ACY-1215 for Relapsed/Refractory Lymphoid Malignancies: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for ACY-1215 for Relapsed/Refractory Lymphoid Malignancies (NCT02091063), a na phase 1, phase 2 study. The primary outcome is Number of Patients Who Experience a Dose-limiting Toxicity (DLT).

2. Clinical Question

3. Trial Design

This was an open-label, single-agent Phase Ib/II study of ACY-1215 for relapsed or refractory lymphoid malignancies. The registry lists a sequential model, no masking, and allocation as not applicable. Enrollment is recorded as 23, but the record does not establish how many participants entered each dose cohort or how many were included in any primary-outcome analysis.

In Phase Ib, patients were to accrue simultaneously to Arm A and Arm B, with cohort selection by alternation. Arm A was assigned ACY-1215 160 mg once daily, and Arm B 160 mg twice daily. Both schedules were described as oral dosing for 28 consecutive days. The registry states that the Phase II frequency would be determined based on Phase Ib results; the arm description says that once the Phase I schedule had been determined, Phase II dosing would be 160 mg twice daily.

The record's description of alternation does not establish random assignment. With no masking and no control group, outcome assessment could be influenced by knowledge of treatment, and comparisons between dose schedules would not have the protections of a randomized controlled comparison. The registry does not report the final dose-selection process or whether the planned Phase II expansion occurred.

The study status is terminated. Its recorded start date is 2014-04-02 and its primary completion date is 2019-02-25. The primary outcome entry explicitly says that data were not collected due to early termination and could not be analyzed or reported. The reason for termination and details of the study's conduct after enrollment 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.

Cohort 1: 160 mg Once Daily (Phase 1)

Cohort 2: 160 mg Twice Daily (Phase 1)

Expansion: 160 mg Twice Daily (Phase 1)

160 mg Twice Daily (Phase 2)

Analysis population for the primary outcome, as defined in the registry: Data was not collected due to early termination of study, therefore data cannot be analyzed or reported.

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 baseline characteristics were collected from the study participants agnostic to their Arm assignment. Baseline characteristics were NOT collected per dose level thus cannot be reported per dose level.

6. Primary Endpoint

The registry lists the primary outcome as Number of Patients Who Experience a Dose-limiting Toxicity (DLT), measured over Up to 1 year.

The primary endpoint was the number of patients who experienced a dose-limiting toxicity, assessed over a timeframe of up to 1 year. A DLT endpoint is used in dose-finding research to identify toxicity that limits the tolerability of a treatment schedule. In this study, the stated aim was to establish the safety of two ACY-1215 dose schedules in patients with relapsed or refractory lymphoid malignancies.

The registry describes a decision rule for Phase I: if more than 1/3 or 2/6 patients experienced a DLT, there would be no expansion. This makes the DLT count relevant to whether the study would proceed to an expansion cohort. However, the registry does not report the operational definition of a DLT, the observation window used for deciding whether a particular event qualified, or the number of participants assessed under each schedule.

Most importantly, the outcome entry says that DLT data were not collected because the study ended early. There is therefore no reported primary endpoint count or estimate to interpret. The separate adverse-event summary is not a substitute for the prespecified DLT outcome: the registry does not state that its adverse-event categories correspond to the DLT definition or timeframe.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a Phase Ib/II study with an open-label, single-agent design and a sequential model. A study's design determines what comparisons its data can support; it does not by itself supply evidence of a treatment effect. Here, there was no control group, masking was absent, and the Phase Ib cohort assignment was described as alternation. The record does not report a randomized allocation method or a statistical analysis plan.

What does a DLT count measure?

The planned primary outcome was a count of patients who experienced a dose-limiting toxicity within a timeframe of up to 1 year. In general, a count records how many people meet a specified event definition; it is not the same as counting every event, since one person may experience more than one event. The registry does not report the detailed DLT definition or the number of patients evaluated for DLT in each cohort. It also states that the DLT data were not collected due to early termination. As a result, no cohort-specific count or comparison can be interpreted.

The registered Phase I rule used the DLT count to determine whether there would be an expansion. A decision threshold specified in advance can guide study conduct, but it is not a result. The record gives the threshold as more than 1/3 or 2/6 patients experiencing a DLT; it does not report whether the threshold was reached or whether expansion proceeded.

Why do denominators matter?

A denominator identifies the group of people to whom a reported count applies. For an event count, the denominator may be those who received treatment, those who could be assessed, or a prespecified analysis population; these are not necessarily interchangeable. The adverse-event summary reports participants at risk separately for serious and other adverse events. The primary DLT endpoint has no reported denominator because its data were not collected. The enrollment entry of 23 should not be substituted for a missing endpoint denominator, and the registry does not explain the difference between enrollment and the adverse-event risk counts.

In general, a confidence interval expresses the statistical uncertainty around an estimate under the assumptions of the analysis. A narrow interval indicates greater precision than a wide interval, while neither interval alone determines whether an effect is clinically important. No primary endpoint estimate or confidence interval is reported in this record, so precision for the planned DLT outcome cannot be assessed.

What can the dose-schedule design establish?

The two Phase Ib cohorts were intended to receive different dosing schedules. Alternation is a cohort-selection procedure stated in the registry, but the record does not describe randomization. In general, random assignment helps balance prognostic factors across groups on average; when assignment is not randomized, differences in participants or care can complicate interpretation of a between-group comparison. Open-label conduct also means that treatment assignment was known. The registry does not describe a blinded outcome assessment procedure.

The study's sequential description and planned transition from Phase Ib to Phase II are features of its design. The registry says Phase II frequency would be determined from Phase Ib results and describes 160 mg twice-daily dosing for Phase II once the Phase I schedule had been determined. It does not report how that decision was made or whether the intended Phase II stage was completed. It would be inappropriate to infer a dose-selection conclusion from the schedule description alone.

How should planning calculations be read?

The stated sample-size convention describes planning illustrations based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. In general, a planning calculation asks how much information a future study might need to detect a chosen effect under specified assumptions. It is not a result from the current trial and is not observed power. The record does not report a sample-size justification or the study's own statistical plan. Because the primary DLT data are not reported, no primary-endpoint effect estimate can be verified from this registry entry or used to draw a conclusion about the DLT question.

For outcomes analyzed as event counts, over-dispersion can matter in general: it occurs when variability in counts exceeds what a simple model assumes, and ignoring it can make uncertainty appear too small. The registry does not report a count model or any fitted analysis, so there is no basis to say whether over-dispersion was assessed. Likewise, no multiplicity procedure, missing-data method, or analysis-population definition is reported. These are limits on what can be learned from the statistical record, not evidence that a particular method was or was not used outside the information registered.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 2 outcome measures and 0 analyses. It identifies DLT count as the primary outcome, but does not provide the results of that measure. The other outcome measure is not described in the available record, so its definition, timing, and result are not reported in the registry record. A multiplicity strategy for handling more than one outcome or analysis is also not reported.

Multiplicity matters in general when several outcomes, comparisons, or time points are tested: the chance of at least one apparently notable result can rise as the number of tests increases. Statistical methods may account for that, but no such approach is reported. With no analysis results, there are no reported p-values or confidence intervals to evaluate for multiplicity.

The primary outcome entry directly attributes the absence of DLT data to early termination. This is different from having a reported DLT outcome with some participants missing; the record says the data could not be analyzed or reported. It does not explain whether other clinical outcomes were collected, why the trial ended, or what follow-up was available.

The record does not define an intention-to-treat, per-protocol, safety, or other analysis population for the primary outcome. Such labels describe which participants are included in an analysis and can affect interpretation, particularly when not everyone has outcome data. The adverse-event summary does identify an all-participants group and its at-risk counts, but that does not establish the population used for the missing primary endpoint. No assumptions about missing outcomes or imputation methods are 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 non-serious adverse event terms

The adverse-event summary lists an all-participants group. It reports 21 participants at risk for serious adverse events, with 0 affected. For other adverse events, it reports 21 at risk and 21 affected. It also lists 1 death. These entries describe participant counts in the registry's categories; they do not provide event-level details or an estimate comparing treatment with a control group.

The record contains no serious adverse-event terms in its list of top serious terms. A zero count of participants affected in the serious category should not be read as proof that no safety concerns occurred across all possible definitions or periods. The summary does not explain the period covered, the event definitions, or the relationship between this safety summary and the primary DLT endpoint.

The death entry is not accompanied by a cause, timing, or attribution to ACY-1215 in the registry information. It therefore cannot be described as treatment-related or unrelated on the basis of this record. The adverse-event risk counts also differ from the enrollment entry of 23; the reason is not reported in the registry record. These figures should be retained as reported rather than combined or used to infer an unreported denominator.

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

The record documents a study intended to examine the safety of two ACY-1215 dose schedules and to use Phase Ib findings to inform Phase II dosing. It also documents that the study was terminated and that the planned primary DLT data were not collected. Consequently, the primary question cannot be answered from the registered results: the record does not show how many participants experienced DLTs under either schedule.

The adverse-event summary supplies limited descriptive safety information, including 0 participants affected by serious adverse events among 21 at risk, 21 affected by other adverse events among 21 at risk, and 1 death. These figures do not establish the cause of an event, whether an event was treatment-related, or whether a DLT occurred. No controlled comparison is available to distinguish outcomes associated with treatment from outcomes that might have occurred without it.

The design description is not evidence that a particular schedule was selected as safer or more tolerable. The registry does not report the dose-selection decision, the completion of a Phase II expansion, or efficacy results. It therefore cannot support a conclusion that ACY-1215 did or did not affect lymphoma or other lymphoid malignancies.

More broadly, absence of a reported primary outcome is not evidence of no toxicity, and a planned endpoint is not evidence that the endpoint was met. The results should be read as an incomplete record of a terminated study: the intended clinical and statistical questions are described, but the primary outcome data needed to answer them are not available in the registry record.

13. Why This Trial Matters Statistically

This study illustrates a basic distinction in clinical research: a carefully described endpoint and decision rule do not substitute for observed outcome data. The record specifies DLT as the primary measure, gives a timeframe of up to 1 year, and describes how the Phase I result was intended to guide expansion. Yet it also states that DLT data were not collected because the study was terminated early. Statistical interpretation must begin with that absence rather than treating design details as findings.

The trial also shows why readers need to distinguish a dose-finding design from a controlled treatment comparison. The cohorts were assigned different schedules by alternation, with no masking and no control group. Those design features describe the planned conduct, but they do not support a randomized comparative estimate. Since the primary outcome is missing, there is no estimate to compare in any case.

Its registry record provides a useful example of why denominators and outcome definitions must be read together. The adverse-event summary reports participants at risk and affected, whereas the planned primary endpoint concerns DLTs. The record does not say these categories are equivalent. Keeping them separate prevents a descriptive safety count from being misrepresented as the missing primary outcome.

Finally, the case demonstrates the value of transparent reporting about study status and unavailable results. The termination status and explicit statement that primary data were not collected place a clear boundary on interpretation. Researchers and readers can identify what the study set out to examine, while recognizing that the registered information does not resolve the planned dose-schedule question.

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 most consequential limitation is that the registry reports no data for the primary DLT outcome because of early termination. It gives no DLT counts, cohort-specific denominators, or estimate of uncertainty. The record also does not explain why the study was terminated or whether termination affected collection of outcomes beyond the primary measure.

The design limits comparative interpretation. It was open label, had no control group, and describes Phase Ib cohort selection by alternation rather than randomization. The record does not report masking of outcome assessors or a method to address differences between dose cohorts. It also does not provide the final decision about Phase II dosing or state whether the planned expansion occurred.

Descriptions of the intended population and schedules are available, but participant characteristics and dose-cohort enrollment are not reported. The enrollment entry is 23, while the adverse-event risk counts are 21; the record does not explain the difference. The adverse-event summary does not include serious-event terms, details about the death, event timing, or treatment attribution. Its categories cannot be assumed to match the DLT definition.

Finally, the registry does not report the statistical analysis plan, endpoint definitions beyond the brief description, missing-data methods, analysis populations, or multiplicity handling. It lists 2 outcome measures and 0 analyses, but the other outcome measure is not described in the available information. These gaps prevent assessment of the intended analysis and restrict conclusions to the descriptive information actually recorded.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: ACY-1215 for Relapsed/Refractory Lymphoid Malignancies — NCT02091063.
• Registry record last updated 2024-08-06; status last verified 2024-07.
• Results first posted 2024-08-06.
• 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 describes an open-label, single-agent Phase Ib/II study of ACY-1215 for relapsed or refractory lymphoid malignancies. It lists a sequential model, enrollment of 23, and a terminated status. The recorded start date is 2014-04-02, and the primary completion date is 2019-02-25.

Phase Ib was intended to evaluate 160 mg once-daily and 160 mg twice-daily schedules, with Phase II dosing described as 160 mg twice daily after the Phase I schedule was determined. The primary outcome was the number of patients experiencing DLTs over up to 1 year. The registry states that these data were not collected due to early termination, so the primary outcome could not be analyzed or reported.

The adverse-event summary lists 21 participants at risk and 0 affected for serious adverse events, 21 at risk and 21 affected for other adverse events, and 1 death. These entries do not replace the missing DLT result. The record does not report the reason for termination, a primary endpoint analysis, or a controlled treatment-effect estimate.