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 Randomized Phase 1/2 Open-Label Trial of PR104 and Sorafenib in Patients With Advanced Hepatocellular Carcinoma (HCC) (NCT00862082), a na phase 1, phase 2 study. The primary outcome is Maximum Tolerated Dose (MTD) of PR104 When Used in Combination With Standard Dose Sorafenib in the Phase I Population.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00862082 |
| Phase | Phase 1, Phase 2 |
| Condition | Hepatocellular Carcinoma |
| Allocation | Not applicable (single group) |
| Design model | Single Group |
| Masking | None (open label) |
| Enrollment | 14 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Proacta, Incorporated |
| Results posted | Yes |
2. Clinical Question
Population
Patients with advanced hepatocellular carcinoma (HCC). The registry record lists 14 participants enrolled. It does not report further eligibility details or the characteristics of the enrolled participants.
Intervention
PR104 given with sorafenib. The record lists PR104 doses of 550 mg/m^2 and 770 mg/m^2. The arm description says PR104 was administered intravenously once every four weeks, in addition to sorafenib 400mg by mouth twice daily.
Comparator
The record lists two PR104 dose groups, but does not establish a like-for-like control comparison. Allocation is recorded as NA and the model as single group. The record therefore does not establish that participants were randomized between the listed doses.
Primary question
The primary outcome is the maximum tolerated dose (MTD) of PR104 when used with standard dose sorafenib in the Phase I population. It is recorded as a numerical dose in mg/m2 over 4 weeks (1 cycle). The MTD result and the criteria used to determine it are not reported in the registry record.
The record’s title describes a randomized trial, while its design fields list allocation as NA and the model as single group. This distinction matters: the listed dose groups should not be treated as randomized arms or as a controlled comparison based on this record alone. The registry lists PR104 550 mg/m^2 plus sorafenib and PR104 770 mg/m^2 plus sorafenib as interventions. It does not report the method for assigning participants to these groups.
The registry summary explains the rationale for evaluating the combination, referring to hypoxia, potentially non-overlapping toxicities, AKR1C3 expression, and preclinical findings. Those statements describe the rationale recorded for the study; they are not results from this clinical trial. The record describes the study as seeking an estimate of PR104 activity in HCC and information relevant to future development. The Phase II primary objective is incomplete in the registry summary and is not reported in the registry record.
3. Trial Design
This is a Phase I/II study of PR104 with sorafenib in patients with advanced hepatocellular carcinoma. The registry record lists Proacta, Incorporated as the sponsor, an enrollment of 14, a start date of 2009-03, a primary completion date of 2010-01, and a status of terminated. It does not report why the study was terminated.
The record lists two intervention regimens: PR104 550 mg/m^2 plus sorafenib and PR104 770 mg/m^2 plus sorafenib. The arm description states that PR104 was to be administered IV once every four weeks, in addition to 400mg sorafenib PO twice daily. The record does not report further details about dose escalation, dose assignment, dose modifications, treatment duration, or criteria for stopping treatment.
The title calls the study randomized, but the registry fields list allocation as NA and the model as single group. Masking is listed as none. The record therefore does not establish a randomized comparison between the dose groups, and it does not describe a separate control group. These design fields limit what can be inferred from any differences between the groups.
The primary endpoint is the maximum tolerated dose of PR104 with standard dose sorafenib in the Phase I population, measured over 4 weeks (1 cycle). Secondary outcomes include serious adverse events and pharmacokinetic measures for PR104 and its metabolites. The registry lists pharmacokinetic outcomes for both dose cohorts, covering maximum plasma concentration, half-life, and area under the curve. The record does not provide outcome results or a statistical analysis plan. It also does not report the planned sample-size justification, interim analyses, or detailed analysis populations.
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 | PR104 550 mg/m^2 + Sorafenib | PR104 770 mg/m^2 + Sorafenib |
|---|---|---|
| STARTED | 8 | 6 |
| COMPLETED | 3 | 5 |
| NOT COMPLETED | 5 | 1 |
Reasons for not completing this period:
| Reason | PR104 550 mg/m^2 + Sorafenib | PR104 770 mg/m^2 + Sorafenib |
|---|---|---|
| Sponsor decision to terminate the study | 5 | 0 |
| Withdrawal by Subject | 0 | 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 | PR104 550 mg/m^2 + Sorafenib | PR104 770 mg/m^2 + Sorafenib | Total |
|---|---|---|---|---|
| Participants analysed | 8 | 6 | 14 | |
| Age, Categorical: <=18 years | Participants | 0 | 0 | 0 |
| Age, Categorical: Between 18 and 65 years | Participants | 7 | 5 | 12 |
| Age, Categorical: >=65 years | Participants | 1 | 1 | 2 |
| Age Continuous | years | 57 (SD 13) | 59 (SD 13) | 58 (SD 13) |
| Sex: Female, Male: Female | Participants | 3 | 0 | 3 |
| Sex: Female, Male: Male | Participants | 5 | 6 | 11 |
| Region of Enrollment: United States | participants | 2 | 1 | 3 |
| Region of Enrollment: Taiwan | participants | 5 | 2 | 7 |
| Region of Enrollment: Hong Kong | participants | 1 | 3 | 4 |
6. Primary Endpoint
The registry lists the primary outcome as Maximum Tolerated Dose (MTD) of PR104 When Used in Combination With Standard Dose Sorafenib in the Phase I Population, measured over 4 weeks (1 cycle).
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | mg/m2 |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint is the maximum tolerated dose (MTD) of PR104 when used with standard dose sorafenib in the Phase I population. The record specifies a numerical endpoint, with units of mg/m2, and a timeframe of 4 weeks (1 cycle). No MTD value is reported in the registry record, and the registry does not describe the specific dose-limiting events, decision rules, or assessment procedures used to determine the MTD.
General: In early-phase combination studies, an MTD endpoint is used to describe a dose selected through assessment of tolerability under the study’s defined rules. It is a dose-finding measure, not a direct measure of tumor response or comparative treatment benefit. The exact meaning of an MTD depends on the protocol’s definitions, observation period, and dose-escalation or dose-selection rules. Those details are not reported in the registry record, so the endpoint’s operational definition cannot be reconstructed from this entry.
The registry lists safety and tolerability outcomes and pharmacokinetic measures as secondary outcomes. These outcomes can address different questions: safety outcomes describe recorded adverse events, while pharmacokinetic measures describe drug concentration over time. Neither type of outcome substitutes for a reported MTD result. With no primary result posted, the registry record does not show what dose was identified as the MTD.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record describes a small Phase I/II study with 14 participants enrolled and two listed PR104 dose groups, each combined with sorafenib. Its primary endpoint is the MTD of PR104 with standard dose sorafenib in the Phase I population, assessed over 4 weeks (1 cycle). However, the MTD value is not reported in the registry record. The record therefore does not show whether an MTD was identified, what dose it was, or how it was determined.
The title calls the study randomized, but allocation is listed as NA and the model as single group. These fields do not establish a randomized comparison. The listed groups should consequently be read as dose groups in the registry, not as treatment and control arms with a supported causal contrast. The study also has no reported outcome analyses: the record lists 0 analyses. Without a posted primary result or analysis, there is no estimate of the primary endpoint to interpret.
The registry includes serious adverse event counts for both dose groups. Serious events affected 5 of 8 participants in the PR104 550 mg/m^2 plus sorafenib group and 2 of 6 participants in the PR104 770 mg/m^2 plus sorafenib group. The number of participants at risk is also given for other adverse events: 8 in the 550 mg/m^2 group and 6 in the 770 mg/m^2 group, with events reported for all participants in each group. These are descriptive registry counts, not a controlled estimate of comparative risk. The record does not provide enough information to attribute events to a particular drug or to establish whether the observed group counts reflect dose differences.
The listed serious-event terms include abdominal pain and fever in absence of neutropenia, each reported as 25.0%; fatigue and sepsis, each 16.7%; and cellulitis and decrease in general condition, each 12.5%. The record does not provide the event-level detail needed to determine timing, recurrence, severity beyond the serious-event classification, or attribution. Death counts are not reported in the registry record.
The record’s rationale cites preclinical findings and biological considerations for studying the combination. These provide context for why investigators considered the regimen, but they do not establish clinical activity in this study. The registry says the study was terminated, but does not report a reason. No response, survival, or other clinical efficacy result is included in the posted record. Thus the entry supports a description of the study’s planned question and some safety counts, but not a conclusion about the MTD or efficacy of the combination.
9. Statistical Methods Explained
General: An early-phase dose-finding study asks which dose can be taken forward under the study’s prespecified safety rules. The maximum tolerated dose is not a universal quantity independent of a protocol: it depends on the definition of a dose-limiting event, the assessment period, and the procedure for selecting or escalating doses. In this record, the MTD is the primary endpoint for the Phase I population, with a timeframe of 4 weeks (1 cycle). The criteria and dose-finding method are not reported in the registry record, so the endpoint cannot be independently reconstructed from the entry.
What does the dose-group information establish?
The interventions list PR104 550 mg/m^2 plus sorafenib and PR104 770 mg/m^2 plus sorafenib. The arm description specifies PR104 IV once every four weeks and sorafenib 400mg PO twice daily. The record does not state how participants were assigned to the dose groups, or whether one dose followed another within a dose-escalation procedure. Although the title includes the word randomized, allocation is recorded as NA and the model as single group. The record therefore does not establish randomized assignment or a controlled comparison.
When assignment is not described, a difference in outcomes between groups cannot automatically be attributed to dose. General: comparisons are most informative when allocation, follow-up, outcome definitions, and analysis are sufficiently specified to support a fair contrast. The available registry fields do not provide that basis for a like-for-like comparison of the two dose groups. Their counts can still be described as observed registry counts, with the limitation that the record does not establish why participants appear in each group.
How should the adverse-event counts be read?
The safety record gives numbers at risk and numbers affected for serious adverse events and other adverse events. In the 550 mg/m^2 plus sorafenib group, 8 participants were at risk for serious events and 5 were affected; in the 770 mg/m^2 plus sorafenib group, 6 were at risk and 2 were affected. For other adverse events, the record gives 8 at risk and 8 affected in the lower-dose group, and 6 at risk and 6 affected in the higher-dose group. These counts describe participants with events, not necessarily the total number of distinct event episodes.
General: a participant count and an event count answer different questions. A participant with repeated events may contribute once to a count of participants affected but more than once to an event total, depending on the reporting method. The registry record does not explain whether repeated events were counted, how events were attributed, or how missing safety observations were handled. The listed event terms and percentages should therefore be read as registry summaries rather than as complete event-level data.
What do the pharmacokinetic outcomes measure?
The registry lists maximum plasma concentration, half-life, and area under the curve for PR104 and its metabolites in the two dose cohorts. General: maximum concentration describes the highest measured drug concentration in the sampling schedule; half-life describes the time course of decline under the specified pharmacokinetic model; and area under the curve summarizes concentration over time. These measures can characterize drug exposure, but interpretation depends on the sampling schedule, assay, model, and analysis population. Those details and the numerical pharmacokinetic results are not reported in the registry record.
The record lists eight outcome measures and 0 analyses. It does not provide estimates, confidence intervals, p-values, or model specifications. A confidence interval, in general, expresses the range of values compatible with an estimate under the method’s assumptions; its width conveys precision, not whether a clinical effect is important. Since no primary estimate or interval is posted, the precision of the MTD assessment cannot be evaluated from this record.
What can planning calculations say?
The stated sample-size planning assumptions describe an illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The illustration is not the trial’s own design justification, and it is not observed power. For non-time-to-event outcomes, such illustrations are expressed as participants per arm; time-to-event calculations use a total event count. The registry record does not report the planned sample-size justification or provide an analyzed primary effect that would allow the planning illustration to be assessed against trial results.
General: a planning calculation asks what sample size would be needed under chosen assumptions about the effect, variability, allocation, and statistical test. It does not tell whether a completed study had a particular probability of success after its results are known. Such calculations are especially difficult to interpret when the observed effect is uncertain or no primary result is reported. The planning assumptions listed for this study should not be mistaken for evidence that the study was designed or powered according to those assumptions.
The registry does not report a statistical analysis plan, including any model for the primary endpoint, handling of incomplete observations, multiplicity adjustment, or analysis population definitions. Without these details, the reader cannot determine how the listed endpoints were intended to be combined or prioritized in formal analysis. The absence of these details is a limitation of the registry record, not evidence that the study protocol lacked them.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists a primary MTD outcome and secondary outcomes covering serious adverse events and pharmacokinetics. It reports eight outcome measures and 0 analyses. The record does not describe a hierarchy among secondary outcomes, adjustments for multiple comparisons, or a statistical plan for interpreting several outcomes together. The Phase II primary objective is incomplete in the registry summary and is not reported in the registry record.
General: multiplicity arises when several hypotheses or outcomes are assessed. If many tests are interpreted together without an appropriate plan, the chance of at least one apparently notable result can increase. A prespecified hierarchy or adjustment can address some multiplicity concerns, but the appropriate approach depends on the study objectives and analysis plan. Since no analysis plan is reported, it is not possible to determine how multiplicity was handled.
The registry record does not describe missing-data rules, the extent of missing outcome data, or methods for handling participants who did not complete assessments. It also does not define analysis populations, such as which participants were included in the primary endpoint or pharmacokinetic analyses. The enrollment count alone does not establish how many participants contributed data to each outcome.
These omissions limit interpretation of the posted safety counts and prevent assessment of the primary endpoint’s analytic population. They do not establish that data were missing or that analyses were conducted improperly; those details are simply not reported in the registry record.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| PR104 550 mg/m^2 + Sorafenib | 5 | 8 | 62.5% |
| PR104 770 mg/m^2 + Sorafenib | 2 | 6 | 33.3% |
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 |
|---|---|
| PR104 550 mg/m^2 + Sorafenib | 8 of 8 |
| PR104 770 mg/m^2 + Sorafenib | 6 of 6 |
Most frequent serious adverse event terms
| Event term | Organ system | PR104 550 mg/m^2 + Sorafenib | PR104 770 mg/m^2 + Sorafenib |
|---|---|---|---|
| Abdominal Pain | Gastrointestinal disorders | 2 of 8 | 0 of 6 |
| Fever in absence of neutropenia | General disorders | 2 of 8 | 0 of 6 |
| Cellulitis | Infections and infestations | 1 of 8 | 0 of 6 |
| Decrease in general condition | General disorders | 1 of 8 | 0 of 6 |
| Fatigue | General disorders | 0 of 8 | 1 of 6 |
| Febrile neutropenia | Blood and lymphatic system disorders | 1 of 8 | 0 of 6 |
| Sepsis | Infections and infestations | 0 of 8 | 1 of 6 |
| Thrombocytopenia | Investigations | 1 of 8 | 0 of 6 |
Most frequent non-serious adverse event terms
| Event term | Organ system | PR104 550 mg/m^2 + Sorafenib | PR104 770 mg/m^2 + Sorafenib |
|---|---|---|---|
| Leukopenia | Blood and lymphatic system disorders | 7 of 8 | 4 of 6 |
| Anemia | Blood and lymphatic system disorders | 4 of 8 | 5 of 6 |
| Neutropenia | Blood and lymphatic system disorders | 6 of 8 | 3 of 6 |
| Aspartate aminotransferase increased | Investigations | 6 of 8 | 3 of 6 |
| Thrombocytopenia | Blood and lymphatic system disorders | 3 of 8 | 5 of 6 |
| Hypoalbuminemia | Metabolism and nutrition disorders | 4 of 8 | 3 of 6 |
| Fatigue | General disorders | 3 of 8 | 3 of 6 |
| Alanine aminotransferase increased | Investigations | 4 of 8 | 2 of 6 |
| Anorexia | Metabolism and nutrition disorders | 3 of 8 | 2 of 6 |
| Abdominal pain | Gastrointestinal disorders | 3 of 8 | 2 of 6 |
Serious events with the highest arm-level rate: abdominal pain (25.0%), fever in absence of neutropenia (25.0%), fatigue (16.7%), sepsis (16.7%), cellulitis (12.5%).
The registry lists serious adverse events for 8 participants at risk in the PR104 550 mg/m^2 plus sorafenib group, with 5 affected, and for 6 participants at risk in the PR104 770 mg/m^2 plus sorafenib group, with 2 affected. For other adverse events, it lists 8 of 8 participants affected in the 550 mg/m^2 group and 6 of 6 affected in the 770 mg/m^2 group. These counts should be read as descriptive records of participants affected, not as evidence of a causal difference between doses or drugs.
The registry also lists serious-event terms and percentages: abdominal pain and fever in absence of neutropenia at 25.0% each; fatigue and sepsis at 16.7% each; and cellulitis and decrease in general condition at 12.5% each. The entry does not explain the denominator or reporting method for each term, nor does it provide event timing, recurrence, severity detail, or attribution. These percentages should not be treated as a complete account of every safety event.
The record does not report death counts. It also does not state how long participants were followed for safety, how events were collected, or how missing safety data were handled. Without those details and without a valid control comparison established by the design fields, the figures describe the registry’s safety reporting but do not establish comparative safety or the cause of any event.
12. What the Result Does, and Does Not, Mean
The registry record identifies a study of PR104 combined with sorafenib in advanced HCC, lists two PR104 dose groups, and describes an MTD endpoint for the Phase I population. It also records serious adverse event counts, other adverse event counts, and planned pharmacokinetic outcomes. The study is listed as terminated, with 14 participants enrolled. These registry entries describe the study and its registry reporting; they do not establish the clinical effect of the regimen.
The primary MTD result is not reported in the registry record. No estimate of tumor response, survival, or other clinical efficacy outcome is included. The rationale in the registry summary refers to biological considerations and preclinical findings, but these are not clinical results from the enrolled participants. The posted safety counts also do not establish that either dose is safer or more harmful, because the record does not establish a like-for-like randomized comparison or provide the context needed for causal interpretation.
The title describes the trial as randomized, but the allocation field is NA and the model is single group. That mismatch means the record does not support treating the listed dose groups as randomized arms. The reason for termination, dose-assignment method, MTD decision rules, analysis populations, missing-data procedures, and statistical analysis plan are not reported in the registry record.
General: a registry entry is a record of study design and reported outcomes, not necessarily a complete account of the protocol or all analyses. Conclusions depend on the completeness and clarity of the posted outcome data and methods. In this case, the information supports a cautious description of enrollment, dose groups, and recorded adverse events, but not a determination of the MTD, comparative safety, or treatment activity.
13. Why This Trial Matters Statistically
This study is statistically notable because its title and its design fields do not tell the same story about comparison. The title describes a randomized trial, while allocation is listed as NA and the model as single group. That distinction affects how dose-group outcomes can be interpreted: without a confirmed assignment mechanism and a suitable comparison, observed group differences cannot be treated as evidence that dose caused an outcome difference.
The primary endpoint is a dose-finding measure rather than a direct efficacy endpoint. Its interpretation depends on protocol rules for defining dose-limiting events and selecting an MTD. Those rules are not reported in the registry record, and the MTD result itself is absent. This makes it impossible to assess the central Phase I result from the entry.
The study also illustrates why participant counts and event summaries need context. The record reports safety counts and lists serious-event terms, but does not report the method of event collection, attribution, follow-up, or missing-data handling. Likewise, pharmacokinetic outcomes are named without numerical estimates or analysis details. These gaps constrain the precision and scope of any interpretation.
Finally, the record lists 0 analyses and does not report a statistical plan, sample-size justification, or the complete Phase II primary objective. These omissions do not prove that such plans or analyses were absent from the study; they mean they cannot be evaluated from the registry record. The case underscores the importance of clear design fields, endpoint definitions, analysis methods, and complete outcome reporting when readers assess early-phase studies.
14. Limitations
- The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
- Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.
The registry record has important gaps specific to this study. Although the title calls it randomized, allocation is recorded as NA and the model as single group. The method of assigning participants to the two PR104 dose groups is not reported. Thus, the record does not establish a randomized comparison or a like-for-like control group.
The primary MTD endpoint is defined only as a numerical dose in mg/m2 over 4 weeks (1 cycle). The rules for dose escalation or selection, dose-limiting events, and the criteria for determining the MTD are not reported in the registry record. Nor is the MTD result itself reported. The Phase II primary objective is incomplete in the summary and is not reported in the registry record.
The entry lists 14 participants enrolled and adverse-event counts by dose group, but does not provide outcome-specific analysis populations, follow-up duration, event attribution, event-level detail, or missing-data handling. Death counts are not reported. Numerical pharmacokinetic results are not included, despite the listed concentration, half-life, and area-under-the-curve outcomes.
The registry says the study was terminated, but does not report the reason. It does not provide a statistical analysis plan, a sample-size justification, or details of interim analyses. These omissions limit interpretation of the study and its reported safety information. They should be understood as limits of the registry record and not as proof that the underlying protocol or study files lacked these details.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Randomized Phase 1/2 Open-Label Trial of PR104 and Sorafenib in Patients With Advanced Hepatocellular Carcinoma (HCC) — NCT00862082.
- Registry record last updated 2013-08-23; status last verified 2013-07.
- Results first posted 2013-08-23.
- Data retrieved from ClinicalTrials.gov on 2026-11-09.
- Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.
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18. Record Summary
The registry record describes a Phase I/II, open-label study of PR104 with sorafenib in patients with advanced hepatocellular carcinoma. It lists an enrollment of 14, a start date of 2009-03, a primary completion date of 2010-01, and a terminated status. Proacta, Incorporated is listed as the sponsor.
The interventions are PR104 550 mg/m^2 plus sorafenib and PR104 770 mg/m^2 plus sorafenib. The primary endpoint is the maximum tolerated dose of PR104 with standard dose sorafenib in the Phase I population, assessed over 4 weeks (1 cycle). The MTD result is not reported in the registry record.
The record lists serious adverse event and pharmacokinetic outcomes, including maximum plasma concentration, half-life, and area under the curve for PR104 and its metabolites. It reports adverse-event counts but no analyses. Although the title describes a randomized study, allocation is listed as NA and the model as single group. The registry record does not establish a randomized comparison, and it does not report the reason for termination or the statistical analysis plan.