Safety Study of the Proteasome Inhibitor PR-171 (Carfilzomib for Injection) in Patients With Hematological Malignancies: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety Study of the Proteasome Inhibitor PR-171 (Carfilzomib for Injection) in Patients With Hematological Malignancies (NCT00150462), a non-randomized phase 1 study. The primary outcome is Number of Participants With Dose-limiting Toxicities (DLTs).

2. Clinical Question

3. Trial Design

This was a phase I safety and pharmacokinetics study of escalating intravenous carfilzomib doses in people with hematological malignancies. The registry records the design as non-randomized, with no masking and a single-group model. It reports enrollment of 48 and lists dose groups from 1.2 mg/m² through 27.0 mg/m², as well as a 20/27 mg/m² regimen and that regimen combined with dexamethasone.

The dose descriptions specify administration by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day cycles for up to 12 cycles for the listed escalating-dose groups. For the 20/27 mg/m² regimen, the record describes 20 mg/m² during Cycle 1 followed by 27 mg/m² in subsequent cycles. The dexamethasone regimen adds 20 mg before each carfilzomib dose, described as 40 mg weekly.

There is an inconsistency in the dose description for the group titled CFZ 15.0 mg/m²: its description says 115.0 mg/m². The registry record does not clarify this discrepancy. The presence of dose groups does not make them randomized comparator arms; the record explicitly identifies the allocation as non-randomized. A protocol description of dose escalation does not establish the precise rules used to assign participants, which are not reported in the registry record.

The study is marked completed. Its listed secondary outcomes are best clinical response, duration of response, time to progression, and progression-free survival. The posted record does not include analyses for those outcomes. It also does not report a randomized comparison, a masking procedure, or a concurrent control treatment.

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: The study was divided into a sequential Dose Escalation phase (Part 1; Arms 1-9), followed by a Dose Expansion phase (Part 2; Arms 10-11) consisting of a carfilzomib-only cohort and a carfilzomib-plus dexamethasone cohort.

Only the first 6 of 11 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety-evaluable: All participants who were enrolled and received at least 1 dose of carfilzomib

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.

Only the first 6 of 12 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Dose-limiting Toxicities (DLTs), measured over 28 days.

The primary endpoint is the number of participants with dose-limiting toxicities (DLTs), assessed over 28 days. The safety-evaluable population is defined as participants who were enrolled and received at least one dose of carfilzomib. The registry describes DLT criteria covering both nonhematologic and hematologic toxicities, graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 3.0.

Among the specified nonhematologic criteria are neuropathy with pain above Grade 2, severe nonhematologic toxicity, and severe nausea, vomiting, or diarrhea that remains uncontrolled despite maximal treatment. Hematologic criteria include prolonged Grade 4 neutropenia without growth factor support, febrile neutropenia, and Grade 4 thrombocytopenia or thrombocytopenia associated with bleeding. The description gives laboratory thresholds and durations for these criteria; those details define what qualifies as a DLT rather than reporting how often DLTs occurred.

In general, early dose-limiting toxicity is used in phase I research to describe whether serious toxicity emerges during an initial, defined observation period as doses are explored. It is a safety measure, not a direct measure of tumor response or long-term benefit. The registry record does not report the primary endpoint counts, the number evaluated for this endpoint, or an estimate comparing dose levels. Thus, the endpoint definition is available, but its observed result cannot be interpreted from the posted results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a dose-limiting toxicity endpoint capture?

The primary endpoint counts participants who meet a prespecified toxicity definition during the stated observation period. It is a participant-level count: the endpoint is whether a participant meets the definition, rather than a total count of every symptom or episode. This distinction matters because one participant could experience more than one qualifying toxicity, while the endpoint may still count that person as a participant with a DLT.

The definition combines different clinical events and thresholds. This makes the endpoint a composite safety measure: a participant can meet it through any qualifying item in the definition. General statistical principle: composite endpoints can be useful for capturing a range of clinically important events, but the overall count does not reveal which component drove the result. Component-level counts would be needed to describe that detail. The registry provides the criteria but does not report the number meeting the composite definition or the component-specific results.

How should non-randomized dose groups be understood?

The record identifies non-randomized allocation and a single-group model. The dose groups are therefore best understood as descriptive cohorts in a dose-ranging study, not as randomized arms in a comparative trial. A randomized comparison aims to make treatment groups comparable, on average, in both measured and unmeasured characteristics. Non-randomized groups do not have that design protection. General statistical principle: observed differences between non-randomized groups can reflect differences in participant characteristics, selection, follow-up, or treatment assignment in addition to the intervention dose.

Consequently, a numerical contrast between two groups would not, by itself, establish that dose caused the difference. The registry's designation and its explicit caution that the arms are not like-for-like controls should guide interpretation. No adjustment strategy or causal analysis is reported in the registry record.

What do confidence intervals and significance tests tell readers?

General statistical explanation: a confidence interval describes the range of values compatible with an estimate under the assumptions of the analysis. It communicates precision as well as the estimate itself. A narrow interval indicates more precision than a wide interval, while an interval spanning a broad range can leave substantial uncertainty about the underlying value. A significance test assesses compatibility with a specified null hypothesis under a statistical model; it does not measure clinical importance or prove that a treatment caused an outcome.

The registry record does not report a primary endpoint estimate, confidence interval, or significance test. It also records zero analyses for the outcomes listed. There are therefore no inferential estimates in the posted results to interpret. The absence of a reported test is not evidence that groups are equivalent, and a descriptive adverse-event count should not be treated as a test of a dose difference.

What is over-dispersion, and is it relevant?

General statistical explanation: over-dispersion occurs when count data vary more than a chosen statistical model expects. If it is ignored, uncertainty can be understated and confidence intervals may be too narrow. Whether over-dispersion matters depends on the outcome structure and model. The registry does not report a count model, model diagnostics, or an analysis plan for the DLT outcome, so it is not possible to say that any particular over-dispersion method was used or needed for the reported results.

How should planning illustrations be read?

General statistical explanation: a sample-size calculation based on an observed effect is a planning illustration, not an observed trial result and not observed power. In this record, the stated planning assumptions are a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and effects expressed as fractions of an observed effect. The record specifies that time-to-event calculations refer to total events, while other calculations refer to participants per arm. These assumptions describe hypothetical planning calculations; they do not convert this non-randomized study into a two-arm trial or establish the study's original design rationale.

The registry does not report a sample-size justification for the trial. Nor does it report the analysis methods used for the posted outcomes, or a protocol-based statistical plan that would explain how missing observations, dose groups, or multiple outcomes were handled. General statistical principle: planning estimates depend on their assumptions and should not be read as a guarantee of precision or as evidence that a study had adequate power for a particular endpoint.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("CFZ 1.2 mg/m²", "CFZ 2.4 mg/m²", "CFZ 4.0 mg/m²", "CFZ 6.0 mg/m²", "CFZ 8.4 mg/m²", "CFZ 11.0 mg/m²")
n      <- c(3, 3, 4, 3, 3, 4)
events <- c(1, 0, 0, 0, 0, 0)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  CFZ 1.2 mg/m²  3  1  33.3  0.8  90.6  6.1  79.2  6.8  80.6
ARM  CFZ 2.4 mg/m²  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  CFZ 4.0 mg/m²  4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2
ARM  CFZ 6.0 mg/m²  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  CFZ 8.4 mg/m²  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  CFZ 11.0 mg/m²  4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary safety endpoint and several secondary outcomes: best clinical response, duration of response, time to progression, and progression-free survival. It reports nine outcome measures, but does not provide analyses for them. The registry record does not describe a multiplicity strategy, such as a hierarchy among outcomes or an adjustment for multiple statistical tests. Without reported analyses, there are no posted outcome-specific tests to evaluate for multiplicity.

Missing-data methods are not reported in the registry record. The primary endpoint population is described as participants who were enrolled and received at least one dose of carfilzomib, but that definition does not explain how participants with incomplete safety follow-up were handled. The record does not specify whether missing observations were excluded, imputed, or otherwise addressed. It also does not report a separate intention-to-treat population or an analysis population for the secondary outcomes.

Interim analyses, stopping rules, and the statistical analysis plan are not reported in the registry record. A phase I description and a stated 28-day DLT timeframe do not establish whether interim reviews took place or how decisions were made during dose exploration. The record also does not report the trial's sample-size justification. These omissions limit assessment of how outcomes were selected, how incomplete records may have affected estimates, and whether the final analyses followed a prespecified plan.

12. 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: febrile neutropenia (33.3%), hyperviscosity syndrome (33.3%), pyrexia (33.3%), bronchitis (33.3%), pneumonia (33.3%).

The serious adverse event summaries give, by dose group, the number of participants affected and the number at risk. They are descriptive counts; they are not the primary DLT result. The registry lists 2 of 3 affected in the CFZ 1.2 mg/m² group, 1 of 3 in CFZ 2.4 mg/m², 3 of 4 in CFZ 4.0 mg/m², 2 of 3 in CFZ 6.0 mg/m², and 2 of 3 in CFZ 8.4 mg/m². It lists 2 of 4 in CFZ 11.0 mg/m², 1 of 3 in CFZ 15.0 mg/m², 3 of 8 in CFZ 20.0 mg/m², 4 of 6 in CFZ 27.0 mg/m², 3 of 7 in CFZ 20/27 mg/m², and 2 of 4 in CFZ 20/27 mg/m² with dexamethasone.

These small group counts should not be read as stable estimates of comparative risk. The trial was non-randomized, and no like-for-like control comparison is reported. The registry also lists six serious adverse event terms at 33.3% each, but does not supply the participant counts or denominator context for those percentages. Death counts are not reported in the registry record. These summaries do not show the full adverse-event profile or establish whether an event met the primary DLT definition.

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

The posted information shows how the study was structured and what its primary safety question was. Carfilzomib was given at different intravenous dose levels to people with hematological malignancies, and the primary endpoint was the number of safety-evaluable participants experiencing a qualifying DLT in the first 28 days. The registry also presents serious adverse event summaries by dose group and lists selected serious event terms.

It does not report the primary endpoint counts or analyses of the listed secondary outcomes. Thus, readers cannot use the registry record to estimate the frequency of DLTs, compare DLT frequency by dose, or assess response and progression outcomes. The serious adverse event counts do not fill that gap: they refer to a distinct safety summary, and the registry does not provide enough detail to treat them as a complete safety analysis.

The record does not establish that carfilzomib caused an observed event, nor does it support claims about comparative safety or efficacy. Non-randomized dose groups are not equivalent to randomized treatment arms, and the group summaries may be influenced by differences in who received each dose. No randomized comparator or masking was used.

General statistical principle: absence of a reported result is not evidence of no effect or no harm. It means the result cannot be evaluated from the registry information available. The design and reported safety summaries can be described, but conclusions about treatment effects, dose selection, or the balance of benefit and harm require results and analyses that are not reported in the registry record.

14. Why This Trial Matters Statistically

This study illustrates why phase I safety research and later comparative trials answer different statistical questions. Dose-limiting toxicity during a defined early period is intended to characterize immediate tolerability across dose levels. A dose-ranging description can show how treatment was explored, but non-randomized dose groups do not provide the same basis for causal comparison as randomized groups.

The registry's endpoint definition is detailed, while the endpoint results are absent. This is an important distinction for interpreting trial records: a clearly specified outcome is not itself an observed result. Without participant counts, analysis methods, and uncertainty estimates for DLTs, the primary safety question remains unanswered by the posted information. The selected serious adverse event summaries offer some descriptive context, but small group counts and missing denominator context for the term-specific percentages constrain their interpretation.

The record also lists response and time-to-event outcomes without reporting analyses. Statistical readers should separate study aims, outcome definitions, event summaries, and inferential results rather than treating them as interchangeable. The non-randomized allocation and absence of a control comparison further limit causal interpretation.

Finally, an internal inconsistency in the CFZ 15.0 mg/m² dose description shows why registry entries need careful reading: the group title and its dose description do not match. The record does not resolve that discrepancy. Together, these features make the study useful for understanding the design and reporting challenges of early dose exploration, while also making clear that the posted record is insufficient for a full statistical assessment of the primary endpoint.

15. 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 for interpretation is that the registry record does not report the primary DLT counts, despite defining the endpoint and its timeframe. It also does not report analyses for the secondary outcomes. Consequently, the posted results do not permit estimation of the primary endpoint or assessment of response, duration of response, time to progression, or progression-free survival.

The safety summaries are limited. Group sizes are small, confidence intervals are not reported, and the record does not provide event-level detail for the serious adverse event terms listed at 33.3%. Death counts are not reported in the registry record. The serious adverse event summaries should not be substituted for DLT results because the record does not state that they use the same definition or observation period.

Design limitations include non-randomized allocation, no masking, and no control group. The dose groups therefore do not support a randomized comparison, and potential differences between groups cannot be separated from dose effects using the posted information. The registry does not report the assignment rules, analysis methods, handling of missing data, multiplicity procedures, interim analyses, stopping rules, or sample-size justification.

The record also contains a dose-description inconsistency: the CFZ 15.0 mg/m² group title is paired with a description stating 115.0 mg/m². The registry does not clarify which description is intended. These reporting gaps and inconsistencies constrain what can be concluded from the record, independently of the clinical importance of the study question.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety Study of the Proteasome Inhibitor PR-171 (Carfilzomib for Injection) in Patients With Hematological Malignancies — NCT00150462.
• Registry record last updated 2017-05-02; status last verified 2017-04.
• Results first posted 2015-12-03.
• 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.

19. Record Summary

This completed phase I study examined intravenous carfilzomib in people with hematological malignancies. The record describes non-randomized allocation, no masking, a single-group model, and enrollment of 48. Dose groups included escalating carfilzomib regimens, a 20/27 mg/m² regimen, and a regimen combining that schedule with dexamethasone.

The primary endpoint was the number of safety-evaluable participants with dose-limiting toxicity during the first 28 days. The endpoint criteria are described, but its results are not reported in the registry record. Serious adverse event counts are listed by group, along with selected serious event terms; these are descriptive and do not provide a randomized comparison. The listed secondary outcomes have no reported analyses. The CFZ 15.0 mg/m² group also has an unresolved inconsistency between its title and dose description.