Akt Inhibitor MK2206, Bendamustine Hydrochloride, and Rituximab in Treating Patients With Relapsed Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Akt Inhibitor MK2206, Bendamustine Hydrochloride, and Rituximab in Treating Patients With Relapsed Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (NCT01369849), a na phase 1, phase 2 study. The primary outcome is Number of Phase I Participants With Dose-Limiting Toxicity Events (Phase I).

2. Clinical Question

The study examined a combination of Akt inhibitor MK-2206, bendamustine hydrochloride, and rituximab in patients with relapsed chronic lymphocytic leukemia or small lymphocytic lymphoma. The phase I portion focused on dose-limiting toxicity and identifying a maximum tolerated dose. The phase II portion was intended to assess the combination in the study population, with secondary outcomes including response, duration of response, minimal-residual disease, treatment-free survival, and biomarker measures.

3. Trial Design

This was a phase I/II study of MK-2206, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia or small lymphocytic lymphoma. The registry reports an enrollment of 15 and a completed status. The study began in 2011-09, and primary completion was recorded as 2014-02. The sponsor was the National Cancer Institute.

The design is listed as single group, with allocation not applicable and no masking. The record therefore does not describe a randomized comparison or a blinded treatment assignment. The phase I dose levels are components of dose evaluation, not independent control arms. The phase II group is also not a concurrent control group. Differences between groups or phases should not be interpreted as treatment effects because the record does not establish that they are comparable.

The registry describes participants receiving MK-2206 by mouth on specified days, rituximab intravenously, and bendamustine intravenously. Treatment was scheduled in repeating courses, with a modified schedule for the first course. The detailed duration of the full treatment schedule is incomplete in the registry record, so it cannot be characterized further from the available description.

The primary endpoint concerned dose-limiting toxicity in the phase I portion, with a timeframe of up to 35 days. The endpoint population description says that 6 participants at Dose Level 1 and 3 participants at Dose Level 2 were included. It also states that one of the 4 participants accrued to Dose Level 2 was ineligible for this endpoint. These endpoint-specific populations should be distinguished from the adverse-event group counts, which list 4 participants at Dose Level 2. The record lists secondary outcomes covering biomarkers, response, minimal-residual disease, and treatment-free survival, but it does not report their results in the information available.

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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Only the patients registered to the Phase I portion of this study were analyzed for this endpoint. One of the 4 patients accrued to dose level 2 was not eligible for this endpoint. Therefore, 6 patients at Dose Level 1 and 3 patients at Dose Level 2 are included in this endpoint.

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: All patients that began protocol treatment were included in the baseline analysis.

6. Primary Endpoint

The registry lists the primary outcome as Number of Phase I Participants With Dose-Limiting Toxicity Events (Phase I), measured over Up to 35 days.

The primary endpoint was the number of phase I participants with dose-limiting toxicity events, assessed up to 35 days. It is a count of participants reporting an event, not a measure of average symptom severity or a comparison of treatment groups. Its stated role was to support dose selection in the phase I portion.

The registry defines the maximum tolerated dose as the dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of patients, using the stated toxicity criteria. Dose-limiting events were non-hematologic events graded 3 or higher and considered at least possibly related to treatment, according to NCI Common Terminology Criteria for Adverse Events version 4.0. That definition determines which events contribute to the endpoint; it is narrower than a count of all adverse events.

The endpoint population description specifies 6 participants at Dose Level 1 and 3 at Dose Level 2. One of the 4 participants accrued to Dose Level 2 was not eligible for this endpoint. The actual number reporting a dose-limiting event at each dose level is not reported in the registry record. Without those observed counts, the endpoint cannot show how frequently dose-limiting toxicity occurred or establish which dose level met the stated dose-selection criterion.

In general, an early-phase toxicity endpoint is used to guide dose evaluation rather than to establish comparative benefit. It provides information about events that meet a prespecified severity and attribution definition during the stated observation period. It does not, by itself, summarize every possible harm or describe outcomes beyond that period.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The interpretation of this record depends on separating the study question, outcome definition, analysis population, and design. The primary endpoint is a count of participants with dose-limiting toxicity events in the phase I portion. The record does not report the count itself, so no event rate, uncertainty interval, or dose-level conclusion can be stated. The population descriptions identify who was eligible for the endpoint, but do not supply its observed result.

What does a count endpoint describe?

A count endpoint records how many participants meet a defined event criterion. To interpret it, readers need both the number meeting the criterion and the relevant analysis population. The same count can have different implications in groups of different sizes, so the denominator matters. In this record, the endpoint population is described as 6 at Dose Level 1 and 3 at Dose Level 2. The endpoint event counts are absent, so a rate cannot be described or reconstructed.

The endpoint is also time-bounded: the registry specifies follow-up of up to 35 days. A count within that period should not be treated as a count over all subsequent treatment or follow-up. In general, a clearly defined observation window helps ensure the events being counted refer to the same period. It does not mean that later events could not occur; those are outside the stated timeframe for this endpoint.

How does the toxicity definition affect interpretation?

The registry's dose-limiting toxicity definition includes non-hematologic events graded 3 or higher and deemed at least possibly related to treatment, using NCI Common Terminology Criteria for Adverse Events version 4.0. A participant contributes to this endpoint only when an event meets the stated definition. This is why the primary endpoint should not be equated with every adverse event, every serious adverse event, or every laboratory abnormality. Those categories can overlap, but they are not interchangeable.

The maximum tolerated dose rule is described in relation to dose levels and the occurrence of qualifying toxicity. It is a decision rule tied to the endpoint, not a direct measure of efficacy. Because the dose-level endpoint counts are not reported, the rule cannot be applied to determine the study's dose-selection result. The registry's note that 6 participants treated at the maximum tolerated dose would be sufficient to identify common toxicities is part of the stated description; it does not establish that the endpoint results or dose decision are available.

Why does the single-group design matter?

In a randomized comparative study, treatment assignment is designed to support comparisons between groups. This record instead lists a single-group model, allocation as not applicable, and no masking. Thus, there is no randomized control group against which to estimate a treatment contrast. Phase I dose levels may help characterize dose-related safety, but the groups should not be treated as exchangeable arms in a controlled efficacy comparison. Differences across dose levels could reflect dose, participant characteristics, timing, or other factors, and this record does not provide a design basis for separating those possibilities.

Even a complete within-group outcome would answer a narrower question than a controlled treatment effect. It could describe outcomes among participants receiving the combination, subject to the endpoint definitions and analysis population. It could not determine what would have happened to comparable participants under another regimen or without this regimen. This distinction applies to the toxicity endpoint as well as the named secondary outcomes.

What do confidence intervals and over-dispersion mean in general?

In general, a confidence interval expresses the statistical uncertainty around an estimated quantity under a specified analysis. A narrower interval indicates greater precision under that method, while a wider interval indicates less precision. A confidence interval does not remove design limitations, correct missing results, or make groups comparable when randomization is absent. Since no observed primary endpoint count or interval is reported in the information available, no interval-based precision claim can be made for this endpoint.

In general, over-dispersion means that observed variation is greater than expected under a chosen probability model. It can make conventional uncertainty estimates too optimistic if the model does not account for that extra variation. This is a general statistical consideration rather than a reported feature of this trial. The registry record does not report an analysis model for the primary endpoint, and the endpoint result is not available to assess whether over-dispersion is relevant.

How should planning illustrations be read?

Sample-size calculations are planning tools. They describe the amount of information a hypothetical design might need under stated assumptions; they do not describe the number of participants who experienced an outcome or the power observed after a study. The calculation assumptions listed for planning illustrations include a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a fraction of an observed effect. Those are calculation assumptions, not evidence that the actual trial was designed or conducted that way.

This study is listed as single group and has no like-for-like control comparison in the registry record. Therefore, a two-arm illustration does not turn it into a comparative study. In general, planning figures also depend on the outcome, analysis method, target effect, and allocation. The registry record does not report a sample-size justification for this trial, so the planning assumptions should not be presented as the trial's own design rationale.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists multiple secondary outcomes, including biomarker analyses, duration of response, minimal-residual disease, overall response rate, and treatment-free survival. When a study assesses several outcomes or performs multiple statistical tests, the chance of at least one apparently notable finding can increase. In general, a prespecified multiplicity strategy can define how that issue is handled, for example by prioritizing outcomes or adjusting inference. The registry record does not report a multiplicity procedure or a statistical analysis plan, so it is not possible to determine whether or how multiple testing was addressed.

The record names the primary endpoint and gives its definition, timeframe, and phase I population, but it does not report the observed event count. It also does not provide the endpoint results for the named secondary outcomes in the information available. No inference about missing observations, exclusions beyond the stated endpoint eligibility detail, or imputation methods can be made from these omissions. The handling of missing outcome data is not reported in the registry record.

The endpoint population description states that only participants registered to the phase I portion were analyzed for the primary endpoint. It specifies 6 participants at Dose Level 1 and 3 at Dose Level 2, and says that one of the 4 accrued at Dose Level 2 was ineligible for this endpoint. This is a specific eligibility statement, not a complete account of all analysis populations or of how all exclusions were handled. The registry record does not report a broader intention-to-treat, per-protocol, or safety analysis population definition.

These gaps matter because the endpoint interpretation depends on who was counted, which events were included, and how unavailable observations were treated. Without the outcome values and analysis details, the reported design and definitions alone cannot establish the estimate, its uncertainty, or the robustness of any conclusion.

11. Safety Results

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

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: febrile neutropenia (25.0%), diarrhea (25.0%), sinusitis (25.0%), neutrophil count decreased (25.0%), tumor lysis syndrome (25.0%).

The serious adverse event figures are reported separately for the study groups. The record lists 2 of 6 participants affected in Phase I: Dose Level 1, 1 of 4 in Phase I: Dose Level 2, and 2 of 4 in Phase II. These are counts of participants with serious adverse events in each listed group. They are not counts of all events, and a participant may have experienced more than one event.

The registry also lists serious adverse event terms with a reported frequency of 25.0%: febrile neutropenia, diarrhea, sinusitis, neutrophil count decreased, tumor lysis syndrome, and renal and urinary disorders - Other, specify. These terms should be read as registry-reported safety information, not as a complete ranking of all possible harms. Event-specific counts and fuller details about timing and severity are not reported in the information available. Death counts are not reported in the registry record.

Serious adverse events are not synonymous with dose-limiting toxicities. The primary endpoint uses a particular severity, attribution, and event-type definition, while the safety figures describe serious events. The reported safety counts therefore cannot be substituted for the missing primary endpoint counts or used to infer the maximum tolerated dose.

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

The record establishes that the study evaluated a combination of MK-2206, bendamustine, and rituximab in a phase I/II setting for relapsed chronic lymphocytic leukemia or small lymphocytic lymphoma. It describes a phase I dose-limiting toxicity endpoint, the toxicity criteria, the follow-up period, and the endpoint-specific populations. It also identifies several secondary outcomes and reports serious adverse event information by group.

However, the primary endpoint's observed number of participants with dose-limiting toxicity is not reported in the registry record. Without that result, readers cannot determine the observed frequency of qualifying events at each dose level or apply the stated maximum tolerated dose rule. The named secondary outcomes are not accompanied by results in the information available, so they cannot establish how participants responded or how long any response lasted.

The study's single-group design is important to the meaning of any outcome. It does not include a randomized control group, and the dose levels are not a like-for-like comparator. The record can describe outcomes among participants receiving the combination, but cannot establish what the outcomes would have been under another treatment or separate the contribution of each drug in the combination. The available information therefore does not support a comparative treatment-effect conclusion.

The serious adverse event counts and terms are safety observations, not proof of overall safety or harm. They refer to the participants and events recorded for the study and do not establish how common the same events would be in a broader population. The serious-event category also differs from the primary dose-limiting toxicity definition.

In general, a study record is most informative when the outcome values, analysis population, missing-data handling, and statistical methods accompany the endpoint definitions. Several of those details are not reported in the registry record. The most defensible interpretation is therefore limited to the design, stated outcomes, and safety information recorded, without extending those details into efficacy or dose-selection claims.

13. Why This Trial Matters Statistically

This trial illustrates why early-phase toxicity endpoints need to be read in the context of their precise definitions. The primary outcome is not simply a count of any unwanted event: it applies a stated severity threshold, attribution condition, and event type. Those rules determine which events contribute to dose evaluation. Comparing this endpoint with broader serious adverse event summaries would mix distinct outcome definitions.

The record also shows why analysis populations need to be explicit. The primary endpoint population is described separately from the adverse-event group counts, including a Dose Level 2 participant who was not eligible for the endpoint. The endpoint-specific denominators and safety denominators should not be assumed to be identical. Careful reporting of eligibility, exclusions, and outcome counts is essential for interpreting a count endpoint.

Another statistical lesson is that study phase and design constrain the claims an analysis can support. A phase I dose evaluation and a phase II assessment may address different aims, but the single-group model does not provide a randomized comparator. Dose levels can inform safety characterization, while they do not automatically support causal efficacy comparisons. This distinction remains important even when a study has several planned outcome measures.

Finally, an outcome definition without its observed result is not enough to evaluate the result. The registry describes the dose-limiting toxicity criteria and the populations included, but the event counts are not reported in the information available. That absence prevents assessment of the endpoint's observed frequency, precision, or dose-selection implication. Statistical interpretation must distinguish between what a protocol or registry says was measured and what the recorded results actually show.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The primary limitation is that the registry record does not report the observed count for the primary dose-limiting toxicity endpoint. Although the timeframe, event definition, and endpoint population are described, the missing result prevents assessment of the endpoint itself and prevents application of the stated dose-selection rule.

The design is listed as single group, with no random allocation or masking. There is no separate randomized control group, so comparisons across phases or dose levels should not be treated as controlled estimates of treatment effect. The registry record does not provide a basis for separating the effects of the three-drug combination or attributing outcomes to one component.

The endpoint-specific population description and adverse-event group counts differ in their stated Dose Level 2 populations. The endpoint includes 3 participants at that level and notes that one of the 4 accrued was ineligible, while the adverse-event group lists 4. These descriptions concern different reporting contexts and should not be combined as if they were one analysis population.

The registry names secondary outcomes but does not report their observed values in the information available. It also does not report the statistical analysis plan, multiplicity approach, missing-data methods, or broader analysis-population definitions. Those details cannot be inferred from the endpoint description or study title. The adverse-event record includes serious-event counts and terms, but the full event-level context and death counts are not reported in the registry record.

Finally, the planning assumptions described for sample-size illustrations are not a reported justification for this trial. The single-group design does not match the hypothetical equal-allocation, two-arm calculation assumptions. The registry record therefore offers no basis for interpreting those planning calculations as the study's actual design rationale or as observed power.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Akt Inhibitor MK2206, Bendamustine Hydrochloride, and Rituximab in Treating Patients With Relapsed Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma — NCT01369849.
• Registry record last updated 2017-09-15; status last verified 2017-08.
• Results first posted 2016-06-28.
• 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

This completed phase I/II study evaluated MK-2206 with bendamustine and rituximab for relapsed chronic lymphocytic leukemia or small lymphocytic lymphoma. The registry lists a single-group design, no masking, and enrollment of 15. Its primary endpoint was the number of phase I participants reporting dose-limiting toxicity events during follow-up of up to 35 days.

The endpoint definition and endpoint-specific populations are described, but the observed dose-limiting toxicity count is not reported in the registry record. The record lists serious adverse event counts by group and names secondary outcomes, while results for those secondary outcomes are not included in the information available. No randomized comparator is described, and the analysis plan, multiplicity approach, and missing-data methods are not reported in the registry record.