other uncertainty measure for DLT probability is reported in the registry record. Without those results, there is no basis for assessing the precision of a dose-specific estimate.
Why is the evaluable population important?
The registry describes participants as evaluable for maximum tolerated dose contour estimation if they experienced a DLT within the first 28 days, regardless of the number of doses received, or if they received at least 21 doses of neratinib and at least 2 doses of temsirolimus during the first 28 days. In general, defining evaluability matters because participants with limited exposure and no observed event may not provide the same information about tolerability as participants with sufficient exposure. The registry description is incomplete at its end, and it does not state the number evaluable at each dose level. The enrollment total of 63 should not be assumed to be the endpoint analysis population.
How should the adverse-event counts be read?
The safety summaries report, for each dose-level group, the number at risk and the number affected for serious adverse events and for other adverse events. In general, counts describe how many participants had an event; they do not by themselves account for differences in group size or duration of observation. A rate comparison would require a clearly defined denominator and a consistent follow-up period. No adjusted safety comparison, time-to-event analysis, or uncertainty estimate is reported in the registry record.
The listed serious adverse event terms include Hypokalaemia, Abdominal pain, Diarrhoea, Vomiting, Hepatocellular injury and Dyspnoea, with percentages recorded for those terms. The registry record does not explain the denominator or population used for each listed percentage. These terms should not be treated as mutually exclusive categories or added together. Serious adverse events also should not be conflated with DLTs: the endpoint definition requires a relationship to the combination and qualifying toxicity criteria in a specified period, while the safety summary is a separate descriptive listing.
What does the sample-size planning language mean?
In general, a sample-size planning illustration estimates how many participants a future comparison might need under stated assumptions. The registry material describes a planning approach based on the observed effect, a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the effect to detect expressed as a fraction of the observed effect. Such illustrations are not the trial's observed power and do not establish the study's original design rationale. They are planning scenarios, not observed trial outcomes. The registry record does not report a detailed trial-specific sample-size justification, and no sample-size planning result should be interpreted as a finding about this study.
More broadly, statistical interpretation requires a clear analysis plan, outcome definitions, populations, and treatment of missing observations. The registry lists no analyses. It does not report model specifications for the DLT contour estimation, adjustment for multiple outcomes, missing-data methods, or interim-analysis procedures. General statistical principles can explain why these details matter, but they cannot fill in methods that are absent from the registry record.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists several secondary outcomes: Best Overall Response, Clinical Benefit Rate, Objective Response Rate and Area Under the Curve Tau. The primary aim was dose finding, while the brief summary also describes preliminary efficacy and pharmacokinetic assessment. When multiple outcomes are examined, general statistical practice considers whether a plan is needed to control the chance of a misleading finding across repeated tests or to distinguish confirmatory from exploratory analyses. The registry record does not report a multiplicity strategy, hierarchy among secondary outcomes, or inferential analyses. It therefore does not support conclusions about adjusted statistical significance across outcomes.
Missing-data methods are not reported in the registry record. The record does not state how missing endpoint assessments, incomplete follow-up, treatment discontinuation, or missing pharmacokinetic measurements were handled. It also does not report the amount or pattern of missing data. These details matter because the analysis can depend on which participants have usable observations and why others do not.
The registry provides a specific description of evaluability for maximum tolerated dose contour estimation, but that description is incomplete and does not give the number evaluable in each group. It does not clearly report analysis populations for the secondary outcomes or safety summaries beyond the at-risk counts listed by dose group. Enrollment of 63 is not equivalent to a count analyzed for every endpoint. Interim analyses and their role in dose decisions are 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 |
|---|---|---|---|
| N120 + T15 | 1 | 3 | 33.3% |
| N120 + T25 | 2 | 6 | 33.3% |
| N120 + T50 | 1 | 5 | 20.0% |
| N120 + T75 | 1 | 4 | 25.0% |
| N160 + T15 | 3 | 6 | 50.0% |
| N160 + T25 | 2 | 4 | 50.0% |
| N160 + T50 | 5 | 7 | 71.4% |
| N160 + T75 | 3 | 6 | 50.0% |
| N200 + T15 | 4 | 5 | 80.0% |
| N200 + T25 | 5 | 8 | 62.5% |
| N200 + T50 | 3 | 5 | 60.0% |
| N240 + T15 | 3 | 4 | 75.0% |
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 |
|---|---|
| N120 + T15 | 3 of 3 |
| N120 + T25 | 5 of 6 |
| N120 + T50 | 5 of 5 |
| N120 + T75 | 4 of 4 |
| N160 + T15 | 4 of 6 |
| N160 + T25 | 4 of 4 |
Most frequent serious adverse event terms
| Event term | Organ system | N120 + T15 | N120 + T25 | N120 + T50 | N120 + T75 | N160 + T15 | N160 + T25 |
|---|---|---|---|---|---|---|---|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | 0 of 3 | 0 of 6 | 0 of 5 | 0 of 4 | 2 of 6 | 1 of 4 |
| Anaemia | Blood and lymphatic system disorders | 0 of 3 | 1 of 6 | 0 of 5 | 0 of 4 | 1 of 6 | 0 of 4 |
| Pneumonia | Infections and infestations | 0 of 3 | 1 of 6 | 1 of 5 | 0 of 4 | 0 of 6 | 0 of 4 |
| Abdominal pain | Gastrointestinal disorders | 0 of 3 | 0 of 6 | 0 of 5 | 0 of 4 | 0 of 6 | 1 of 4 |
| Colitis | Gastrointestinal disorders | 0 of 3 | 0 of 6 | 0 of 5 | 1 of 4 | 0 of 6 | 0 of 4 |
| Ileus | Gastrointestinal disorders | 0 of 3 | 0 of 6 | 0 of 5 | 1 of 4 | 0 of 6 | 0 of 4 |
| Vomiting | Gastrointestinal disorders | 1 of 3 | 0 of 6 | 0 of 5 | 0 of 4 | 0 of 6 | 0 of 4 |
| Mucosal inflammation | General disorders | 0 of 3 | 1 of 6 | 0 of 5 | 0 of 4 | 0 of 6 | 0 of 4 |
| Hepatocellular injury | Hepatobiliary disorders | 1 of 3 | 0 of 6 | 0 of 5 | 0 of 4 | 0 of 6 | 0 of 4 |
| Lung abscess | Infections and infestations | 0 of 3 | 0 of 6 | 0 of 5 | 0 of 4 | 1 of 6 | 0 of 4 |
Most frequent non-serious adverse event terms
| Event term | Organ system | N120 + T15 | N120 + T25 | N120 + T50 | N120 + T75 | N160 + T15 | N160 + T25 |
|---|---|---|---|---|---|---|---|
| Diarrhoea | Gastrointestinal disorders | 3 of 3 | 5 of 6 | 5 of 5 | 4 of 4 | 3 of 6 | 4 of 4 |
| Nausea | Gastrointestinal disorders | 2 of 3 | 3 of 6 | 2 of 5 | 3 of 4 | 2 of 6 | 3 of 4 |
| Anaemia | Blood and lymphatic system disorders | 0 of 3 | 3 of 6 | 3 of 5 | 2 of 4 | 3 of 6 | 3 of 4 |
| Stomatitis | Gastrointestinal disorders | 2 of 3 | 2 of 6 | 3 of 5 | 3 of 4 | 2 of 6 | 2 of 4 |
| Asthenia | General disorders | 2 of 3 | 2 of 6 | 2 of 5 | 2 of 4 | 3 of 6 | 1 of 4 |
| Pyrexia | General disorders | 0 of 3 | 3 of 6 | 3 of 5 | 2 of 4 | 3 of 6 | 1 of 4 |
| Vomiting | Gastrointestinal disorders | 0 of 3 | 3 of 6 | 1 of 5 | 3 of 4 | 2 of 6 | 2 of 4 |
| Decreased appetite | Metabolism and nutrition disorders | 2 of 3 | 3 of 6 | 0 of 5 | 3 of 4 | 1 of 6 | 2 of 4 |
| Cough | Respiratory, thoracic and mediastinal disorders | 1 of 3 | 4 of 6 | 1 of 5 | 1 of 4 | 3 of 6 | 1 of 4 |
| Fatigue | General disorders | 1 of 3 | 3 of 6 | 2 of 5 | 0 of 4 | 2 of 6 | 2 of 4 |
Serious events with the highest arm-level rate: hypokalaemia (50.0%), abdominal pain (40.0%), diarrhoea (33.3%), vomiting (33.3%), hepatocellular injury (33.3%).
The safety record gives dose-level counts for participants at risk and participants affected by serious adverse events and other adverse events. For example, the N120 + T15 group lists 3 at risk, with 1 affected by a serious adverse event and 3 affected by other adverse events. The N160 + T50 group lists 7 at risk, with 5 affected by a serious adverse event and 7 affected by other adverse events. These are group-specific counts; they are not a randomized comparison and should not be interpreted as evidence that one dose is safer than another.
The listed serious adverse event terms are Hypokalaemia (50.0%), Abdominal pain (40.0%), Diarrhoea (33.3%), Vomiting (33.3%), Hepatocellular injury (33.3%) and Dyspnoea (33.3%). The registry record does not report the denominator or analysis population for these term percentages, or whether a participant could contribute to more than one term. The death counts are not reported in the group records.
Serious adverse events and DLTs are distinct summaries. The primary DLT definition includes relatedness, grading and a 28-day timeframe; the safety counts do not establish that each serious event met those criteria. The safety information is descriptive and does not include uncertainty estimates or adjusted comparisons.
12. What the Result Does, and Does Not, Mean
The registry record documents a phase 1, sequential, non-randomized study intended to assess a combination of neratinib and temsirolimus in people with solid tumors. It identifies dose-limiting toxicity through day 28 as the primary endpoint and describes a population intended for maximum tolerated dose contour estimation. It also lists preliminary efficacy and pharmacokinetic objectives. These details describe what the study set out to investigate.
The record does not report the primary endpoint results, a maximum tolerated dose, or results for the listed secondary outcomes. It therefore does not establish the observed frequency or probability of DLT, the precision of a dose-specific estimate, or the efficacy and pharmacokinetic findings. The planned outcomes cannot be treated as observed results. No treatment-effect conclusion follows from this registry information.
The safety summaries provide counts by dose-level group and list selected serious adverse event terms with percentages. Those figures document reported events, but the registry does not give enough detail to interpret the term percentages' denominators or to make adjusted comparisons. The group counts also arise from non-randomized sequential assignment. They are not evidence of a controlled difference between doses.
In general, a dose-finding study addresses a different question from a randomized efficacy trial. Its purpose can be to characterize tolerability across dose levels and inform future research, while a randomized comparison is designed to support a direct contrast between assigned treatments. Neither purpose can be evaluated fully without outcome results and methods. For this study, the registry record's missing analyses and endpoint results limit conclusions to the design description and posted safety counts.
The record does not report enough information to assess how complete follow-up was, how missing observations were handled, or how dose decisions were made. Those omissions do not establish that the study had no such procedures; they mean that the procedures are not reported in the registry record. Interpretation should remain bounded by what the record actually states.
13. Why This Trial Matters Statistically
This study illustrates a statistical distinction that matters in early-phase clinical research: dose-finding and treatment-effect estimation are related but different tasks. A study designed to identify a tolerable dose level needs clearly specified toxicity criteria, an observation window, an evaluable population, and a dose-assignment strategy. The registry provides some of these details, including the 28-day DLT window and elements of the toxicity definition, but does not report the complete definition or the decision algorithm.
Its sequential, non-randomized structure also illustrates why dose groups should not automatically be treated as comparative arms. Group counts can describe what was recorded at each level, but the design does not create randomized comparability. That distinction is important when readers encounter safety counts or try to infer a dose-response pattern.
Good statistical reporting would connect the stated endpoint to its analysis population, estimate, uncertainty, and decision criteria. It would also make clear how secondary outcomes, missing observations, and multiple analyses were handled. The registry record does not report those elements or any analyses, limiting the ability to judge precision and interpret dose selection.
The study is therefore useful as an example of how a clear design objective can coexist with incomplete posted results. The listed adverse-event counts offer descriptive information, but the intended primary dose-finding question cannot be answered from the registry record alone. This distinction helps readers separate a trial's stated purpose from the evidence available to assess whether that purpose was met.
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 most direct limitation for interpretation is that the registry record does not report the primary DLT results or an estimated maximum tolerated dose. Although the record identifies a primary endpoint, its timeframe and part of its definition, it does not give the dose-specific estimates, uncertainty, or the number included in each endpoint analysis.
The DLT definition is incomplete in the record, ending after examples and “etc.” The description of the evaluable population also appears incomplete. The dose-finding algorithm, escalation and stopping rules, decision thresholds, and details of contour estimation are not reported in the registry record. These omissions prevent independent assessment of how the dose-selection objective was operationalized.
The non-randomized sequential design does not support like-for-like comparisons between dose-level groups. The registry does not report how participant characteristics or other possible differences were accounted for. The safety counts are descriptive, and the denominators for the listed serious-event-term percentages are not reported in the registry record. Death counts are not listed in the group records.
The registry lists secondary outcome names but not results, definitions, analysis populations, or uncertainty estimates. It also does not report missing-data methods, multiplicity handling, interim analyses, or a detailed sample-size justification. Overall enrollment of 63 does not reveal how many participants contributed to each outcome. These are limits of what the registry record reports; they should not be read as proof that the study did not collect or use additional information.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Study Evaluating Neratinib In Combination With Temsirolimus In Subjects With Solid Tumors — NCT00838539.
- Registry record last updated 2018-09-18; status last verified 2018-08.
- Results first posted 2018-02-26.
- 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
NCT00838539 is a completed phase 1 study sponsored by Puma Biotechnology, Inc., evaluating neratinib with temsirolimus in subjects with solid tumors. It was non-randomized, unmasked and sequential, with enrollment of 63. The study began in 2009-04 and reached primary completion in 2011-06.
The primary objective was to identify maximum tolerated dose or doses for the combination. The primary endpoint was probability of DLT from the first dose through day 28. The listed secondary outcomes were Best Overall Response, Clinical Benefit Rate, Objective Response Rate and Area Under the Curve Tau.
The registry reports dose-level safety counts and selected serious adverse event terms, but lists no analyses and does not report the primary endpoint or secondary outcome results. Details of the dose-finding algorithm, missing-data handling, multiplicity strategy and analysis populations are not reported in the registry record.