A Phase 1 Study of IXAZOMIB in Adult Patients With Advanced Nonhematologic Malignancies: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Phase 1 Study of IXAZOMIB in Adult Patients With Advanced Nonhematologic Malignancies (NCT00830869), a non-randomized phase 1 study. The primary outcome is Part 1: Number of Participants With Dose Limiting Toxicity (DLT).

2. Clinical Question

This is a dose-finding question, not a comparative efficacy question. The study aimed to characterize safety, establish the maximum tolerated dose, and inform a phase 2 dose. It also recorded pharmacokinetic and pharmacodynamic outcomes, best overall response, and ixazomib concentration in postdose tumor samples. The registry lists these as secondary outcomes, but does not report their results in the record.

3. Trial Design

The study was open-label, multicenter, phase 1, nonrandomized, and single-group. It was designed around dose escalation rather than allocation to a concurrent control. Participants received intravenous ixazomib in Part 1 at listed dose levels from 0.125 mg/m^2 to 2.34 mg/m^2. The regimen was described as dosing on Days 1, 4, 8 and 11, followed by 10 days of rest in 21-day cycles, for a maximum of 12 cycles or until progressive disease or unacceptable toxicity.

Part 2 used 1.76 mg/m^2 in separate groups identified by cancer type: non-small cell lung cancer, head and neck cancer, soft tissue sarcoma, prostate cancer, and a group described as various solid tumors suitable for biopsy. The listed treatment description retains the 21-day cycle schedule and continuation limits. Part 2 therefore extends the study into specified tumor groups, but does not provide a randomized comparison with another treatment.

The registry reports enrollment of 116 and marks the study completed. The recorded start date is 2009-03-02, and the primary completion date is 2012-04-20. These are registry dates, not evidence about the duration of treatment or follow-up for any individual participant. The protocol's planned sample-size justification, detailed escalation rules, and stopping boundaries are not reported in the registry record.

For the primary outcome, the registry defines a DLT population based on Cycle 1 treatment and completion. Participants whose Cycle 1 was interrupted by a DLT were included. This definition matters because the primary outcome does not necessarily use every enrolled participant as its denominator. The number included in that analysis and the number with a DLT 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.

Before assignment: Participants with diagnosis of nonhematologic malignancies were enrolled in 1 of the 2 parts, Part 1: Dose escalation to determine maximum tolerated dose (MTD), and Part 2: Expansion at MTD in 5 expansion cohorts.

Only the first 6 of 12 groups are shown.

Period 1: Part 1

Reasons for not completing this period:

Period 2: Part 2

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The DLT population included all participants who received all Cycle 1 doses of ixazomib and who had completed Cycle 1. If Cycle 1 was interrupted by a DLT, the participant was included in this population.

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: The safety population included all participants who received at least 1 dose of ixazomib.

Only the first 6 of 13 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Part 1: Number of Participants With Dose Limiting Toxicity (DLT), measured over Part 1: Cycle 1 Day 1 up to Cycle 1 Day 21.

The primary endpoint is the number of Part 1 participants with a dose-limiting toxicity during Cycle 1, from Cycle 1 Day 1 through Cycle 1 Day 21. The registry describes DLT as toxicity related to ixazomib and assessed according to NCI CTCAE version 3.0. The listed criteria include specified severe blood-count abnormalities, neuropathy, gastrointestinal toxicity, QTc prolongation, nonhematologic toxicity, and treatment delay caused by toxicity. Some criteria depend on duration, symptoms, supportive treatment, or investigator judgment.

A DLT endpoint is used in early dose-finding research to identify toxicities that may constrain dose escalation and to inform a dose for later study. It focuses on a defined early treatment interval, rather than capturing every possible adverse event throughout treatment. Its interpretation depends on the toxicity definitions, attribution, assessment period, and population used. Here, the registry supplies a population definition: participants who received all Cycle 1 doses and completed Cycle 1, including participants whose cycle was interrupted by a DLT.

The registry record does not report the primary endpoint result, the analyzed participant count, or dose-specific DLT counts. Consequently, it does not support a numerical description of the observed DLT frequency or a conclusion about which dose met a particular tolerability criterion.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

This was a single-group, nonrandomized dose-escalation study. In this design, participants are assigned to dose cohorts as part of the escalation structure, not randomly allocated between treatments. The study can describe what was observed at the tested dose levels, but a cohort comparison is not equivalent to a randomized treatment contrast. Cohorts may differ in dose, study part, tumor type, or other participant characteristics; the registry does not report a method that would make them comparable for causal inference.

What does dose escalation contribute?

Dose escalation is a way to investigate safety across planned dose levels and help select a dose for subsequent research. The primary endpoint's focus on Cycle 1 DLTs gives the study a defined early safety measure. Interpretation still depends on who entered the DLT population, whether assessments were complete, and how toxicity attribution and grading were applied. The registry describes the DLT criteria and population definition, but does not report the DLT counts, analyzed denominators, escalation algorithm, or decision rules. Those details are not reported in the registry record.

What do counts and percentages say?

A count reports the number of participants recorded as having an event under a particular definition. A percentage expresses a count in relation to a denominator, but the denominator must be clear before the percentage can be interpreted as a risk. For the serious adverse event term percentages, the registry does not report the denominator or calculation method. The group-level at-risk and affected counts provide context for serious and other adverse events, but they are not interchangeable with the DLT population or primary endpoint.

Small cohort counts can be imprecise: a change in one participant's status can materially alter a proportion when a group is small. This is a general statistical point, not a finding about any unreported DLT result. Confidence intervals, when reported, describe uncertainty around an estimate under the statistical method used; the registry record does not report a confidence interval for the primary endpoint.

Why is there no causal comparison?

Randomization helps make treatment groups comparable, on average, with respect to both measured and unmeasured baseline characteristics. This trial was nonrandomized and had no control group. Therefore, comparing the reported event counts across dose cohorts or tumor groups cannot isolate a dose effect from differences in group composition, exposure, or study part. The registry explicitly identifies the arms as not being a like-for-like control comparison.

What are the planning assumptions?

The registry's planning description specifies a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the target effect expressed as a fraction of the observed effect. It distinguishes planning illustrations for participants per arm from time-to-event illustrations that use total events. These are generic assumptions for planning calculations, not the design of this nonrandomized single-group trial. Any such calculated sample sizes are planning illustrations, not observed power, and should not be treated as trial results. The registry does not report the trial's own sample-size justification, and no calculated planning values are stated in the record.

What analyses can be assessed?

The registry lists no analyses. Thus, the record does not identify a fitted model, adjustment variables, hypothesis tests, multiplicity procedure, or approach to uncertainty for the primary outcome. For a count endpoint, a simple count and its denominator would provide a descriptive result; uncertainty could be presented with an interval, but no such interval is recorded. General statistical methods cannot replace missing trial-specific results or establish what analysis was actually performed.

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("Part 1: Ixazomib 0.125 mg/m^2", "Part 1: Ixazomib 0.25 mg/m^2", "Part 1: Ixazomib 0.5 mg/m^2", "Part 1: Ixazomib 1 mg/m^2", "Part 1: Ixazomib 1.33 mg/m^2", "Part 1: Ixazomib 1.76 mg/m^2")
n      <- c(1, 1, 1, 7, 4, 6)
events <- c(0, 0, 0, 1, 0, 1)
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  Part 1: Ixazomib 0.125 mg/m^2  1  0  0.0  0.0  97.5  0.0  79.3  1.3  84.2
ARM  Part 1: Ixazomib 0.25 mg/m^2  1  0  0.0  0.0  97.5  0.0  79.3  1.3  84.2
ARM  Part 1: Ixazomib 0.5 mg/m^2  1  0  0.0  0.0  97.5  0.0  79.3  1.3  84.2
ARM  Part 1: Ixazomib 1 mg/m^2  7  1  14.3  0.4  57.9  2.6  51.3  3.2  52.7
ARM  Part 1: Ixazomib 1.33 mg/m^2  4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2
ARM  Part 1: Ixazomib 1.76 mg/m^2  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 14 outcome measures, including pharmacokinetic measures, pharmacodynamic measures, best overall response, and tumor-sample concentration, in addition to the primary outcome. When a study examines multiple outcomes or multiple comparisons, the chance of at least one apparently notable result can increase. Statistical plans often address this through prespecified outcome hierarchies or multiplicity adjustments. The registry does not report a multiplicity strategy, so it is not possible to determine whether or how multiple testing was handled.

The record also lists zero analyses. It does not report primary endpoint results, confidence intervals, missing-data counts, or a method for handling missing outcome assessments. The effect of missing data therefore cannot be evaluated. In general, missing outcome information can affect both the denominator and the interpretation of a count, particularly when completion or toxicity influences whether a participant is assessed.

The primary outcome population is defined as participants who received all Cycle 1 doses and completed Cycle 1, with participants whose cycle was interrupted by a DLT included. This is the only specific primary analysis population definition in the record. The number meeting that definition and the handling of participants who did not meet it are not reported in the registry record. The enrollment figure of 116 should not be assumed to be the primary endpoint denominator.

Interim analyses, data-monitoring procedures, and prespecified statistical analysis details are not reported in the registry record. Without these details and the outcome results, the record does not allow assessment of selective reporting, analysis-population sensitivity, or robustness to alternative assumptions.

12. 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: dyspnoea (100.0%), pulmonary embolism (100.0%), gastrointestinal haemorrhage (100.0%), thrombocytopenia (66.7%), pneumonia (33.3%).

The registry separates serious adverse events from other adverse events and reports group-level counts for participants at risk and affected, alongside deaths. These are descriptive safety summaries, not estimates from a randomized comparison. The listed cohorts have different doses or tumor groups, and the record warns that they are not like-for-like controls.

For example, the Part 1 group receiving 1.76 mg/m^2 lists 6 participants at risk for serious adverse events and 4 affected; the corresponding other adverse event fields list 6 at risk and 6 affected. These figures describe the registry's group entries, not the primary DLT endpoint. The record lists 3 deaths in the Part 1 dose groups at 1 mg/m^2, 1.33 mg/m^2, and 2.34 mg/m^2, respectively, and also lists deaths in some Part 2 groups. A death count does not by itself establish cause or treatment relationship.

The serious adverse event terms are accompanied by percentages, including dyspnoea at 100.0%, pulmonary embolism at 100.0%, gastrointestinal haemorrhage at 100.0%, thrombocytopenia at 66.7%, pneumonia at 33.3%, and disease progression at 33.3%. The denominator and calculation method for these percentages are not reported in the registry record. They should not be interpreted as incidence among all participants without that information. Group size, event definition, attribution, and assessment period all matter when interpreting safety counts.

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

This study's stated purpose was to characterize safety, establish a maximum tolerated dose, and inform a phase 2 dose for intravenous ixazomib in adults with advanced nonhematologic malignancies. Its primary outcome was designed to measure participants with a qualifying DLT in Cycle 1. The registry record provides the endpoint definition and population criteria, but not the DLT result.

Accordingly, the record does not establish how many participants experienced DLT, what proportion of the primary analysis population was affected, or which dose was selected on the basis of the primary endpoint. It also does not provide a reported estimate of treatment efficacy. Secondary outcomes are listed, but their results are not reported in the registry record.

The adverse event summaries offer separate descriptive information, including group-level serious and other event counts and deaths. They do not provide a randomized comparison, and the registry does not report the denominator for the serious-event term percentages. These safety entries cannot be used as a substitute for the missing primary DLT result or as proof that ixazomib caused any particular event.

More generally, a phase 1 dose-escalation study addresses early safety and dose selection; its design does not answer whether treatment is better than an alternative. Here, the lack of a control group and the absence of posted primary outcome results sharply limit what can be concluded from the registry record. The design and outcome definitions are informative, but the record alone does not support a quantitative conclusion about tolerability or benefit.

14. Why This Trial Matters Statistically

The study is statistically notable for the difference between a carefully specified endpoint and an unavailable endpoint result. The registry defines the DLT criteria, observation window, and population, all of which are essential for interpreting an early safety outcome. Yet without the numerator and denominator, the primary outcome cannot be quantified. This illustrates why an endpoint description and an endpoint result answer different questions.

The design also shows why dose-escalation cohorts should not be treated as conventional comparison arms. The study includes multiple dose levels and later tumor-specific groups, but no randomized allocation or concurrent control. Apparent differences between these cohorts may reflect the design and group composition rather than a causal dose response. Statistical methods cannot remove this limitation without appropriate design information and reported analyses.

Finally, the record distinguishes several kinds of safety information: DLTs during Cycle 1, serious adverse events, other adverse events, and deaths. Each has its own definition and context. Treating them as interchangeable would obscure the purpose of the primary endpoint and could overstate what the recorded counts show. The missing analysis details and absent primary result further emphasize the importance of complete registry outcome reporting for transparent interpretation.

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 does not report the DLT result or the number of participants included in its analysis population. Although the endpoint definitions are detailed, no dose-specific primary outcome counts or uncertainty estimates are reported. The record therefore cannot establish the observed DLT frequency or the basis for dose selection.

The nonrandomized, single-group design has no concurrent control. The dose cohorts and tumor-specific groups are not like-for-like comparisons, so their event counts cannot establish comparative safety or efficacy. The record does not report baseline characteristics by cohort, participant-level outcome data, or an adjustment analysis that might clarify differences between groups.

For serious adverse event terms, the denominator and percentage calculation are not reported in the registry record. Death counts are listed, but the group figures do not establish cause or treatment relationship. Missing-data handling, multiplicity procedures, interim analyses, the statistical analysis plan, and the trial's sample-size justification are not reported in the registry record.

The registry lists secondary outcomes but does not report their results in the record. These limitations are specific to the available registry information; they do not establish what may have been analyzed or reported elsewhere.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Phase 1 Study of IXAZOMIB in Adult Patients With Advanced Nonhematologic Malignancies — NCT00830869.
• Registry record last updated 2019-09-09; status last verified 2019-07.
• Results first posted 2019-09-09.
• 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

This completed, open-label, multicenter phase 1 study evaluated intravenous ixazomib in adults with advanced nonhematologic malignancies. It used a nonrandomized, single-group dose-escalation design, with Part 1 dose levels from 0.125 mg/m^2 to 2.34 mg/m^2 and Part 2 groups receiving 1.76 mg/m^2. The registry reports enrollment of 116, a start date of 2009-03-02, and a primary completion date of 2012-04-20.

The primary outcome was the number of Part 1 participants with a DLT during Cycle 1. The registry defines the endpoint and its population but does not report the result, analysis denominator, or statistical analyses. Serious and other adverse event group figures are available, but they are descriptive and do not create a randomized comparison. The record does not report a multiplicity plan, missing-data method, or trial-specific sample-size justification.