Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12D Variant of Mutated RAS in HLA-A*11:01 Patients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12D Variant of Mutated RAS in HLA-A*11:01 Patients (NCT03745326), a non-randomized phase 1, phase 2 study. The primary outcome is Phase I: Number of Grades 1, 2, 3, 4, and/or 5 and Type of Serious and/or Non-serious Toxicities Experienced by Participants at Each Dose Level.

2. Clinical Question

The underlying clinical question is whether administration of these modified cells can be undertaken while characterizing toxicities across dose levels in this population. This is an early-phase investigation, and the registry’s primary outcome is oriented toward safety description. It does not set up a randomized efficacy comparison, nor does the posted information establish that differences between dose groups represent treatment effects. The small enrollment recorded in the registry further means that the estimates and event descriptions should be read as limited observations rather than precise population-level rates.

3. Trial Design

The registry describes NCT03745326 as a Phase I/II study with non-randomized allocation, no masking, and a sequential model. The sponsor is the National Cancer Institute. Enrollment is recorded as 5. The study began on 2019-05-16, its primary completion date is listed as 2022-08-23, and its status is terminated. These administrative details do not explain why the study was terminated; that reason is not reported in the registry record.

The Phase I arm was organized by escalating cell-dose levels, with a non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine followed by the modified cells. The Phase II description divides participants into cohorts according to pancreatic cancer diagnosis or another diagnosis and refers to the maximum tolerated dose. The Phase I and Phase II portions therefore have different roles in the stated design, but the available record does not give further detail about the sequential decision rules or how participants moved between stages.

The brief summary describes screening, leukapheresis, preparative chemotherapy, cell administration, supportive medication, inpatient recovery, and follow-up. It describes assessment by medical history, examination, scans, photography, and heart, lung, and laboratory tests. These are protocol descriptions, not evidence that every listed procedure or treatment was received by every enrolled participant. The registry record does not report a randomized control group or masking, so observed outcomes cannot be interpreted as a blinded, randomized contrast.

The registry lists five outcome measures and no analysis records. It does not report a statistical analysis plan, sample-size justification, interim analysis procedures, or dose-escalation decision criteria. The sample-size illustrations associated with the posted results are planning exercises based on an observed effect, not the original trial’s design rationale and not observed power. Since the study is non-randomized, comparisons among its dose levels remain descriptive and potentially affected by differences in who entered each level and when.

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.

Before assignment: No participants were enrolled on Arm 2/Phase 2 because the study was closed due to lack of accrual and the study outcomes overlapped with another protocol's eligibility. Participants did not complete Phase 1; therefore Phase 2 did not start.

Received KRAS PBLs -1x10^8 Total Cells

Received KRAS PBLs - 3x10^8 Total Cells

Received KRAS PBLs -1x10^9 Total Cells

Received KRAS PBLs - 3x10^9 Total Cells

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: No participants were enrolled on Arm 2/Phase 2 because the study was closed due to lack of accrual and the study outcomes overlapped with another protocol's eligibility. Participants did not complete Phase 1; therefore Phase 2 did not start.

6. Primary Endpoint

The registry lists the primary outcome as Phase I: Number of Grades 1, 2, 3, 4, and/or 5 and Type of Serious and/or Non-serious Toxicities Experienced by Participants at Each Dose Level, measured over from the start of cyclophosphamide, through the first follow-up evaluation (6 weeks [± 2 weeks]) following administration of the cell product) until off study, whichever comes first, an average of 2.3 months.

The primary endpoint counts the number and type of serious and non-serious toxicities at each Phase I dose level, classified by severity grade. The registry states that toxicity assessment used CTCAE v5.0. It defines grades as mild, moderate, severe, life-threatening, and death related to an adverse event. A serious adverse event is defined by outcomes such as death, life-threatening experience, hospitalization, disruption of normal life functions, congenital anomaly or birth defect, or an important medical event that may require intervention to prevent such outcomes.

A toxicity count is useful in early-phase research because it describes the range and severity of harmful events observed during treatment and follow-up. Reporting by dose level can help characterize the safety experience at the administered levels. However, counts alone do not convey how long participants were observed, whether events were related to the cell product or other parts of the regimen, or how precisely an event rate is estimated. The record’s timeframe runs from the start of cyclophosphamide through the first follow-up evaluation, described as 6 weeks [± 2 weeks] after cell administration, or until off study, whichever came first; the listed average is 2.3 months.

The primary endpoint is not a tumor-response measure. Although the brief summary mentions tumor shrinkage as an objective, numerical results for that objective are not reported in the registry record. The registry entries also do not give numerical primary-endpoint counts broken down by grade and toxicity type. Thus the endpoint definition can be interpreted, but its complete results cannot be reconstructed from the registry information available.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies the primary outcome as a count: the number of toxicities of specified grades and types, separated by dose level. A count outcome records how many events occur, rather than measuring a continuous quantity such as weight or a time-to-event outcome such as survival time. Count data can be summarized with event totals, affected-participant counts, and rates when an appropriate exposure denominator is available. Here, the registry includes group counts at risk and affected for serious and non-serious events, but it does not provide the full primary endpoint count by grade and type.

What does a count tell the reader?

A count is a direct description of observed events, but it is not automatically an event rate. A participant may experience more than one event, and a count of events is not the same as a count of participants with at least one event. The primary endpoint wording refers to the number of toxicities, whereas the adverse-event summary also reports how many participants were affected. Those are related but distinct summaries. The posted safety figures should not be treated as interchangeable measures of events and people.

For an event rate, a denominator should reflect who was observed and for how long, or otherwise be appropriate to the design. The registry specifies a follow-up window for toxicity assessment: from cyclophosphamide initiation through the first follow-up evaluation, described as 6 weeks [± 2 weeks] after cell administration, or until off study, whichever came first. It also lists an average of 2.3 months. Differences in individual observation time can matter because participants followed for different periods have different opportunities to experience and report events. Exposure-adjusted rates are not reported in the registry record.

Why can percentages be unstable?

General statistical interpretation: a percentage is calculated from an event count relative to a denominator. When the denominator is very small, a single observation can move the percentage substantially. In this study, the risk sets listed for dose groups are small, so percentages should not be interpreted as precise estimates for a wider population. A percentage alone also hides how many participants or events underlie it. For the serious-event terms, the registry lists percentages but does not report the denominator or clarify whether the percentage refers to participants, events, or another unit. That ambiguity limits interpretation.

General statistical interpretation: uncertainty intervals communicate how much statistical uncertainty surrounds an estimate. Wider intervals generally indicate less precision; with sparse observations, intervals can be wide. The registry entries do not include confidence intervals for the adverse-event figures, and no inferential analyses are listed. Therefore, the posted point summaries should not be mistaken for precise rates. No new interval or significance test can be inferred from the information in the registry record.

What does over-dispersion mean for counts?

General statistical interpretation: some count-data models assume that the variability in counts follows a specified relationship to the average count. Over-dispersion means that the observed variability is greater than that assumption allows. If over-dispersion is present and ignored, standard errors may be too small and uncertainty may be understated. Whether a count model or an adjustment for over-dispersion would be appropriate depends on the data structure, number of observations, and analysis objective. The statistical model and any over-dispersion assessment are not reported in the registry record, so no claim can be made that such a model was used or needed for the posted results.

The non-randomized, sequential design also matters methodologically. Dose-level groups are not exchangeable by virtue of allocation, as randomized groups would be intended to be. Participants at different levels may differ in characteristics or treatment history, and the order in which levels were studied may matter. A simple comparison of their observed event counts would not isolate a causal dose effect. The registry explicitly notes that the arms are not a like-for-like control comparison.

There are no analysis records listed. The registry record does not report a model, adjustment variables, hypothesis tests, confidence intervals, missing-data method, or multiplicity procedure. The primary outcome description says all participants will be evaluable for toxicity from the time of their first treatment with cyclophosphamide, but the posted information does not specify how incomplete follow-up or unavailable event assessments were handled. These omissions limit assessment of precision and analytic robustness.

The sample-size assumptions describe planning illustrations based on a stated fraction of an observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. They are illustrations for planning rather than the original trial’s sample-size rationale. Any sample-size output should therefore be read as a hypothetical planning calculation, not as evidence that the study had adequate power or as observed power. The protocol’s own sample-size justification is not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists five outcome measures and no analysis records. It does not report a statistical analysis plan that explains which outcomes were primary for formal testing, how multiple outcomes or dose-level summaries were handled, or whether any interim analyses were planned. A multiplicity procedure is not reported in the registry record. Without a stated analysis plan, readers cannot determine whether any reported tests were adjusted for multiple comparisons or whether a nominal result would have been treated as confirmatory.

Multiplicity is a general concern when many outcomes, event types, grades, or groups are examined. The more comparisons considered, the greater the chance that an apparently notable pattern arises by chance alone. This does not mean that descriptive safety summaries should be omitted; it means that patterns among many summaries should not be treated as confirmatory findings without an appropriate prespecified analysis. The posted information does not identify a prespecified testing hierarchy or multiplicity adjustment.

The registry’s primary endpoint calls for toxicity counts by grade and type, but the numerical results at that level are not reported in the registry record. The adverse-event summary supplies serious and non-serious affected counts by dose level, along with a list of serious terms and percentages. These summaries do not resolve whether all events were captured or how repeat events were counted in the primary endpoint.

Missing-data handling is also not reported in the registry record. The endpoint description says participants are evaluable for toxicity from first cyclophosphamide treatment, and it specifies an endpoint window, but it does not say how missing assessments, withdrawal, or differing follow-up duration were handled. Analysis populations beyond this description are not reported in the registry record. As a result, the available information does not establish whether the posted figures use all enrolled participants, all treated participants, or another defined analysis set for every outcome.

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: pelvic pain (100.0%), bronchopulmonary hemorrhage (50.0%), diarrhea (50.0%), disease progression (50.0%), metabolism and nutrition disorders - other, specify: failure to thrive (50.0%).

The adverse-event summary reports serious events among participants at risk by dose level: 1 affected of 1 at risk at Dose Level 1x10^8 Total Cell Dose, 0 affected of 1 at risk at Dose Level 3x10^8 Total Cell Dose, 0 affected of 1 at risk at Dose Level 1x10^9 Total Cell Dose, and 1 affected of 2 at risk at Dose Level 3x10^9 Total Cell Dose. For non-serious events, the corresponding figures are 1 of 1, 1 of 1, 1 of 1, and 2 of 2. Deaths are listed as 0, 0, 0, and 1 for those groups.

These are sparse group summaries, not estimates with reported uncertainty intervals. The number at risk in each group is very small, so a proportion can change markedly with an individual observation. The groups are also non-randomized and sequential, so comparing their figures does not establish that one dose caused more or fewer events than another. The registry’s serious-term percentages include Pelvic pain at 100.0% and four terms at 50.0%; their denominator and counting basis are not specified in the registry record. Those percentages should therefore be treated cautiously and not translated into broader risk estimates.

The figures describe what the registry reports; they do not establish causal attribution to the cell product, chemotherapy, or another aspect of care. The registry definition of serious events includes a range of clinical consequences, and the primary endpoint also includes non-serious events. Full grade-by-type primary outcome counts are not reported in the registry record.

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

The registry describes a Phase I/II investigation of modified peripheral blood lymphocytes targeting G12D-mutated KRAS in HLA-A*11:01 patients. Its primary endpoint is a toxicity count, classified by seriousness, grade, type, and dose level. The posted safety summary includes serious and non-serious affected counts by dose group and a list of serious adverse-event terms. These are descriptive observations from a non-randomized, sequential study with enrollment recorded as 5.

The figures do not establish that the modified cells are effective or ineffective against cancer. Although tumor shrinkage appears as an objective in the brief summary, numerical tumor-response results are not reported in the registry record. Nor do the safety counts establish a comparative effect between dose levels. Participants were not randomized to dose groups, and the registry cautions that the arms are not a like-for-like control comparison. The event patterns could not, on their own, distinguish dose effects from chance variation or differences among participants.

The safety summaries also do not provide a complete account of the primary endpoint as defined. Grade- and type-specific toxicity counts are not reported in the registry record, and no inferential analyses or uncertainty intervals are listed. The percentages attached to serious adverse-event terms have no stated denominator in the registry information. That prevents a confident interpretation of those percentages as participant-level event probabilities.

General statistical interpretation: early-phase safety findings are useful for describing observed events and identifying areas for further study, but sparse observations do not yield precise population estimates. An event count, an affected-participant count, and a risk estimate are not interchangeable. The interpretation depends on the counting unit, follow-up, and analysis population, details that are incomplete in the registry record.

The study’s termination status is recorded, but the reason is not reported in the registry record. The status alone does not show whether termination was related to safety, efficacy, recruitment, feasibility, or another consideration. Overall, the posted information supports a cautious description of limited safety observations and the study’s design. It does not support a treatment recommendation or a definitive conclusion about benefit, harm relative to another treatment, or the likely outcome for a broader patient population.

13. Why This Trial Matters Statistically

This trial raises statistical issues common to early-phase studies of complex cell-based interventions. Its primary endpoint is a count of toxicities by grade and type, while the posted adverse-event summary also distinguishes participants affected from participants at risk. Keeping those measures separate is essential: event counts can include repeated events, whereas affected-participant counts describe people with an event. A clear interpretation depends on knowing which quantity is reported and how observation time is handled.

The sequential, non-randomized dose structure makes descriptive reporting especially important. Dose groups can help characterize what was observed at each level, but they do not function as randomized control groups. Apparent differences across levels cannot be assigned to dose without accounting for the design and potential group differences. The very small risk sets also make percentages fragile, and the registry’s serious-term percentages lack a stated denominator.

The endpoint definition is detailed about toxicity grading and the observation window, yet the registry does not report numerical grade-specific primary endpoint results, analysis methods, missing-data handling, or uncertainty intervals. This contrast illustrates why a precise endpoint definition is not a substitute for complete results and a transparent analysis plan. Readers need both to judge what was measured and how confidently the findings can be interpreted.

The record also demonstrates the distinction between an early-phase safety objective and an efficacy objective. The brief summary mentions tumor shrinkage, but no numerical response results are reported in the registry record. Sample-size planning illustrations based on an observed effect should likewise remain separate from evidence of trial power or from the protocol’s own planning rationale, which is not reported. These statistical distinctions help keep descriptive findings, exploratory signals, and causal conclusions from being conflated.

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 main limitation is the sparse enrollment and very small risk sets within the dose groups. Such data can describe events that were reported, but they provide little precision for estimating how often those events would occur in a wider population. A participant’s experience can strongly influence a group summary. The registry does not report confidence intervals or other uncertainty estimates for the adverse-event figures.

The non-randomized, sequential design limits comparisons across dose levels. The groups are not like-for-like controls, and any differences may reflect participant characteristics, study timing, or other factors rather than dose. Masking was absent, according to the registry. No statistical adjustment or sensitivity analysis is reported in the registry record.

There is a gap between the defined primary endpoint and the posted outcome detail. The endpoint calls for counts by toxicity grade and type, but numerical grade-specific results are not reported in the registry record. The listed serious-term percentages lack a stated denominator and counting basis. The available adverse-event figures therefore cannot fully answer the primary endpoint as specified.

Follow-up is described through the first evaluation at 6 weeks [± 2 weeks] after cell administration or until off study, whichever came first, with an average of 2.3 months. Individual follow-up duration and exposure-adjusted event rates are not reported in the registry record. The handling of incomplete assessments, missing data, repeat events, and analysis populations is also not reported.

No numerical tumor-response results, analysis records, or statistical plan are listed in the registry record. The reason for termination is not reported in the registry record. These limitations restrict interpretation to the design description and posted safety summaries; they do not permit a complete assessment of efficacy, comparative safety, or the study’s stopping rationale.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12D Variant of Mutated RAS in HLA-A*11:01 Patients — NCT03745326.
• Registry record last updated 2026-05-19; status last verified 2026-05.
• Results first posted 2026-05-19.
• 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

NCT03745326 is a Phase I/II, non-randomized, unmasked, sequential study sponsored by the National Cancer Institute. It evaluated peripheral blood lymphocytes modified with a murine T-cell receptor recognizing the G12D variant of mutated RAS in HLA-A*11:01 patients. Enrollment is recorded as 5. The study began on 2019-05-16, primary completion is listed as 2022-08-23, and the status is terminated.

The primary endpoint concerns the number, grade, and type of serious and non-serious toxicities by Phase I dose level. The registry lists adverse-event counts by dose group and serious-event terms with percentages, but numerical grade-specific primary outcome results, analysis records, and tumor-response results are not reported in the registry record. The dose groups are not randomized controls, and the small risk sets limit precision. The reason for termination, missing-data approach, and statistical analysis plan are not reported in the registry record.