Imprime PGG, Alemtuzumab, and Rituximab in Treating Patients With High Risk Chronic Lymphocytic Leukemia: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Imprime PGG, Alemtuzumab, and Rituximab in Treating Patients With High Risk Chronic Lymphocytic Leukemia (NCT01269385), a na phase 1, phase 2 study. The primary outcome is Maximum Tolerated Dose (MTD) of PGG Beta Glucan in Combination With Alemtuzumab and Rituximab Assessed by Analyzing the Number of Dose-limiting Toxicity Events (Phase I).

2. Clinical Question

The trial also set out to study side effects and the best dose of PGG beta-glucan with the two monoclonal antibodies, and to assess activity in earlier-stage, high-risk chronic lymphocytic leukemia. The listed secondary outcomes include overall response rate at dose level 2, time to disease progression, duration of response among evaluable patients with an objective response, time to subsequent therapy, and participants with grade 3 or higher adverse events. Results for these outcomes are not reported in the registry record. Consequently, the record supports describing the question and study structure, but not drawing a conclusion about response, disease control, or the chosen dose.

3. Trial Design

NCT01269385 is a completed phase I/II study sponsored by Mayo Clinic. The registry lists a planned enrollment of 22 participants. The trial started in 2011-01 and reached primary completion in 2014-06. Its design is recorded as single-group, with no masking and allocation not applicable. There is no concurrent untreated group or randomized comparator; the different dose levels represent treatment cohorts in the dose-finding portion.

Participants received PGG beta-glucan, alemtuzumab, and rituximab. The described regimen gave PGG beta-glucan intravenously over 2-4 hours on days 1, 5, 10, 17, 24, and 31; alemtuzumab subcutaneously on days 3, 4, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26, 29, 31, and 33; and rituximab intravenously on days 10, 17, 24, and 31. The registry description says treatment continued in the absence of disease progression or unacceptable toxicity, but the recorded text ends before that description is complete.

The phase I primary endpoint concerned the maximum tolerated dose of PGG beta-glucan in combination with the other agents. Toxicity for this decision was assessed during the first cycle, defined as 35 days. The record describes an escalation rule based on cohorts of three and a maximum of six patients at a dose level. The phase II outcomes include response and time-to-event measures. The registry lists seven outcome measures in total, but reports no analysis entries. No randomization-based treatment contrast can be inferred from this design, and the registry record does not report a control comparison.

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: All Phase I patients that were eligible and completed cycle 1 treatment were used in the MTD assessment.

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 were included in primary and secondary analyses were included in baseline information.

6. Primary Endpoint

The registry lists the primary outcome as Maximum Tolerated Dose (MTD) of PGG Beta Glucan in Combination With Alemtuzumab and Rituximab Assessed by Analyzing the Number of Dose-limiting Toxicity Events (Phase I), measured over First cycle of treatment (35 days).

The primary endpoint is the maximum tolerated dose (MTD) of PGG beta-glucan combined with alemtuzumab and rituximab, assessed by counting participants with dose-limiting toxicity (DLT). The assessment timeframe is the first treatment cycle, defined as 35 days. The endpoint population is eligible phase I patients who completed cycle 1 treatment.

The registry defines the MTD as the dose level below the lowest dose that induces DLT in at least one-third of patients, described as at least 2 of a maximum of 6 new patients. It also describes treating three patients at a dose level for at least 5 weeks to assess toxicity. If no DLT occurs among those three patients, three new patients are accrued and treated at the next higher dose level. If DLT occurs in 2 or 3 of three patients at a dose level, the next three patients are treated at the next lower dose level, if only three patients had been enrolled and treated there. The record says the number of patients reporting a DLT is tabulated.

This endpoint is used in early dose-finding because a regimen needs a tolerability-based dose decision before later-stage outcomes such as response can be interpreted at a selected dose. The rule is a protocol decision procedure, not evidence that a dose has a particular level of safety. The actual DLT counts and the selected MTD are not reported in the registry record, so the endpoint result cannot be stated.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

How does the dose-finding rule work?

The primary analysis is based on counting participants with dose-limiting toxicity during the first 35-day cycle. The registry describes a cohort-based escalation procedure. Three patients are treated at a dose level for at least 5 weeks for toxicity assessment. If none has a DLT, three new patients are treated at the next higher dose level. If 2 or 3 of three patients have a DLT, the next three patients are treated at the next lower dose level, when only three patients had previously been treated at that lower level. The record defines the MTD as the dose below the lowest dose inducing DLT in at least one-third of patients, expressed as at least 2 of a maximum of 6 new patients.

This is a decision rule for assigning subsequent treatment cohorts. It is not a randomized experiment and does not, by itself, estimate a causal effect of dose. The dose levels are observed in a sequence governed by earlier toxicity findings, so later cohorts are not necessarily comparable with earlier cohorts. The DLT counts needed to follow the rule to its conclusion are not reported in the registry record. Thus the rule can be explained, but its outcome cannot be reconstructed.

What do participant counts represent?

The primary endpoint is a binary participant-level outcome: whether an eligible phase I participant completing cycle 1 experienced a DLT. For such an outcome, counts identify how many participants had an event among those assessed. They do not describe the number of events if a participant can experience more than one event, and they do not supply an event rate unless the relevant denominator is also specified. The registry specifies the intended primary population but does not report the DLT numerators or the number assessed at each dose level.

The adverse-event figures use participants at risk and participants affected, reported separately for serious and other adverse events. Those counts should be read as participant counts in each dose-level group. The categories are not interchangeable with the primary DLT outcome. Seriousness describes an adverse event classification; DLT is a protocol-defined role in a dose decision. The registry record does not provide a mapping between the serious adverse events and DLT status.

Why does the single-group design matter?

A single-group study can describe events among people receiving the regimen and can implement a dose-escalation rule. It cannot provide a direct randomized estimate of how outcomes differ from a control regimen. In a dose-finding study, dose groups are also formed through the escalation process rather than through random assignment. Any apparent differences in counts between levels should therefore be read descriptively, not as a controlled comparison. The record identifies allocation as not applicable and masking as none.

General statistical explanation: randomization helps balance measured and unmeasured prognostic factors between treatment groups on average. Without a randomized comparator, differences in patient characteristics, timing, or other factors can contribute to observed differences. This concern applies even when counts are presented side by side; displaying multiple groups does not create a controlled comparison.

What does uncertainty mean for small event counts?

General statistical explanation: an estimate from a small number of participants has sampling uncertainty because a different set of participants could yield a different count. A confidence interval describes a range of values compatible with the observed data under the chosen method and assumptions. Wider intervals indicate less precision. Counts near zero may be especially difficult to interpret as estimates of the underlying event frequency, because a low observed count does not establish that the event cannot occur. No confidence intervals or other uncertainty estimates for the adverse-event counts are reported in the registry record.

Over-dispersion is a general concern when event counts vary more than an assumed statistical model expects. A model that assumes less variation than the data actually contain can understate uncertainty. The registry record does not report a count model, over-dispersion assessment, or inferential analysis for the primary or safety outcomes, so no claim about such modeling can be made for this trial.

How should the secondary outcomes be understood?

The listed secondary outcomes include overall response rate at dose level 2, time to disease progression, duration of response among evaluable participants who achieved an objective response, time to subsequent therapy, and participants with grade 3 or higher adverse events. These outcomes answer different questions. Response rate is a binary outcome; time to progression, response duration, and time to subsequent therapy concern elapsed time until an event. A time-to-event analysis generally needs to account for participants who have not experienced the event by the end of observation, often called censoring. The registry record does not report the event counts, follow-up summaries, censoring details, analysis methods, or estimates for these outcomes.

The record lists seven outcome measures and zero analysis entries. A sample-size planning illustration is described in the record as using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the target effect defined as a stated fraction of the observed effect. For time-to-event outcomes, the stated planning quantity is total events; for other outcomes, it is participants per arm. These are planning assumptions, not evidence that the trial enrolled a randomized two-arm comparison, and no specific sample-size outputs are reported in the registry record. Any such planning values are not observed power. A planning calculation cannot replace the unreported outcome estimates or establish what the trial observed.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Phase I: Dose Level 0", "Phase I: Dose Level 1", "Phase I: Dose Level 2")
n      <- c(3, 3, 6)
events <- c(0, 0, 1)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Phase I: Dose Level 0  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Phase I: Dose Level 1  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Phase I: Dose Level 2  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9

11. Multiplicity, Missing Data and Analysis Populations

The registry lists seven outcome measures, including a phase I dose-finding endpoint and secondary outcomes covering response, disease progression, response duration, subsequent therapy, and adverse events. When a study examines multiple outcomes, the possibility of chance findings increases if many results are tested without an appropriate plan. General statistical practice may address this through a prespecified hierarchy, adjustment, or a clear distinction between primary and exploratory questions. The multiplicity strategy for this trial is not reported in the registry record. No analysis entries are listed, and results for the secondary outcomes are not reported in the registry record.

The registry specifies the primary endpoint population as eligible phase I patients who completed cycle 1 treatment. That description indicates that completing cycle 1 was part of the MTD assessment population; it does not provide a participant flow or explain how many people were eligible, completed the cycle, or were omitted from the analysis. Missing-data rules, reasons for missing observations, and sensitivity analyses are not reported in the registry record. The analysis populations for the phase II outcomes are also not reported in the registry record.

These omissions matter because the interpretation of a participant count depends on who was included and how incomplete observation was handled. For a toxicity endpoint, excluding participants who did not complete the assessment period could affect the count if the reasons for non-completion are related to toxicity. This is a general methodological concern, not evidence that such exclusions occurred in this trial. The record does not describe whether incomplete cycle 1 observations were counted, imputed, or otherwise addressed.

Likewise, time-to-event outcomes require information about follow-up and participants whose event status is not known at the end of observation. The handling of censoring and loss to follow-up is not reported in the registry record. There is no basis in the record to infer the analysis plan, interim analyses, missingness assumptions, or sample-size justification. Without these details and the endpoint results, statistical precision and robustness cannot be evaluated.

12. 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: urticaria (25.0%), diarrhea (14.3%), febrile neutropenia (7.1%), gastritis (7.1%), fever (7.1%).

The registry reports serious and other adverse-event participant counts separately for dose levels 0, 1, and 2. Serious adverse events affected 0 of 4 participants at dose level 0, 1 of 4 at dose level 1, and 4 of 14 at dose level 2. Other adverse events affected 4 of 4, 4 of 4, and 14 of 14 participants, respectively. The recorded number of deaths is 0 at each dose level. These are descriptive counts within the listed groups, not comparisons against a control group.

The registry also identifies selected serious-event terms and percentages: urticaria, 25.0%; diarrhea, 14.3%; febrile neutropenia, 7.1%; gastritis, 7.1%; fever, 7.1%; and dehydration, 7.1%. These are the posted values for those terms. The record does not provide enough detail to determine whether participants could contribute more than one term, how events were attributed to treatment, or the observation duration for each participant. The percentages should not be treated as evidence that the listed events were caused by the regimen.

Serious adverse events are not synonymous with dose-limiting toxicities. The DLT assessment was the primary dose-finding endpoint, but its counts are not reported in the registry record. The serious-event figures therefore cannot be substituted for the missing DLT results or used to identify the MTD. With no randomized control group and no reported uncertainty intervals, these values describe the recorded groups without establishing comparative risk or a precise underlying event frequency.

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

The record establishes that a phase I/II, single-group trial enrolled 22 participants and evaluated a combination of PGG beta-glucan, alemtuzumab, and rituximab in high-risk chronic lymphocytic leukemia. Its primary phase I question was dose-finding: identify the MTD through DLT assessment during the first 35-day cycle. The record explains a cohort-based decision rule, but it does not report the DLT counts or the resulting MTD. The available registry information therefore does not establish which dose met the study’s MTD criterion.

The adverse-event counts show how many participants in the listed dose-level groups were recorded as having serious or other adverse events, along with selected serious-event terms and death counts. They do not establish that the combination caused those events, because the record does not provide a control group or a causal comparison. They also do not answer the primary endpoint, because serious adverse events and DLTs are different classifications unless the protocol explicitly treats a given event as a DLT; such a mapping is not reported in the registry record.

The record lists response and time-to-event outcomes, but their results are not reported in the registry record. No response estimate, progression estimate, response-duration estimate, or time-to-subsequent-therapy result can be stated from the listed information. The presence of an outcome in a registry does not mean that its numerical result is available or that a particular result was observed.

General statistical explanation: an observed count is a description of a particular group. An estimate of a broader event frequency requires consideration of uncertainty, and a treatment effect requires a suitable comparison and analysis. Neither a planning illustration nor a dose-level count is a substitute for such an estimate. The trial’s posted information should therefore be read as a description of study design and recorded adverse-event counts, with the principal efficacy and dose-finding results unavailable in the registry record. It does not support a conclusion about treatment benefit, lack of benefit, or comparative safety.

14. Why This Trial Matters Statistically

This trial is statistically notable because its primary question is about dose selection rather than a randomized comparison of treatment effects. In a phase I dose-finding study, toxicity observations determine whether additional participants are treated at a higher or lower dose. That sequence makes the dose cohorts part of a decision process. It also means that counts across dose levels should not be interpreted as though participants had been randomly assigned to comparable groups.

The endpoint definition matters as well. The primary outcome is not simply any adverse event: it is the MTD assessed through DLT counts in a specified population and timeframe. The record describes a threshold rule that uses cohorts of three and a maximum of six new patients, with the first cycle defined as 35 days. Keeping this endpoint separate from general serious-event reporting is essential. The adverse-event counts alone cannot reconstruct the MTD decision.

The registry information also illustrates the difference between a registered outcome and a reported result. The record names response and time-to-event outcomes, but does not provide their estimates, analysis methods, or uncertainty measures. Without those results, readers cannot evaluate the precision of the outcomes or compare them with another treatment. A sample-size planning illustration, even when available, would describe planning assumptions rather than observed power or a trial result.

More broadly, a transparent dose-finding record would allow readers to see the actual DLT counts by dose, the population included in each assessment, and the rule’s resulting dose decision. Those results are not reported in the registry record. What remains interpretable is the study’s design, its stated endpoint, and the adverse-event counts recorded by dose level. Distinguishing those descriptive details from unreported inferential claims is the central statistical lesson of this trial.

15. Limitations

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

The main trial-specific limitation is that the registry record does not report the primary endpoint result. It describes the DLT decision rule and assessment period, but not the number of DLTs by dose level or the resulting MTD. This prevents assessment of whether the planned dose-finding rule selected a dose and how the observed toxicity pattern informed that selection.

The study is recorded as single-group, with no masking and allocation not applicable. There is no randomized control comparison in the record, so adverse-event counts across the dose levels cannot establish a comparative treatment effect. The dose cohorts arise within a dose-finding design and may not be directly comparable. The record also does not report participant characteristics by dose level that could help readers understand cohort composition.

Although the registry reports serious and other adverse-event counts, it does not report uncertainty intervals, event attribution details, observation time by group, or the relationship between serious events and DLT classification. The listed percentages for selected serious-event terms are descriptive and should not be treated as causal estimates. The registry’s zero death counts do not establish that the risk of death is absent.

Results for the listed response and time-to-event outcomes are not reported in the registry record. Nor are the statistical analysis plan, multiplicity approach, interim analyses, missing-data handling, or sample-size justification reported in the registry record. The primary endpoint population is described as eligible phase I patients who completed cycle 1, but participant flow and the handling of those who did not complete the cycle are not given. The regimen description itself ends mid-sentence, leaving the full treatment continuation details not reported in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Imprime PGG, Alemtuzumab, and Rituximab in Treating Patients With High Risk Chronic Lymphocytic Leukemia — NCT01269385.
• Registry record last updated 2020-06-23; status last verified 2018-08.
• Results first posted 2020-06-23.
• 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.

19. Record Summary

NCT01269385 is a completed phase I/II, single-group trial sponsored by Mayo Clinic. It enrolled 22 participants and studied PGG beta-glucan with alemtuzumab and rituximab in high-risk chronic lymphocytic leukemia. The primary phase I endpoint was the maximum tolerated dose, assessed through participant counts for dose-limiting toxicity during the first 35-day cycle among eligible phase I patients who completed cycle 1.

The registry describes a cohort-based dose-escalation rule and records adverse-event counts for dose levels 0, 1, and 2, including serious events, other events, and deaths. The DLT counts and selected MTD are not reported in the registry record. Results for the listed response and time-to-event outcomes are also not reported in the registry record. The single-group design does not provide a randomized control comparison; the available event counts are descriptive rather than comparative.