Agatolimod Sodium, Rituximab, and Yttrium Y 90 Ibritumomab Tiuxetan in Treating Patients With Recurrent or Refractory Non-Hodgkin Lymphoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Agatolimod Sodium, Rituximab, and Yttrium Y 90 Ibritumomab Tiuxetan in Treating Patients With Recurrent or Refractory Non-Hodgkin Lymphoma (NCT00438880), a na phase 1, phase 2 study. The primary outcome is Maximum Tolerated Dose of CpG 7909 as Determined Using the Number of Participants With a DLT at Each Dose Level.

2. Clinical Question

The clinical rationale in the record proposes that the biological therapy, antibody treatment, and radiolabeled antibody might act through different mechanisms against cancer cells. That rationale explains why the combination was studied; it is not itself evidence about outcomes. The primary question is narrower: whether dose-limiting toxicities occurred during observation after CpG 7909 at the planned dose levels, and which dose would meet the stated rule for the maximum tolerated dose.

For the primary dose-finding question, only participants accrued to the Phase I portion were used. The registry says participants were observed for at least 10 weeks post treatment, with the primary endpoint timeframe extending up to 3 months. The study also lists progression-free survival and duration of response as secondary outcomes. Their definitions, analysis results, and estimates are not reported in the registry record, so those outcomes cannot resolve the clinical question from the information recorded.

3. Trial Design

This was a Phase I/II, single-group trial sponsored by Mayo Clinic. Its status is completed. The registry records enrollment of 38 and lists the study start as 2004-10 and primary completion as 2010-10. Allocation is recorded as NA, and masking is listed as none. These features mean the design was not a randomized, masked comparison of the combination against a separate control treatment.

The registered treatment combined agatolimod sodium, rituximab, and yttrium Y 90 ibritumomab tiuxetan. The intervention list also includes indium In-111 ibritumomab tiuxetan, imaging procedures, and laboratory biomarker analysis. The arm description identifies Arm I but gives only See Detailed Description; the registry record does not report a fuller arm regimen in the registry record for this analysis.

The Phase I portion used cohorts of 6 participants at each CpG 7909 dose level: 0.08 mg/kg, 0.16 mg/kg, 0.32 mg/kg, and 0.48 mg/kg. Participants were observed for at least 10 weeks post treatment. Under the stated escalation rule, if at most one of the 6 participants experienced a dose-limiting toxicity, a new cohort of 6 would be treated at the next higher dose. The registry defines the maximum tolerated dose as 0.48 mg/kg or the largest dose level where 1 or fewer participants reports a dose-limiting toxicity.

The primary endpoint was evaluated using participants accrued to Phase I only. The adverse-event record separately gives Phase I and Phase II counts, but these do not substitute for the unreported dose-level counts for the primary endpoint. The registry lists progression-free survival and duration of response as secondary outcomes. Their reported results, analysis methods, and the relationship between the Phase I and Phase II treatment procedures are not reported in the registry record.

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

Analysis population for the primary outcome, as defined in the registry: Only participants accrued to the Phase I portion of this study were used to determine the maximum tolerated dose.

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 participants accrued to this study were analyzed for baseline characteristics

6. Primary Endpoint

The registry lists the primary outcome as Maximum Tolerated Dose of CpG 7909 as Determined Using the Number of Participants With a DLT at Each Dose Level, measured over at least 10 weeks post treatment up to 3 months..

The primary endpoint is the number of participants with a dose-limiting toxicity at each CpG 7909 dose level, used to determine the maximum tolerated dose. The registry describes observing participants for at least 10 weeks post treatment, with the endpoint timeframe stated as at least 10 weeks post treatment up to 3 months. Only participants accrued to the Phase I portion were used for this dose-finding determination.

The registry defines dose-limiting toxicity through blood-count thresholds and non-hematologic toxicity. The stated criteria include absolute neutrophil counts or platelet counts below 10*10^9/L for 14 days; absolute neutrophil counts greater than 0.5 or less than 1*10^9/L; platelet counts greater than 10 or less than 50*10^9/L for 28 days; and any grade 3 non-hematologic toxicity not explainable by another obvious cause, assessed using CTCAE v3.0. The wording of the neutrophil criterion is not clarified in the record, so it should not be silently reinterpreted.

In general, a dose-limiting toxicity endpoint helps identify dose levels at which treatment-related toxicity becomes unacceptable under a study's prespecified rule. It is used in dose-finding because the purpose is to characterize tolerability across planned dose levels, rather than to compare treatment effects against a control group. The record's stated rule uses the observed number of participants with a DLT at each dose. However, those dose-level counts and the resulting maximum tolerated dose are not reported in the registry record. Therefore, the endpoint's definition is available, but the primary result cannot be read from the posted record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies the design as single-group, with allocation recorded as NA and masking as none. In general, a single-group study describes outcomes among people receiving the study treatment without a concurrent randomized control group. Its descriptive results can characterize what was recorded in that group, but cannot by themselves separate treatment effects from the course of disease, other care, or differences in who entered the study. The design therefore does not support a randomized between-treatment estimate.

How does the dose-finding rule work?

The Phase I procedure organizes participants into cohorts at planned CpG 7909 dose levels. The record specifies dose levels of 0.08 mg/kg, 0.16 mg/kg, 0.32 mg/kg, and 0.48 mg/kg, with cohorts of 6 participants. The rule says that if at most one of the 6 participants experiences a DLT, a new cohort is treated at the next higher dose. The record defines the maximum tolerated dose as 0.48 mg/kg or the largest dose level where 1 or fewer participants reports a DLT.

In general, such a rule translates observed toxicity counts into a dose-escalation decision. It is not an estimate of comparative efficacy. The interpretation depends on complete dose-specific counts and consistent application of the DLT definition during the specified observation period. The registry does not report those dose-specific counts, the actual escalation path, or the dose selected. The rule can therefore be explained, but its outcome cannot be reconstructed from the posted record.

What do the endpoint counts represent?

The primary outcome is a number of participants with a DLT at each dose level. Counts are directly interpretable as observed events under the endpoint definition, but they do not convey precision by themselves. In general, an uncertainty interval around a proportion can show how compatible the observed data are with a range of underlying event rates. No such dose-level proportions or intervals are reported in the registry record, and no interval can be stated without the relevant observations.

The DLT definition combines blood-count criteria with a grade 3 non-hematologic toxicity not explainable by another obvious cause, assessed using CTCAE v3.0. The record's neutrophil criterion reads absolute neutrophil counts greater than 0.5 or less than 1*10^9/L; that wording may be ambiguous, and the registry does not clarify it. A statistical interpretation should preserve the recorded definition rather than assume an intended threshold.

How should adverse-event counts be read?

The adverse-event summary separates participants affected by serious events from those affected by other events, and reports Phase I and Phase II separately. The at-risk and affected counts are descriptive. They do not tell whether events were caused by the study treatment, whether a participant had one or multiple events, or whether the event met the primary DLT definition. The serious-event term percentages are listed in the registry, but the registry entries do not provide dose-level breakdowns or further details needed to interpret severity, timing, or attribution. General statistical practice distinguishes participant-level incidence from event counts; the posted counts are expressed as participants affected.

What analysis information is absent?

The registry record does not report a statistical analysis plan, inferential model, confidence intervals, or dose-level DLT results. It lists 4 outcome measures and no analyses. The record does not report whether interim analyses were performed, how missing outcome data were handled, or how secondary outcomes were analyzed. These omissions mean there is no basis for describing an adjusted analysis or a formal hypothesis test for the primary endpoint.

Progression-free survival and duration of response are listed as secondary outcomes. In general, time-to-event outcomes require clear definitions of the event, the time origin, censoring rules, and methods for handling incomplete follow-up. Those details and the outcome results are not reported in the registry record. No interpretation of event-time estimates or precision is therefore possible from these registry entries.

Any planning illustration based on an observed effect should not be confused with observed power or with the original study's design justification. The registry record does not report a sample-size justification. General sample-size calculations depend on their assumptions, including the target effect and allocation. The record's planning assumptions describe a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect stated as a fraction of the observed effect. Those assumptions are not evidence that this single-group trial was planned or analyzed as a two-arm comparison. The record does not report a trial-specific justification or an observed-power analysis.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 4 outcome measures, including the primary dose-limiting toxicity endpoint and the secondary outcomes progression-free survival and duration of response. It reports no analyses. A multiplicity strategy—how to control the chance of misleading findings when several outcomes or comparisons are examined—is not reported in the registry record. No adjustment method, outcome hierarchy beyond the primary and secondary labels, or prespecified testing sequence is available in the record.

Missing-data handling is also not reported in the registry record. The registry entries do not say how participants with incomplete toxicity observation were treated, how missing follow-up affected the secondary outcomes, or whether any participants were excluded from particular analyses. The primary endpoint specifies observation for at least 10 weeks post treatment, but the record does not state how deviations from that observation period were handled.

The primary endpoint population is described as participants accrued to the Phase I portion, who were used to determine the maximum tolerated dose. That is the only explicit analysis-population detail in the record. The registry does not report the membership or analysis rules for the Phase II population, nor whether all enrolled participants contributed to each secondary outcome. A statement that the study enrolled 38 does not identify how many were assessed for a given endpoint.

The record does not describe interim analyses, stopping rules beyond the dose-escalation rule, or a statistical plan for inferential testing. The dose-escalation rule is a design procedure and should not be mistaken for a reported analysis of the observed outcomes. Without dose-level counts and analysis details, readers cannot assess whether the final dose selection followed the stated rule or how missingness and multiple outcomes may have influenced interpretation.

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: platelet count decreased (50.0%), neutrophil count decreased (33.3%), leukocyte count decreased (23.3%), constipation (12.5%), tumor pain (12.5%).

The adverse-event record reports Phase I and Phase II separately. In Phase I, 14 of 30 participants at risk were affected by serious adverse events, and 30 of 30 were affected by other adverse events. In Phase II, 5 of 8 participants at risk were affected by serious adverse events, and 8 of 8 were affected by other adverse events. These are participant counts, not counts of all individual events.

The registry also lists serious adverse-event terms with percentages: platelet count decreased, 50.0%; neutrophil count decreased, 33.3%; leukocyte count decreased, 23.3%; constipation, 12.5%; tumor pain, 12.5%; and febrile neutropenia, 3.3%. The record does not provide further detail in the registry record about the attribution of these events to treatment, their timing, or their overlap with the DLT criteria. The percentages should therefore be read as reported terms, not as proof of causation or as dose-specific risks.

Serious adverse events are not interchangeable with dose-limiting toxicities: the primary endpoint uses its own criteria and observation window. The registry does not report death counts. These safety figures describe what the record lists, but do not provide a controlled comparison or establish the relative safety of another treatment.

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

The record establishes that a Phase I/II single-group study of agatolimod sodium with rituximab and yttrium Y 90 ibritumomab tiuxetan was conducted in previously treated CD20+ non-Hodgkin lymphoma. It gives the intended Phase I dose levels, cohort rule, DLT definition, and a summary of adverse events by phase. Those details help explain the trial's design and the kind of safety information it was set up to collect.

The primary result is not available in the registry record. Specifically, the number of participants with a DLT at each CpG 7909 dose level and the maximum tolerated dose determined from those counts are not reported. A completed status and a planned escalation rule do not reveal the observed results. The secondary outcomes, progression-free survival and duration of response, are also listed without results or analysis details in the record.

Accordingly, the posted information does not quantify the combination's effect on lymphoma outcomes, establish whether the treatment improved outcomes, or determine how it compared with another regimen. The study has no randomized comparator in the registered design, so the adverse-event summaries are descriptive rather than comparative. They also cannot be used as a substitute for the missing dose-specific DLT data.

General statistical interpretation distinguishes the existence of a study from the evidence available to answer its questions. Here, the registry describes how the primary endpoint was intended to be measured, but does not give the observed endpoint values. Without those values, neither the dose-finding conclusion nor its precision can be assessed. The adverse-event figures can be reported as recorded, with caution about attribution and definitions, but they do not fill that gap.

13. Why This Trial Matters Statistically

This trial is statistically notable for making the Phase I dose-finding question explicit. The registry states the CpG 7909 dose levels, cohort size, observation period, DLT criteria, and the rule for moving to a higher dose. Those elements show how an early-phase study can turn toxicity observations into a dose-selection decision. They also clarify which observations would be needed to evaluate whether the registered rule was followed.

The record also illustrates why an endpoint definition and an endpoint result are different kinds of information. The primary endpoint is described in detail, yet the dose-level counts needed to apply the rule are not reported. The maximum tolerated dose therefore cannot be inferred from the protocol description or from general adverse-event totals. This distinction is important when reading registry entries: a clearly specified outcome does not guarantee that its observed values are posted.

The single-group design shapes the limits of interpretation. It can describe the participants and events recorded in the study, but it does not create a randomized control contrast. The Phase I and Phase II adverse-event summaries are separated by phase, but this separation does not make them like-for-like treatment groups or provide a causal comparison.

Finally, the record identifies secondary outcomes but does not provide their results or analysis methods. This makes transparent reporting particularly important for understanding both the dose-finding outcome and the broader clinical questions. For statisticians and clinical researchers, the case underscores the value of complete outcome reporting, explicit analysis populations, and clear descriptions of missing-data and multiplicity procedures.

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 central limitation is that the registry record does not report the primary dose-level DLT counts or the resulting maximum tolerated dose. Without these values, the main Phase I decision cannot be checked against the stated rule. The record also does not identify the number actually assessed at each dose level, the escalation path, or whether every planned dose level was reached.

The DLT criteria are listed, but the neutrophil threshold wording—absolute neutrophil counts greater than 0.5 or less than 1*10^9/L—is not clarified. The registry entries also do not specify how a participant was classified if several criteria occurred, or how deviations from the observation period were handled. These details matter for reproducibility, but are not reported in the registry record.

The study is single-group, with no randomized comparator. Therefore, the adverse-event summaries cannot show comparative risk, and no causal treatment contrast can be estimated from this design. The record does not report attribution detail for the serious adverse events or death counts. It also does not provide dose-specific safety summaries that could be aligned with the primary endpoint.

Progression-free survival and duration of response are listed as secondary outcomes, but their outcome definitions, results, uncertainty estimates, and analysis methods are not reported in the registry record. The registry does not report a statistical analysis plan, missing-data procedures, a multiplicity strategy, or a sample-size justification. Enrollment and completion dates describe the study record but do not resolve these reporting gaps. These limitations restrict interpretation to the design and descriptive adverse-event information that is actually recorded.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Agatolimod Sodium, Rituximab, and Yttrium Y 90 Ibritumomab Tiuxetan in Treating Patients With Recurrent or Refractory Non-Hodgkin Lymphoma — NCT00438880.
• Registry record last updated 2016-02-04; status last verified 2015-09.
• Results first posted 2014-09-01.
• 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

The registry record describes NCT00438880, a completed Phase I/II, single-group study sponsored by Mayo Clinic. It lists enrollment of 38, a start date of 2004-10, and primary completion in 2010-10. The study examined agatolimod sodium with rituximab and yttrium Y 90 ibritumomab tiuxetan in previously treated CD20+ non-Hodgkin lymphoma.

The primary endpoint was the number of participants with a DLT at each CpG 7909 dose level, used to determine the maximum tolerated dose. The record gives the dose levels and escalation rule but does not report dose-level DLT counts or the selected dose. Progression-free survival and duration of response are listed as secondary outcomes without results in the registry record.

Adverse-event summaries are given separately for Phase I and Phase II, along with listed serious-event terms. These figures are descriptive and do not provide a randomized comparison. Analysis methods, missing-data procedures, multiplicity handling, and the primary dose-finding result are not reported in the registry record.