Phase 1b/2 Study of Carfilzomib in Relapsed Solid Tumors, Multiple Myeloma, or Lymphoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase 1b/2 Study of Carfilzomib in Relapsed Solid Tumors, Multiple Myeloma, or Lymphoma (NCT00531284), a non-randomized phase 1, phase 2 study. The primary outcome is Phase 1b: Number of Participants With Dose-limiting Toxicities (DLT).

2. Clinical Question

3. Trial Design

This was a Phase 1b/2, multicenter, open-label study sponsored by Amgen. The registry reports non-randomized allocation and a parallel model. Enrollment was 184, and the study status is completed. The recorded start was 2007-09 and primary completion was 2014-10. The population spanned relapsed solid tumors, multiple myeloma, and lymphoma, with several disease-specific and dose-specific cohorts.

Carfilzomib was given using bolus or intravenous infusion schedules. Solid tumor cohorts included bolus schedules and infusion doses listed at 36 mg/m², 45 mg/m², or schedules beginning at 20 mg/m² followed by another dose. Multiple myeloma and lymphoma cohorts also included infusion schedules with varying subsequent doses. Some multiple myeloma cohorts combined carfilzomib with weekly dexamethasone 40 mg. These cohort descriptions indicate variation in both dose and administration; they should not be treated as arms of a single randomized comparison.

The registry summary describes Phase 1b objectives as evaluating safety and tolerability in participants with relapsed solid tumors, relapsed and/or refractory multiple myeloma, and refractory lymphoma. It describes a Phase 2 objective of assessing overall response rate after 4 cycles in relapsed solid tumors. The listed primary outcome, however, is the number of Phase 1b participants with dose-limiting toxicities during 28 days. The full protocol, detailed eligibility criteria, allocation rationale, and justification for the total enrollment are not reported in the registry record.

Although secondary outcomes include response, duration of response, progression-free survival, time to progression, and pharmacokinetic measures, the record does not provide outcome analysis entries. Consequently, the design and recorded safety counts can be described, but treatment-effect estimates for response or time-to-event outcomes cannot be interpreted from this 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.

Before assignment: Phase 1b followed a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD). For Phase 2 (bolus), a Simon 2-stage design was planned using the MTD from phase 1b. The first stage of the Simon's 2-stage design was carried out; however, the study did not progress to the second stage.

Only the first 6 of 17 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Dose-limiting toxicity analysis was based on subsets of the safety population including participants exposed to carfilzomib in Cycle 1 who experienced a DLT or completed 28 days of evaluation after the first dose of carfilzomib. Participants enrolled into the expansion cohorts (MTD dose expansion, carfilzomib + DEX) were not evaluated for DLT.

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 18 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Phase 1b: Number of Participants With Dose-limiting Toxicities (DLT), measured over 28 days.

The listed primary endpoint is the number of Phase 1b participants with dose-limiting toxicities (DLTs) during the first 28 days. Participants were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. The registry defines a DLT as treatment-related neuropathy with pain at Grade 2 or higher, non-hematologic toxicity at Grade 3 or higher, Grade 4 neutropenia or thrombocytopenia lasting 7 or more days, or thrombocytopenia with bleeding.

The endpoint is used in early-phase studies to characterize treatment-limiting toxicity at the dose levels being examined. The registry states that the maximum tolerated dose for each of the solid tumor, multiple myeloma, and lymphoma populations was defined as the dose level at which < 33% of participants experienced a DLT during the first 28-day cycle. This definition describes the intended decision criterion; it is not itself a reported finding that a particular dose met the criterion.

The registry describes the DLT analysis population as subsets of the safety population: participants exposed to carfilzomib in Cycle 1 who experienced a DLT or completed 28 days of evaluation after the first dose. The description is incomplete in the registry record, including a truncated statement about expansion cohorts. Most importantly, the number of participants with DLTs by cohort and the resulting dose-level conclusions are not reported in the registry record. The endpoint’s definition can therefore be explained, but its observed results cannot be evaluated.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the endpoint count?

The primary outcome is a participant count: the number of Phase 1b participants meeting the registry’s DLT definition during the first 28 days. A count is an intuitive description of how many observed participants met the outcome, but it depends on how many participants were evaluated. For that reason, a count is most interpretable alongside its analysis population and the number assessed. Here, the registry describes a subset of the safety population, but does not report the cohort-level DLT counts or complete the population description.

The DLT definition is based on specified types and grades of toxicity, including treatment-related neuropathy with pain at Grade 2 or higher, non-hematologic toxicity at Grade 3 or higher, and specified blood-related toxicities. A definition makes the endpoint operational: it sets rules for deciding which events count. It does not show how consistently the rules were applied or how many participants met them. Those details and results are not reported in the registry record.

What does the maximum tolerated dose rule mean?

The record defines the maximum tolerated dose separately for solid tumors, multiple myeloma, and lymphoma as the dose level at which < 33% of participants experienced a DLT during the first 28-day cycle. This is a decision rule described in the registry. It is not an observed result, and the rule alone does not establish which dose was selected. The observed numbers by dose and population are needed to apply it; those numbers are not reported in the registry record.

Why does the cohort structure matter?

General statistical explanation: random allocation helps balance measured and unmeasured participant characteristics between groups on average. This study is recorded as non-randomized, and its cohorts differ in disease group, dose, schedule, and sometimes use of dexamethasone. As a result, a contrast between two cohorts would be vulnerable to confounding: outcome differences could arise from differences in who entered each cohort or how treatment was given, rather than from the treatment difference alone. The record explicitly notes that its arms are not a like-for-like control comparison.

Open-label means that the study was not masked. General statistical explanation: awareness of treatment assignment can affect outcome assessment or reporting, especially for outcomes that involve judgment. The registry does not report procedures intended to limit such effects. This does not establish that assessment was biased, but it means masking cannot be assumed as a safeguard.

How should the safety counts be read?

The safety listing reports participants at risk and participants affected for serious adverse events and other adverse events by cohort. These counts describe observed events in the recorded cohorts. They are not randomized comparisons, and counts from cohorts of different sizes should not be read as directly comparable measures of risk. General statistical explanation: uncertainty around an event proportion depends in part on the number of participants observed; small cohorts generally provide less precise estimates than larger cohorts. No confidence intervals for the serious adverse-event counts are reported in the registry record.

The record separately lists serious adverse-event terms and percentages. A term-specific percentage needs a clearly defined numerator and denominator to be interpreted. The registry record does not state the denominator for the listed term percentages. They should therefore be read as registry-reported percentages whose population basis is unclear, not as percentages of all enrolled participants.

What can be said about efficacy analysis?

The registry summary names overall response rate after 4 cycles as the Phase 2 objective for relapsed solid tumors. Secondary outcomes include response throughout the study and time-to-event outcomes. But the record reports zero analysis entries and gives no effect estimates, confidence intervals, or test results for these outcomes. A stated endpoint or objective is not a result. Without the analysis results and the population used for each analysis, efficacy cannot be quantified from this record.

General statistical explanation: a confidence interval expresses the range of estimates compatible with the data under a specified statistical method. It communicates precision as well as the estimated value. Since no interval estimates for DLT or efficacy outcomes are reported, the precision of those outcomes cannot be assessed. A p-value, even if present, would address compatibility with a specified null model and would not by itself describe the magnitude or clinical importance of an effect.

What statistical plan is documented?

The record identifies endpoints, timeframes, the DLT definition, and the maximum tolerated dose criterion. It does not report a complete statistical analysis plan, sample-size justification, interim analysis approach, missing-data method, or multiplicity strategy. These should not be inferred from the phase labels or from the presence of multiple outcomes. Any more detailed account of those methods is not reported in the registry record.

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("P1B ST: CFZ 20 mg/m² Bolus", "P1B ST: CFZ 20/27 mg/m² Bolus", "P1B ST: CFZ 20/36 mg/m² Bolus", "P1B ST: CFZ 36 mg/m²", "P1B ST: CFZ 45 mg/m²", "P1B ST: CFZ 20/45 mg/m²")
n      <- c(3, 3, 6, 6, 6, 6)
events <- c(0, 0, 1, 0, 2, 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  P1B ST: CFZ 20 mg/m² Bolus  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  P1B ST: CFZ 20/27 mg/m² Bolus  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  P1B ST: CFZ 20/36 mg/m² Bolus  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  P1B ST: CFZ 36 mg/m²  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  P1B ST: CFZ 45 mg/m²  6  2  33.3  4.3  77.7  9.7  70.0  9.9  71.0
ARM  P1B ST: CFZ 20/45 mg/m²  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0

11. Multiplicity, Missing Data and Analysis Populations

The study lists multiple outcome measures, including DLTs, response, duration of response, progression-free survival, time to progression, and pharmacokinetic measures. It also spans several disease populations and treatment cohorts. When many outcomes or subgroup comparisons are examined, the chance of finding an apparently notable result by chance can increase. General statistical explanation: multiplicity methods can control or describe that issue, but the appropriate approach depends on the planned hypotheses and analysis structure. A multiplicity strategy is not reported in the registry record.

The Phase 2 summary identifies overall response rate after 4 cycles as an objective, while the listed primary endpoint is the Phase 1b DLT count. The record does not explain how the various objectives and outcomes were prioritized for statistical testing, nor does it report a hierarchy of tests. No analysis entries are listed, so there are no posted test results to interpret in light of multiple outcomes.

Missing-data procedures and outcome-specific analysis populations are not reported in the registry record. The primary endpoint description gives a partial account of the DLT population, including participants exposed in Cycle 1 who experienced a DLT or completed 28 days of evaluation, but its further description is truncated. The record does not state how participants with incomplete evaluation, early discontinuation, or missing outcome measurements were handled. It also does not provide participant flow by cohort or the number assessed for each outcome.

These omissions matter because an analysis can differ depending on which participants are included and how incomplete observations are treated. The overall enrollment of 184 does not establish the denominator for any particular endpoint or cohort. No assumption about missing outcomes, analysis populations, interim monitoring, or sample-size rationale can be made from the registry record.

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: proteinuria (50.0%), renal tubular necrosis (50.0%), respiratory distress (50.0%), disease progression (36.4%), pain (33.3%).

The serious adverse-event listing gives the number at risk and the number affected in each cohort. These are descriptive counts, not comparisons against a control group. Cohorts differ in disease population, dose, schedule, and number of participants, so the counts do not by themselves support a like-for-like safety ranking. The record does not report deaths in the group entries; a death count is therefore not available from this record.

For example, the Phase 2 solid tumor bolus cohort lists 65 participants at risk and 27 affected for serious adverse events. This is an observed count within that cohort. It is not an estimate of excess risk attributable to carfilzomib, since no randomized comparator is present. The record also lists participants affected by other adverse events, but these counts do not establish severity or causation for every event.

The listed serious-event terms include Proteinuria, Renal tubular necrosis, and Respiratory distress, each shown as 50.0%; Disease progression is listed as 36.4%, while Pain and Dyspnoea are listed as 33.3% each. The registry record does not specify the denominator or exact calculation basis for these term-specific percentages. These figures should not be treated as percentages of all 184 participants or as cohort-specific incidence estimates without that information. The data are safety descriptions, not medical advice or a controlled assessment of treatment effects.

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

The record establishes that this was a completed, open-label Phase 1b/2 study of carfilzomib across relapsed solid tumors, multiple myeloma, and lymphoma. It documents different dose and administration cohorts, with dexamethasone included in some multiple myeloma cohorts. It also defines a Phase 1b DLT endpoint, its 28-day timeframe, and a criterion used to define the maximum tolerated dose within each of three disease populations.

What the available record does not establish is the observed DLT count at each dose, the maximum tolerated dose selected in any population, or the overall response rate in the Phase 2 solid tumor cohort. Although the summary names response and other clinical outcomes, estimates and analyses for them are not reported in the registry record. No comparison of treatment effect against a randomized control is available.

The adverse-event entries provide cohort-level counts for participants affected by serious and other events, and the record lists serious-event terms with percentages. These data can describe what was recorded in the listed cohorts, but cannot isolate an effect caused by carfilzomib. The non-randomized design, heterogeneous cohorts, lack of a like-for-like control, and unclear basis for the term-specific percentages limit comparative interpretation.

General statistical explanation: an observed event count is not the same as a precise estimate of underlying risk. Its interpretation depends on the number evaluated, the outcome definition, follow-up, and completeness of observation. Here, the primary DLT results and the analysis details needed to assess precision are absent. Thus the record supports a description of study aims, treatment groups, endpoint definitions, and reported safety counts, but not a conclusion about the magnitude or certainty of efficacy or comparative safety.

14. Why This Trial Matters Statistically

This trial is statistically notable for the range of populations and treatment cohorts addressed within one registry record. Solid tumors, multiple myeloma, and lymphoma are represented, and the listed regimens vary by dose, administration method, and use of dexamethasone. That structure makes it important to keep each cohort and its intended question distinct rather than treating all participants as one homogeneous group.

The primary DLT outcome illustrates how endpoint definitions and decision rules shape early-phase interpretation. The registry specifies toxicity categories, a 28-day evaluation period, and a maximum tolerated dose criterion for each disease population. Yet the outcome counts needed to apply that criterion are not reported in the registry record. A well-defined rule can clarify a study’s intended decision process, but it cannot substitute for the observed data.

The non-randomized, open-label design also matters. It is appropriate to describe the observed safety counts and study objectives, while recognizing that cohort differences are not controlled treatment comparisons. The Phase 2 response objective is distinct from the listed Phase 1b primary safety endpoint, and the registry record does not provide the response analyses needed to evaluate that objective.

More broadly, the record demonstrates why registry interpretation requires separating plans from results. Endpoints, treatment schedules, and outcome names describe what was to be studied; they do not reveal what the data showed. Here, the missing primary and efficacy results, incomplete analysis-population details, and unreported methods for multiplicity and missing data prevent a fuller statistical assessment. The distinction between descriptive safety reporting and evidence of comparative treatment effects is central to reading this study accurately.

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 primary limitation for interpretation is that the registry record does not report the observed results for the primary DLT endpoint or the Phase 2 overall response objective. It lists zero analysis entries. Without outcome counts or estimates, the intended dose decision and response findings cannot be assessed. Confidence intervals and other measures of precision are also not reported.

The design is non-randomized and open-label, with no like-for-like control comparison. The cohorts differ across disease groups and treatment regimens, and some multiple myeloma cohorts include dexamethasone. Any cross-cohort contrast would therefore be descriptive and potentially confounded by population and regimen differences.

The DLT analysis-population description is incomplete, and participant flow or endpoint-specific denominators are not reported. The registry does not explain handling of incomplete follow-up or missing outcomes. Detailed eligibility criteria, statistical analysis methods, multiplicity procedures, sample-size justification, and interim analysis plans are not reported in the registry record.

Safety reporting also has limits. Cohort counts describe participants affected but do not identify a treatment-attributable risk in the absence of a randomized comparator. The denominators for the listed serious-event term percentages are not stated, and the group entries do not give a death count. These limitations prevent a comprehensive assessment of either comparative safety or outcome precision using the registry record alone.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Phase 1b/2 Study of Carfilzomib in Relapsed Solid Tumors, Multiple Myeloma, or Lymphoma — NCT00531284.
• Registry record last updated 2017-08-15; status last verified 2017-07.
• Results first posted 2015-12-09.
• 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

NCT00531284 is a completed, multicenter, open-label Phase 1b/2 study sponsored by Amgen. It enrolled 184 participants with relapsed solid tumors, multiple myeloma, or lymphoma. The recorded start was 2007-09 and primary completion was 2014-10. Treatment cohorts received carfilzomib using different bolus or infusion schedules; some multiple myeloma cohorts also received dexamethasone.

The listed Phase 1b primary endpoint was the number of participants with DLTs during 28 days. The study summary also describes a Phase 2 objective of evaluating overall response rate after 4 cycles in relapsed solid tumors. The registry record gives the DLT definition and maximum tolerated dose criterion, but does not report the DLT outcome counts, dose conclusions, or response analyses. It includes cohort-level adverse-event counts and serious-event terms, but no randomized control comparison. Detailed statistical methods, missing-data handling, and multiplicity procedures are not reported in the registry record.