Phase 1/2 Study of Carfilzomib for the Prevention of Relapse and GVHD in Allo-HCT for Hematologic Malignancies: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase 1/2 Study of Carfilzomib for the Prevention of Relapse and GVHD in Allo-HCT for Hematologic Malignancies (NCT02145403), a na phase 1, phase 2 study. The primary outcome is Phase I: Maximum Tolerated Dose (MTD) of Carfilzomib.

2. Clinical Question

The investigators’ stated hypothesis was that adding carfilzomib to standard conditioning for allogeneic transplantation would decrease post-transplant relapse and treatment-related mortality by decreasing severe graft-versus-host disease, with an overall improvement in transplant outcomes. This is the study rationale, not a finding. The primary endpoint addresses tolerability during dose escalation rather than directly measuring relapse, survival, or graft-versus-host disease. Those outcomes appear among the listed secondary measures, but their results are not reported in the registry record.

3. Trial Design

NCT02145403 is recorded as a completed Phase 1/2 study sponsored by the University of Michigan Rogel Cancer Center. The registry lists 53 participants enrolled. Its design is single-group, with no allocation to parallel randomized groups and no masking. The listed conditions are hematologic malignancies, relapse, and graft-versus-host disease. The study concerns allogeneic hematopoietic cell transplantation for high-risk hematologic malignancies.

The Phase 1 component sought a maximum tolerated dose of carfilzomib. The registry describes a standard 3+3 dose-escalation approach: participants began at dose level 1, 20 mg/m^2. If none of the first 3 participants at a dose level developed a protocol-defined dose-limiting toxicity, escalation would proceed. If a dose-limiting toxicity occurred, the cohort would be expanded to 6. Escalation would proceed only if fewer than 2 of 6 participants developed a dose-limiting toxicity; otherwise, the protocol called for de-escalation to the previous level. The maximum tolerated dose was defined as the highest dose level at which no more than 1 of 6 participants experienced a dose-limiting toxicity.

The intervention list includes carfilzomib and tacrolimus. The detailed administration description gives the level 1 carfilzomib schedule: intravenous administration over 30 minutes on days +1, +2, +6 and +7. The registry’s adverse-event group labels include maximum carfilzomib dose levels of 20 mg/m^2, 27 mg/m^2, 36 mg/m^2 and 45 mg/m^2. These are dose-level labels, not randomized comparisons. The dates recorded are a start in 2014-10 and primary completion on 2018-11-26; the study status is completed.

The registry lists Phase II measures for progression/relapse-free survival, overall survival, acute and chronic graft-versus-host disease, and non-relapse mortality, along with regimen-related toxicities. However, it does not report results for these outcomes or describe how Phase 2 treatment assignment or comparisons were handled. The record lists 8 outcome measures and no analysis records.

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: Two patients who consented never began treatment.

Phase I: Max Dose 20 mg/m^2 (Day 1-7)

Phase I: Max Dose 27 mg/m^2 (Day 1-7)

Phase I: Max Dose 36 mg/m^2 (Day 1-7)

Phase I: Max Dose 45 mg/m^2 (Day 1-7)

Analysis population for the primary outcome, as defined in the registry: Phase 1 study participants

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 Phase I: Maximum Tolerated Dose (MTD) of Carfilzomib, measured over Up to day 28.

The primary endpoint is the Phase I maximum tolerated dose of carfilzomib, expressed in milligrams per square meter and assessed up to day 28. In dose-finding research, this endpoint is used to identify a dose level that meets prespecified tolerability rules. The protocol description defines dose-limiting toxicity (DLT) per protocol, but the specific DLT criteria are not reported in the registry record.

The registry describes a 3+3 escalation rule. At each dose level, escalation could follow if none of the first 3 participants experienced a DLT. A cohort would expand to 6 if a DLT occurred, and escalation would proceed only if fewer than 2 of 6 experienced a DLT. If at least 2 of 6 developed DLTs, the protocol called for dose de-escalation. The highest level at which no more than 1 of 6 participants experienced a DLT defined the MTD.

This endpoint is a rule-based dose selection measure, not an estimate of comparative benefit. It does not by itself quantify relapse risk, survival, or the incidence of graft-versus-host disease. Although the registry names the endpoint and its decision rule, it does not report the observed MTD or the dose-limiting toxicity counts used to select it. Therefore, the endpoint’s result cannot be interpreted from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical approach described for the primary endpoint is a 3+3 dose-escalation rule. This is a cohort-based decision procedure: participants are enrolled in small groups at a dose level, and observed dose-limiting toxicities determine whether enrollment moves to a higher dose, expands at the current dose, or returns to a lower dose. Here, the registry says that enrollment began at 20 mg/m^2. If no DLT occurred among the first 3 participants, escalation would follow. If a DLT occurred, the cohort would expand to 6; escalation would occur only when fewer than 2 of 6 had a DLT. At 2 or more DLTs among 6, the protocol specified de-escalation. The MTD was defined as the highest dose level at which no more than 1 of 6 experienced a DLT.

This rule gives an operational definition for dose selection, but it is not a guarantee that the selected dose is optimal for every patient or outcome. It depends on the protocol’s DLT definition and observation window. The endpoint timeframe is up to day 28, while the exact protocol definition of DLT is not reported in the registry record. The record also does not report the observed DLT counts at each level or the resulting selected dose. Consequently, the stated rules can be explained, but their application and result cannot be reconstructed from the posted information.

The Phase II outcomes include time-to-event measures: progression/relapse-free survival and overall survival. In general, a Kaplan-Meier estimate describes the probability of remaining event-free over time while accounting for participants whose follow-up ends before an event is observed. Such participants are censored at their last known follow-up under the method’s assumptions; censoring is not the same as experiencing the event. The registry names Kaplan-Meier estimates for these outcomes but does not report estimates, confidence intervals, follow-up summaries, event definitions beyond the outcome names, or details of censoring and analysis populations.

The listed outcomes also include cumulative incidence of acute and chronic graft-versus-host disease and non-relapse mortality. In general, cumulative incidence is used when a competing event can prevent the event of interest from occurring. For example, death without relapse can prevent a later relapse from being observed. Treating competing events as ordinary censoring can answer a different question and may misstate the absolute probability of the event of interest. The record names cumulative incidence measures but does not specify the estimation procedure, competing-event definitions, or reported results.

Regimen-related toxicities are listed as a count outcome. In general, counts can be highly variable, and their interpretation depends on the observation period, participant exposure, and whether the count refers to events or participants with at least one event. The registry gives no numerical result for this outcome or further analysis details. The adverse-event listing separately provides numbers at risk and numbers affected for serious and other adverse events by dose-level group. These are descriptive safety summaries; the registry does not report inferential comparisons across dose levels.

For any estimated treatment contrast, a confidence interval describes a range of values compatible with the data and the specified statistical model. A narrower interval generally indicates greater precision, while a wider interval indicates more uncertainty. A confidence interval would not correct for bias from a nonrandomized design, incomplete follow-up, or unmeasured differences between groups. No confidence intervals or effect estimates are reported for the clinical outcomes in this registry record.

In general, over-dispersion occurs when count variability exceeds what a simple count model assumes. If present, it can make standard errors too small and tests too optimistic unless the analysis accounts for it. No count-model specification or dispersion assessment is reported. The registry record also does not report a statistical analysis plan, interim-analysis procedures, adjustment methods, or model covariates. Those methods should not be inferred from the outcome names alone.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 8 outcome measures, including the Phase I MTD and Phase II survival, toxicity, graft-versus-host disease, and non-relapse mortality outcomes. When a study evaluates multiple outcomes, the chance of at least one apparently unusual result can increase if each is tested separately without a prespecified strategy. In general, multiplicity can be addressed through a hierarchy of endpoints, adjusted significance thresholds, or a clear distinction between primary and exploratory analyses. The registry record does not report a multiplicity strategy, endpoint hierarchy beyond naming the Phase I primary measure, or adjusted analyses.

No analysis records are listed. This means the registry record does not provide analysis-level results, such as outcome estimates, uncertainty intervals, or tests, for interpreting the listed measures. It also does not report whether interim analyses were planned or conducted. The analysis plan and any interim-analysis details are not reported in the registry record.

Missing data and analysis populations are important for interpreting survival and event outcomes. In general, incomplete follow-up can affect time-to-event estimates, while missing endpoint assessments can alter the population contributing to a dose-finding or toxicity summary. The record does not describe missing-data methods, censoring rules, exclusions, or whether analyses used intention-to-treat, per-protocol, safety, or other populations. The enrollment count of 53 does not establish that all enrolled participants contributed to every endpoint.

Without reported methods for missing observations, endpoint-specific denominators, and multiplicity, the precision and robustness of any result cannot be assessed from this registry record. Those details should not be inferred from the study’s phase, outcome labels, or dose-escalation description.

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: blood and lymphatic system disorders - other (50.0%), atrial fibrillation (33.3%), chills (33.3%), erythema multiforme (33.3%), febrile neutropenia (33.3%).

The registry reports serious and other adverse-event counts separately for four carfilzomib dose-level groups. At 20 mg/m^2, 1 of 3 participants at risk had a serious adverse event and 3 of 3 had another adverse event; 1 death is listed. At 27 mg/m^2, the corresponding counts are 2 of 3 and 0 of 3, with 2 deaths listed. At 36 mg/m^2, they are 25 of 41 and 16 of 41, with 18 deaths listed. At 45 mg/m^2, they are 4 of 4 and 3 of 4, with 2 deaths listed.

These figures are descriptive and have different group sizes. The dose groups are not randomized arms, so apparent differences across them are not controlled comparisons. The deaths listed are not identified as treatment-related in these summary counts, and the record does not establish causation. A listed serious adverse event is not necessarily a dose-limiting toxicity: the registry’s DLT definition is per protocol, and detailed DLT counts are not reported.

The registry also lists serious adverse-event terms with percentages: blood and lymphatic system disorders - Other, 50.0%; atrial fibrillation, chills, erythema multiforme, febrile neutropenia, and infections and infestations - Other, each 33.3%. These percentages are reported as listed; the record does not explain their denominator in the displayed summary. They should not be read as comparative risks or as evidence of causation.

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

This trial’s primary statistical question concerns dose selection: the maximum tolerated dose of carfilzomib under the stated Phase I rules. The registry describes how dose escalation was intended to proceed, but it does not report the MTD result. The dose-level labels in the safety summary are not enough to identify which dose, if any, met the protocol definition. As a result, the posted record cannot establish the primary endpoint value.

The record also identifies outcomes relevant to relapse, survival, graft-versus-host disease, non-relapse mortality, and toxicity. Naming an outcome does not constitute an observed result. Since the registry does not report these results, it cannot support conclusions about the magnitude or precision of any change in those outcomes. The investigators’ stated hypothesis remains a study rationale rather than a demonstrated finding in the posted record.

The single-group design is important. Without a randomized control group, the dose-level groups do not provide a like-for-like comparison, and differences across them may reflect factors other than dose. A single-group study can describe observed outcomes in its participants, but it does not by itself establish what would have happened under an alternative treatment or transplant approach. The adverse-event counts should therefore be understood as descriptive registry summaries, not causal estimates.

General statistical interpretation also depends on uncertainty and completeness. Estimates accompanied by confidence intervals can show the range of precision, while transparent follow-up and analysis-population details help readers assess how observations contributed. The registry record does not report outcome estimates, confidence intervals, detailed missing-data methods, or a statistical analysis plan. The strongest supported reading is limited to the design, protocol dose-escalation rules, listed outcomes, enrollment, and safety counts. The information does not establish efficacy, comparative benefit, or the selected MTD.

13. Why This Trial Matters Statistically

This study is statistically notable because its primary endpoint is a dose-finding decision rather than a conventional comparison of treatment groups. The 3+3 rules translate observed DLT counts into escalation, cohort expansion, or de-escalation decisions. Interpreting that endpoint requires the DLT definition, the observation period, and the counts at each dose level. The registry gives the decision framework and a timeframe up to day 28, but does not report the resulting MTD or the DLT counts used to select it.

The Phase 1/2 structure connects early dose assessment with later outcomes of clinical interest, including survival, relapse, graft-versus-host disease, and non-relapse mortality. Statistically, these questions require different summaries. Dose-limiting toxicity informs tolerability under a defined rule; time-to-event outcomes require follow-up-aware estimates; and outcomes with competing events may require cumulative-incidence methods. The registry names these measures, but the analysis results and detailed methods are not reported.

The single-group design also illustrates why study structure matters to interpretation. The dose-level safety summaries are not randomized comparisons. Descriptive counts can characterize what was recorded in each group, but they do not isolate a causal effect of dose or treatment. The registry’s safety data can be stated accurately while keeping that distinction clear.

Finally, the record demonstrates the difference between a completed study and a complete statistical account. Completion status and enrollment are documented, but outcome estimates, uncertainty, analysis populations, missing-data handling, and multiplicity methods are not reported. Those omissions limit what can be concluded from the registry record without changing what the study set out to examine.

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 direct limitation is that the primary endpoint result is not reported in the registry record. Although the protocol description defines the MTD decision rule, the record does not give the DLT counts by dose level or identify the selected dose. It also does not provide the protocol’s detailed DLT criteria, beyond stating that they were defined per protocol.

The Phase II outcomes are named but their results are not reported. This includes progression/relapse-free survival, overall survival, regimen-related toxicities, acute and chronic graft-versus-host disease, and non-relapse mortality. Outcome estimates, confidence intervals, event counts, follow-up information, and endpoint-specific denominators are not reported. The record lists 8 outcome measures but no analysis records.

The single-group design has no randomized control group. The safety summaries are organized by dose-level group, but these groups are not like-for-like randomized comparators. Differences between them cannot be attributed to dose from these data alone. The registry also does not report enough detail to determine whether the listed deaths were related to treatment.

Further interpretation is limited by absent information about missing observations, censoring, analysis populations, multiplicity, statistical models, interim analyses, and the analysis plan. These methods are not reported in the registry record and should not be inferred. The record documents the study’s design and some descriptive safety information, but it is not a complete report of the statistical results.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Phase 1/2 Study of Carfilzomib for the Prevention of Relapse and GVHD in Allo-HCT for Hematologic Malignancies — NCT02145403.
• Registry record last updated 2022-01-03; status last verified 2021-12.
• Results first posted 2020-01-06.
• 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

NCT02145403 is a completed Phase 1/2, single-group study sponsored by the University of Michigan Rogel Cancer Center. It enrolled 53 participants and investigated carfilzomib in allogeneic hematopoietic cell transplantation for high-risk hematologic malignancies. The registry lists carfilzomib and tacrolimus as interventions and describes a Phase I 3+3 dose-escalation framework, with the primary endpoint defined as maximum tolerated dose up to day 28.

The registry lists Phase II survival, toxicity, graft-versus-host disease, and non-relapse mortality outcomes, but does not report their results. It also does not report the selected MTD, DLT counts, statistical analysis plan, or analysis-level results. Descriptive adverse-event counts are listed for four dose-level groups, which are not randomized comparison arms. The record supports describing the study structure and the posted safety counts, but not determining the primary endpoint result or drawing comparative conclusions.