MLN0128 Compared to Sorafenib in Advanced or Metastatic Hepatocellular Carcinoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for MLN0128 Compared to Sorafenib in Advanced or Metastatic Hepatocellular Carcinoma (NCT02575339), a randomized phase 1, phase 2 study. The primary outcome is Phase I: Maximum Tolerated Dose (MTD) of MLN0128.

2. Clinical Question

The study had distinct phase I and phase II objectives. Phase I focused on dose escalation and identifying a maximum tolerated dose. Phase II was described as a randomized comparison of MLN0128 and sorafenib. Its listed outcomes include overall survival and progression-free survival; phase I listed safety, survival, time to progression, progression-free survival, objective response and disease control outcomes.

Those planned questions should not be mistaken for answered questions. The record does not provide an estimate of the maximum tolerated dose, a dose-limiting toxicity summary, or a treatment-effect estimate comparing the phase II arms. It also does not report phase II outcome results. The available record therefore describes the questions and planned treatment groups, but cannot establish the relative outcomes of the two treatments.

3. Trial Design

This was an open-label, randomized phase I/II study with a parallel-group design and no masking. Its stated enrollment was 11. The registry lists the study as terminated. It records a start date of 2016-07-18 and a primary completion date of 2018-06-26; the reason given for the missing phase I primary endpoint data is early termination by the funder.

In phase I, the planned approach was dose escalation of oral MLN0128 in successive cohorts. The listed weekly dose levels were 15mg, 20mg and 30mg. The schedule specified dosing on days 1, 8, 15 and 22. The primary objective was to determine the maximum tolerated dose. The registry does not report results establishing that dose, and it does not report which dose was selected for the phase II recommended dose.

In phase II, eligible subjects were to be randomized 1:1 to MLN0128 or sorafenib. The experimental arm description specifies MLN0128 at the recommended phase II dose once weekly. The control arm description specifies sorafenib 400mg by mouth twice a day daily. The 1:1 allocation describes the planned randomization; the record does not provide group enrollment or phase II treatment counts.

The study was open label, meaning the registry did not specify masking of participants or study personnel. Randomization describes the intended assignment process, not proof that a completed comparison can be analyzed. Enrollment of 11 is recorded for the study, but the record does not say how enrollment was distributed across phases, dose cohorts or randomized arms. It also does not report the number of participants who received treatment, completed follow-up or contributed to particular outcome analyses.

The secondary outcomes cover several kinds of endpoints. Phase I lists adverse effects, overall survival, time to progression, progression-free survival, objective response and disease control. Phase II lists overall survival and progression-free survival. The record contains 12 outcome measures but reports 0 analyses. The listed outcomes therefore indicate what was registered for measurement; they do not establish that results were collected or that treatment groups were compared.

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.

Study Treatment

Reasons for not completing this period:

Follow up

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Data for this primary objective was neither collected nor analyzed due to the early termination of the study by the funder.

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: This study was terminated at Phase I.The official reason for study termination was Funder Decision due to lack of accrual. Dose level 1 has 7 subjects since one of the subjects (subject #6) had to come off treatment early but did not have a DLT and so the subject was replaced to have the appropriate number of subjects for the dose decision.

6. Primary Endpoint

The registry lists the primary outcome as Phase I: Maximum Tolerated Dose (MTD) of MLN0128, measured over From start of treatment Day 1 (D1) until completion of two cycles of treatment (maximum 56 days).

The primary endpoint was the phase I maximum tolerated dose of MLN0128. It is a dose-finding measure rather than a measure of comparative tumor response or survival. The registry defines the maximum tolerated dose as the dose level at which fewer than 33% of subjects experience a dose limiting toxicity. The timeframe was from the start of treatment on Day 1 until completion of two treatment cycles, with a maximum of 56 days.

In general, a dose-limiting toxicity rule is used during dose escalation to identify a dose that meets a prespecified safety criterion. This kind of endpoint helps guide selection of a dose for later study; it does not by itself answer whether a treatment improves a clinical outcome or how it compares with another treatment. Interpretation depends on observing and classifying toxicities within the stated assessment period and applying the stated threshold.

In this record, the endpoint is defined, but its result is not available. The registry explicitly says that data for the primary objective were neither collected nor analyzed because the funder terminated the study early. No maximum tolerated dose estimate or dose-limiting toxicity count is reported for the endpoint. Consequently, the registered definition cannot be applied to identify a dose from the posted primary-endpoint results.

The registry lists survival, progression and response measures as secondary outcomes, but does not post their analyses. These outcomes address different clinical questions from dose finding and would require their own result data and analysis. Their appearance in the registration does not substitute for a reported endpoint estimate.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does randomization contribute?

In general, randomization assigns participants to treatment groups using a chance-based process. When implemented as planned, it can reduce systematic differences in measured and unmeasured characteristics between groups, supporting a fairer comparison. It does not guarantee that groups will be identical, especially in a small study, and it does not replace reporting the actual allocation, follow-up, outcomes and analysis. The registry describes 1:1 randomization for phase II, but does not report arm counts or comparative analyses. The stated study enrollment of 11 cannot be treated as the sample size in either phase II arm because the distribution by phase and group is not reported.

What does the open-label design mean?

Open label means that the study was not masked. In general, knowledge of assigned treatment can influence expectations, reporting of symptoms, decisions about additional care and assessment of outcomes that require judgment. Some outcomes are less dependent on subjective assessment than others, but no assumption about outcome assessment procedures is warranted. The registry reports no masking and does not describe additional procedures to limit bias. Randomization and masking address different concerns: random assignment may help balance baseline characteristics, while masking can reduce some effects of treatment knowledge after assignment.

How should the phase I endpoint be understood?

Maximum tolerated dose is a dose-finding endpoint. The registry defines it using the proportion of subjects with a dose limiting toxicity and specifies a threshold of fewer than 33%. In general, applying such a rule requires a defined toxicity assessment, a specified observation window, and evaluable participants at each dose level. The record gives a timeframe ending after two cycles or a maximum of 56 days, but does not report endpoint data or analyses. It is therefore not possible to determine from the primary endpoint whether any dose level met the rule.

The dose escalation descriptions list three weekly dose levels and successive cohorts. Those descriptions tell readers how dosing was planned; they do not report an estimated dose-response relationship or identify a recommended phase II dose. A safety count at a dose level is not interchangeable with the primary endpoint: the endpoint specifically depends on dose-limiting toxicity classification during its stated timeframe, and the posted adverse-event entries do not supply that analysis.

What can the safety counts establish?

Counts with an at-risk denominator provide descriptive information about how many people in the recorded group had an event. In general, denominators matter because the same event count can have different implications in groups of different sizes. The registry entries report at-risk and affected counts by phase I dose level, alongside deaths. They do not establish causation, and they are not a comparison between randomized MLN0128 and sorafenib groups. The level 3 entries have no participants at risk, so they do not provide an observed safety experience at that level in the posted entries.

A percentage attached to a serious-event term also needs a clear denominator and ascertainment context for interpretation. The registry lists gastric hemorrhage at 14.3%, but the record does not report in this entry the basis needed to treat that figure as an arm-specific rate or a comparative estimate. General statistical interpretation should distinguish a reported event label from a risk estimate suitable for comparing treatments.

What is a confidence interval, and why is none interpretable?

In general, a confidence interval expresses the uncertainty around an estimated quantity under a specified statistical method and its assumptions. A narrower interval indicates greater precision under that method; a wider interval indicates less precision. It does not, by itself, establish clinical importance or remove bias. The registry does not report a confidence interval for the maximum tolerated dose or a phase II treatment effect. There is consequently no interval from which to assess the precision of those questions.

A p-value, when reported, addresses compatibility between observed data and a specified null model under stated assumptions; it is not the probability that a treatment works or that the null hypothesis is true. The record reports no analyses and gives no p-values for treatment outcomes. No inferential conclusion should be reconstructed from the enrollment or safety counts alone.

What does the planning illustration mean?

In general, sample-size planning uses assumptions about the effect to detect, the significance level, allocation, and statistical model to illustrate how much information a future study might need. The registry’s planning description specifies a two-sided significance level of 0.05, equal allocation, a normal approximation, and effects framed as fractions of an observed effect. For time-to-event planning, it describes a total event count; for other outcomes, it describes participants per arm. These are planning assumptions, not observed trial results, and they are not evidence of achieved power.

The record does not report the trial’s own sample-size justification or a statistical analysis plan. The planning illustration should not be confused with the study’s observed enrollment, which is 11, or with an analysis of the terminated study. No planned or achieved sample-size figure for a particular outcome can be inferred from the general assumptions alone.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists multiple outcomes across two phases: safety, survival, progression, response and disease control measures. When a study examines multiple endpoints or time points, general statistical practice considers whether tests or interpretations are prioritized or adjusted, because repeated testing can increase the chance of a seemingly notable finding. The registry record does not report a multiplicity strategy, a hierarchy among the secondary outcomes, or an analysis plan explaining how multiple results would be interpreted.

The record reports 12 outcome measures and 0 analyses. It does not give outcome-level participant counts, missing-data amounts, reasons for missing observations, or methods for handling missing values. In general, missing outcomes can affect both the amount of information available and the comparability of groups; interpretation depends on how much is missing, why it is missing, and the methods used. Those details are not reported in the registry record.

The record also does not report analysis populations, such as which enrolled, randomized or treated participants would be included in each analysis. The planned phase II allocation is described as 1:1, but no group enrollment or analysis population is presented. The study-level enrollment of 11 cannot establish the denominator for any outcome or analysis. For the phase I primary endpoint, the registry specifically states that data were neither collected nor analyzed because of early termination by the funder. Without those endpoint observations and analysis details, neither the primary dose-finding result nor a phase II comparison can be assessed.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: gastric hemorrhage (14.3%).

The registry reports serious adverse events by phase I MLN0128 dose level. At 15 mg, 7 were listed at risk and 1 was affected. At 20mg, 4 were listed at risk and 0 were affected. At 30mg, both figures were 0. These entries describe the registry’s recorded groups; they are not randomized comparisons with sorafenib and do not establish that treatment caused an event.

For other adverse events, the recorded figures are 7 at risk and 7 affected at 15 mg, 4 at risk and 4 affected at 20mg, and 0 at risk and 0 affected at 30mg. Deaths are listed as 7 for the 15 mg group, 2 for the 20mg group and 0 for the 30mg group. The record does not state that these deaths were treatment-related, and the counts alone should not be read as evidence of causation.

Gastric hemorrhage is the listed serious-event term, with 14.3% reported. The record does not provide enough context in this entry to interpret that percentage as a comparative rate or to determine its denominator. The level 3 group has no participants listed at risk, so its zero affected count is not evidence of an observed absence of events among treated participants. These safety entries should be read as descriptive registry data, with the reported group sizes and missing context in mind.

12. What the Result Does, and Does Not, Mean

The record establishes that a randomized, open-label phase I/II study was registered to examine MLN0128 and sorafenib in advanced or metastatic hepatocellular carcinoma. It describes a phase I dose-escalation approach, a phase II randomized comparison, a maximum tolerated dose definition, and several secondary outcomes. It also records enrollment of 11 and termination of the study.

It does not establish the phase I maximum tolerated dose. The registry explicitly says that primary endpoint data were neither collected nor analyzed because of early termination by the funder. It also does not establish whether MLN0128 and sorafenib differed in survival, progression or response outcomes. Although phase II randomization and outcomes are described, the record reports 0 analyses and no comparative outcome estimates.

Safety entries provide counts by phase I dose level, but do not establish that events or deaths were caused by treatment. The counts are not a randomized comparison between MLN0128 and sorafenib. The record does not report the distribution of enrollment across phases or groups, so the study-wide enrollment cannot be used as the denominator for an unreported treatment comparison.

In general, absence of a reported result is not evidence that two treatments have the same effect, nor is it evidence that a treatment is beneficial or harmful. A conclusion about relative effects requires outcome data, an appropriate analysis and information about uncertainty. Those results are not reported. The defensible interpretation is limited to the registered design, the missing primary endpoint result, the termination status and the descriptive safety entries.

13. Why This Trial Matters Statistically

This record illustrates why a registered research question and an answered research question are not the same thing. The study specified a clinically relevant dose-finding objective and a planned randomized comparison, but the registry states that the phase I primary endpoint was not collected or analyzed and reports 0 analyses overall. A clearly defined endpoint cannot support inference without endpoint observations.

The record also shows why phase I and phase II objectives need separate interpretation. Phase I sought a maximum tolerated dose using a toxicity threshold. Phase II was intended to compare MLN0128 with sorafenib and listed survival and progression outcomes. The dose-finding objective and comparative outcomes answer different questions. Safety entries by dose level do not substitute for the dose-limiting toxicity analysis, and neither dose-level counts nor planned randomization substitute for comparative phase II results.

The small recorded study enrollment and the unreported allocation across phases and groups further limit what can be inferred about the amount of information available for any comparison. The record does not support calculations of treatment effects, confidence intervals or statistical significance. It is also important that a terminated study’s missing results cannot be interpreted as a null finding.

For biostatistical reading, the key distinction is between design features, registered outcomes, descriptive safety counts and analyzed estimates. Only the first three are represented in the posted information. This distinction prevents overreading a study’s planned comparison or its adverse-event entries as evidence about comparative efficacy or causation.

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 important trial-specific limitation is the absence of the phase I primary endpoint result. The registry attributes this absence to early termination by the funder and states that the endpoint data were neither collected nor analyzed. The maximum tolerated dose question therefore remains unanswered in the posted record.

The registry reports enrollment of 11 but does not report how enrollment was divided among the phase I and phase II portions, the dose-escalation groups or the randomized arms. It does not report how many participants received treatment or contributed to follow-up. Consequently, the study-level enrollment cannot serve as an outcome denominator or clarify how much information was available for a phase II comparison.

No comparative efficacy analyses are reported, despite registered survival, progression and response outcomes. The record gives no effect estimates or uncertainty intervals for these outcomes and no analysis populations. It also does not report a statistical analysis plan, missing-data handling, multiplicity approach, or sample-size justification. These omissions prevent assessment of the planned inferential framework.

The safety entries are limited to phase I dose-level counts, and they do not establish treatment causality. The registry does not provide enough context for the reported gastric hemorrhage percentage to interpret it as a comparative rate. The zero entries at 30mg accompany zero participants listed at risk, so they cannot describe an observed safety experience in that group. Overall, the record is useful for identifying the intended design and the limits of the posted results, but it cannot support conclusions about treatment efficacy or a selected tolerated dose.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: MLN0128 Compared to Sorafenib in Advanced or Metastatic Hepatocellular Carcinoma — NCT02575339.
• Registry record last updated 2022-07-26; status last verified 2022-07.
• Results first posted 2022-03-31.
• 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.

18. Record Summary

NCT02575339 was an open-label, randomized phase I/II parallel study of MLN0128 and sorafenib in advanced or metastatic hepatocellular carcinoma. The registry records enrollment of 11, a start date of 2016-07-18, a primary completion date of 2018-06-26 and terminated status.

Phase I planned escalating weekly MLN0128 doses and had a primary objective of determining maximum tolerated dose, defined by a dose-limiting toxicity threshold. Phase II planned 1:1 randomization between weekly MLN0128 at the recommended phase II dose and sorafenib 400mg twice a day daily. The registry states that the phase I primary endpoint data were not collected or analyzed because of early termination by the funder.

The record lists 12 outcome measures and 0 analyses. It includes descriptive phase I safety entries but no reported primary endpoint estimate or phase II comparative outcome results. The record does not establish a maximum tolerated dose or a relative treatment effect.