S1702 Isatuximab in Treating Patients With Relapsed or Refractory Primary Amyloidosis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for S1702 Isatuximab in Treating Patients With Relapsed or Refractory Primary Amyloidosis (NCT03499808), a na phase 2 study. The primary outcome is Assess Efficacy by Confirmed Overall Hematologic Response.

2. Clinical Question

The study focuses on hematologic response in relapsed or refractory systemic AL amyloidosis. Its response categories are based on free light chain measurements and, for complete response, serum and urine immunofixation. The posted record also lists toxicity and several time-to-event outcomes, including overall survival, duration of response, time to hematologic response, and progression-free survival. Results for these secondary outcomes are not reported in the registry record.

3. Trial Design

This is a phase II, single-group study sponsored by SWOG Cancer Research Network. The registry describes isatuximab treatment for patients with previously treated AL amyloidosis that has relapsed or is refractory. Allocation is listed as not applicable, and masking is listed as none. There is no randomized control arm in the record, so the study is not a comparative trial.

The registry lists enrollment of 43. The primary outcome population is described separately as 35 participants who received treatment and are analyzable. The reasons that the primary outcome population differs from the enrollment figure are not reported in the registry record. The record does not establish whether any difference reflects eligibility, treatment receipt, outcome availability, or another reason.

Isatuximab is given intravenously on days 1, 8, 15, and 22 of the first course, then on days 1 and 15 of subsequent courses. Treatment repeats every 28 days for up to 24 courses, unless disease progression or unacceptable toxicity occurs. Laboratory biomarker analysis is also listed as an intervention, but procedural details are not reported in the registry record.

The study started on 2018-06-06, reached primary completion on 2023-08-30, and is marked completed. The primary outcome timeframe is described as beginning at enrollment and continuing until progression or death due to any cause, whichever occurs first, assessed up to 4 years. The registry record does not report a randomization procedure, blinding, or a separate control condition. It also does not report the rationale for the enrollment target or a detailed statistical analysis plan.

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: 35 participants who received treatment and are analyzable.

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.

6. Primary Endpoint

The registry lists the primary outcome as Assess Efficacy by Confirmed Overall Hematologic Response, measured over From date of enrollment until progression or death due to any cause, whichever occurs first, assessed up to 4 years.

The primary endpoint is the confirmed overall hematologic response rate, defined as the percentage of participants with partial response or better. The registry names partial response, very good partial response, and complete response as qualifying categories. It specifies a 95% confidence interval, but the response estimate and interval are not reported in the registry record.

The categories use free light chain measurements. Partial response is defined as a decrease in dFLC of at least 50%, while dFLC remains > 4.0 mg/dL. Very good partial response is defined as dFLC < 4.0 mg/dL. Complete response requires free light chain ratio values within the stated normal range of 0.25 - 1.65 and negative serum and urine immunofixation.

In general, a hematologic response endpoint captures a change in the disease-related blood markers specified by the study. Combining response categories into a rate of partial response or better gives a single summary of the proportion meeting one of the stated thresholds. It does not, by itself, describe the duration of response, changes in organ function, or survival. Those are distinct outcomes, and results for the listed secondary outcomes are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a response rate represent?

In general, a response rate is the proportion of an analyzed group that meets a prespecified response definition. Here, the qualifying outcome is confirmed overall hematologic response of partial response or better. The registry describes the endpoint as a percentage of participants, but does not report the observed response percentage or the number meeting the response criteria. The population specified for this outcome is 35 treated participants who are analyzable.

The response categories are threshold-based. Partial response requires a dFLC decrease of at least 50% while the dFLC remains > 4.0 mg/dL. Very good partial response uses dFLC < 4.0 mg/dL. Complete response additionally requires a free light chain ratio within 0.25 - 1.65 and negative serum and urine immunofixation. These definitions describe how participants are classified; they do not reveal how many met any category.

How should a confidence interval be understood?

In general, a confidence interval expresses the statistical uncertainty around an estimated quantity, such as a response proportion. A narrower interval indicates greater precision under the assumptions of the method used; a wider interval indicates less precision. The registry specifies a 95% confidence interval for the primary endpoint but does not report its limits. The interval therefore cannot be interpreted or used to assess precision from the posted results. The method used to calculate it is not reported in the registry record.

What can a single-group design establish?

In general, a single-group study can describe outcomes among participants receiving the study treatment. It has no concurrent randomized comparator with which to estimate a treatment contrast. As a result, an observed response proportion would describe the treated study population, but would not by itself distinguish treatment effects from other possible explanations for the outcome. This is a design limitation, not a flaw in calculating a within-group proportion. The registry lists allocation as not applicable and masking as none.

How should time-to-event outcomes be read?

Overall survival and progression-free survival are listed as secondary outcomes, along with duration of response and time to hematologic response. In general, time-to-event methods account for the time until an event and may also account for participants whose event status is not observed by the end of follow-up. The registry names 24-month estimates for overall survival, duration of response, and progression-free survival, but does not report estimates, event counts, confidence intervals, or the analysis methods. It also does not report censoring rules or how incomplete follow-up was handled. These details cannot be inferred from the outcome names.

What do the planning assumptions mean?

In general, a sample-size planning illustration estimates the size of a future study under chosen assumptions. The record describes planning assumptions based on a fraction of the observed effect, two-sided significance level 0.05, equal allocation, and a normal approximation. It characterizes these calculations as planning illustrations rather than the trial's own design. Such planning values are not observed power and do not show how likely the trial was to detect an effect after the study was completed. The observed effect and the resulting planning values are not reported in the registry record, so their implications cannot be evaluated.

The record does not report the study's sample-size justification, a prespecified statistical analysis plan, interim analyses, or the method used for the primary response confidence interval. It also contains no analysis entries. In general, these details help readers understand how outcomes were planned and analyzed; their absence from the registry record means that the posted information is insufficient to reconstruct the analysis.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists several secondary outcomes in addition to the primary hematologic response endpoint: toxicity, overall survival, duration of response, time to hematologic response, and progression-free survival. Considering multiple outcomes can create multiplicity concerns, because repeated statistical testing may increase the chance of at least one apparently noteworthy result by chance. In general, a statistical plan may address this through a testing hierarchy or adjustment, but the registry record does not report whether any multiplicity procedure was planned or used. Secondary outcome results are also not reported in the registry record.

The primary outcome population is described as 35 participants who received treatment and are analyzable, while enrollment is listed as 43. The record does not explain the difference or state how participants without an analyzable response were handled. It does not report the amount or pattern of missing outcome data, whether any missing values were imputed, or whether sensitivity analyses were performed. These omissions prevent assessment of how robust the endpoint result would be to missing data, even if the estimate were available.

The registry record does not report a detailed analysis population definition beyond the treated, analyzable description, nor does it specify rules for confirming response or adjudicating ambiguous assessments. It also does not identify an intention-to-treat analysis or a per-protocol analysis. These are not interchangeable populations, and the applicable approach cannot be inferred. The posted record contains no analysis entries, so details about multiplicity and missing-data handling are not reported in the registry record.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: lung infection (8.6%), hypokalemia (8.6%), abdominal pain (5.7%), gastrointestinal disorders-other (5.7%), vomiting (5.7%).

The safety summary lists 15 participants affected by serious adverse events among 35 at risk, and 32 affected by other adverse events among 35 at risk. The registry also records one death in the adverse-event summary. These are descriptive entries, not estimates comparing isatuximab with another treatment. Because the study has no control group, the figures do not show how event frequency compares with another group or what would have occurred without study treatment.

The listed serious-event terms include lung infection and hypokalemia, each reported as 8.6%; abdominal pain, gastrointestinal disorders-Other, vomiting, and fever, each reported as 5.7%. The registry does not report further detail about event timing, severity grades, recurrence, or the relationship of each event to treatment. It also does not report whether participants could contribute to more than one listed term. The one death should not be interpreted as treatment-related: the record does not state a causal relationship.

In general, an adverse event recorded during a study is not necessarily caused by the treatment. The event counts describe what the registry reports for this study group; they do not alone establish causation, comparative risk, or an individual's likelihood of experiencing an event.

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

The registry record establishes that this phase II study evaluated isatuximab in previously treated relapsed or refractory systemic AL amyloidosis, using confirmed hematologic response of partial response or better as the primary endpoint. It supplies response definitions, a 95% confidence interval specification, and a treated, analyzable population description. It does not report the primary response estimate or confidence limits. Therefore, the posted results do not quantify the primary outcome.

The record also reports adverse-event counts and selected serious-event terms. These describe recorded events among participants at risk, but the single-group design does not provide a randomized safety comparison. The counts do not establish that treatment caused the events or the death listed in the summary. Results for the listed survival and response-duration outcomes are not reported in the registry record.

In general, a single-group phase II study can provide descriptive information about outcomes in the group receiving the intervention. Without a comparator, it cannot establish a treatment contrast against usual care, another treatment, or no treatment. Even a reported response rate would need to be interpreted in light of the population analyzed, missing outcome data, endpoint assessment, and the uncertainty interval. Those details are not fully.

The record does not establish why enrollment differs from the treated, analyzable primary outcome population, how absent outcomes were handled, or what statistical methods were used beyond naming a 95% confidence interval. It does not report the trial's sample-size rationale or a detailed analysis plan. Accordingly, it supports a description of the study design and stated endpoint, but not a quantified conclusion about efficacy, a comparative treatment claim, or an explanation of the observed adverse-event pattern.

13. Why This Trial Matters Statistically

For biostatisticians and clinical researchers, this record illustrates the difference between a prespecified outcome definition and a posted outcome result. The primary endpoint is defined in detail, including thresholds for partial response, very good partial response, and complete response, and the record specifies a confidence interval. Yet the estimate and interval themselves are not reported. A registry entry can therefore document what was intended to be measured without supplying the information needed to judge the observed magnitude or precision.

The study also highlights the interpretive limits of a single-group design. The treatment schedule and study population are described, but there is no randomized comparator. Any observed outcome in such a group is descriptive and cannot provide a randomized estimate of how outcomes differ under another treatment condition. This distinction remains important even when the endpoint is clinically specific and objectively defined.

Finally, the record leaves key analysis questions unresolved: how the enrollment figure relates to the analyzable primary population, how missing outcomes were handled, whether multiple secondary outcomes were addressed in a prespecified way, and which statistical methods were used. In general, these details affect how reproducible and interpretable a result is. Here, the absence of a posted primary result and analysis entries limits statistical assessment. The lesson is not that the treatment did or did not produce a particular outcome, but that study design, reporting completeness, and numerical results are all necessary for a clear interpretation.

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.

Several limitations specific to this record constrain interpretation. First, although the primary endpoint and its response thresholds are described, the response estimate and 95% confidence interval are not reported in the registry record. The primary efficacy result therefore cannot be quantified. The listed secondary outcomes also lack reported results, including the outcomes with 24-month estimates.

Second, the study is single-group, with allocation listed as not applicable and masking as none. There is no concurrent comparator, so the record cannot support a randomized comparison. Third, enrollment is listed as 43, whereas the primary outcome population is described as 35 treated and analyzable participants. The reason for this difference and the treatment of participants without analyzable outcomes are not reported.

The registry record does not report the primary endpoint calculation method, missing-data procedures, response confirmation procedures beyond the stated definitions, or a detailed analysis plan. It also does not report a sample-size justification or whether multiplicity was addressed. These gaps make it difficult to assess the analysis independently.

Safety interpretation is also limited. The record lists serious and other adverse-event counts, selected serious-event terms, and one death, but does not provide comparative data or state whether events were considered treatment-related. Event timing and further detail are not reported in the registry record. These limitations do not establish that a particular outcome occurred or did not occur; they define what can be evaluated from the posted information.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: S1702 Isatuximab in Treating Patients With Relapsed or Refractory Primary Amyloidosis — NCT03499808.
• Registry record last updated 2025-09-09; status last verified 2025-02.
• Results first posted 2025-02-27.
• 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

NCT03499808 is a completed phase II, single-group study of isatuximab in previously treated relapsed or refractory systemic AL amyloidosis. Enrollment is listed as 43. The primary outcome population is described as 35 treated participants who are analyzable. Isatuximab is administered intravenously on a repeating 28-day course schedule, for up to 24 courses unless progression or unacceptable toxicity occurs.

The primary endpoint is confirmed overall hematologic response of partial response or better, with a 95% confidence interval specified. The registry record does not report the response estimate or interval. It lists toxicity, survival, response duration, time to hematologic response, and progression-free survival as secondary outcomes, but their results are not reported. The adverse-event summary records serious events affecting 15 of 35 at risk, other events affecting 32 of 35 at risk, and one death. The single-group design and missing outcome results limit efficacy and comparative safety interpretation.