PU-H71 in Patients With Solid Tumors and Low-Grade Non-Hodgkin's Lymphoma That Have Not Responded to Standard Treatment: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for PU-H71 in Patients With Solid Tumors and Low-Grade Non-Hodgkin's Lymphoma That Have Not Responded to Standard Treatment (NCT01581541), a non-randomized phase 1 study. The primary outcome is Number of Participants With Cycle 1 Dose-limiting Toxicities (DLTs).

2. Clinical Question

The stated study objective was to evaluate the safety and effectiveness of PU-H71 in people whose solid tumors or non-Hodgkin's lymphoma had not responded to standard treatment. Statistically, the primary question is narrower than that broad objective: it concerns qualifying toxicities in cycle 1. Other listed outcomes include best response under RECIST v1.1, days on treatment, and pharmacokinetic measures. Their numerical results are not reported in the registry record information, so the record does not allow a quantitative assessment of those outcomes.

3. Trial Design

This was a phase I, nonrandomized, unmasked study using a sequential model. Enrollment was 17. The record identifies solid tumors and lymphoma as the conditions and lists PU-H71 as the intervention. With no randomized allocation and no control arm, the design describes experience among people receiving the study drug at different dose levels rather than estimating a comparative treatment effect.

The listed cohorts span PU-H71 doses of 10 mg/m^2, 20 mg/m^2, 40 mg/m^2, 60 mg/m^2, 80 mg/m^2, 110 mg/m^2, 150 mg/m^2, 200 mg/m^2, 266 mg/m^2, 354 mg/m^2, and 470 mg/m^2. The record characterizes the model as sequential, but does not report the exact cohort-assignment rules, escalation algorithm, stopping boundaries, or the rationale for each dose step. Those details are not reported in the registry record.

PU-H71 was described as an intravenous infusion over one hour on days 1 and 8 of a 21-day cycle. The first cycle was planned in hospital, with subsequent cycles outpatient. The summary describes blood and urine testing, eye examinations, tumor sampling, and imaging to monitor response. Treatment was to continue while side effects remained tolerable and disease did not worsen, with dose adjustment possible. The registry record does not report the number of cycles received by each participant or the duration of follow-up.

The study started on 2011-04-26, and primary completion is listed as 2014-09-03. Its status is terminated. The reason for termination, the planned enrollment target, and any amendments to the design are not reported in the registry record. Those missing details matter when considering whether the intended study conduct and the observed enrollment aligned with the original plan.

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.

Only the first 6 of 11 groups are shown.

Overall Study

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 Number of Participants With Cycle 1 Dose-limiting Toxicities (DLTs), measured over Cycle 1 (21 days).

The primary endpoint is the number of participants with cycle 1 dose-limiting toxicities, with cycle 1 defined as 21 days. It is a count endpoint: it records how many participants met the study's prespecified toxicity definition during the initial treatment period. The definition includes specified severe non-hematologic toxicities, hematologic toxicities, and unresolved ocular toxicity, with exceptions described in the registry. A qualifying event was considered dose-limiting if it occurred during cycle 1 and was thought related to study drug administration.

In a phase I dose-escalation context, an early toxicity endpoint is used to describe tolerability at the tested dose levels and to inform dose decisions. General statistical context: such an endpoint focuses on events during a defined exposure window, so it does not by itself describe all later toxicities or the total safety experience over longer treatment. A count also needs its corresponding denominator to communicate how common the event was among those assessed.

The registry defines dose reduction after the event resolved to grade 2 or lower, and permits no more than 2 dose reductions per participant. However, the observed count for the primary endpoint and the analysis population used to derive it are not reported in the registry record. Without those results, the endpoint's observed frequency cannot be described from this record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical interpretation starts by distinguishing the design from the outcomes. This is a phase I, nonrandomized, unmasked study described as sequential. The listed dose cohorts are successive exposure groups, not randomized treatment arms. General statistical context: random allocation tends to balance measured and unmeasured participant characteristics across groups, on average. Without randomization, differences between cohorts can reflect participant mix, timing, or other factors as well as dose. The registry record does not report enough detail to assess those factors.

What does a count endpoint represent?

The primary outcome is a count of participants meeting a defined dose-limiting toxicity criterion during cycle 1, a 21-day period. A count is most interpretable alongside the number of participants assessed in that same period. General statistical context: a count without its denominator does not directly convey the event proportion, and an event proportion without uncertainty may be unstable when the group is small. The primary count and its analysis population are not reported in the registry record, so neither the endpoint frequency nor its precision can be evaluated.

The endpoint definition requires an event during cycle 1, a judgment that it was related to study drug administration, and a specified toxicity criterion. This combines timing, attribution, and severity. Such an operational definition makes clear which events qualify for the primary endpoint, but it does not mean every adverse event in the safety listing qualifies as a dose-limiting toxicity. The registry also describes exceptions for particular toxicities and a dose-reduction rule after resolution. The specific process for event adjudication is not reported in the registry record.

How should dose cohorts be compared?

The record presents multiple dose levels, but the allocation is nonrandomized and sequential. General statistical context: a comparison across sequential cohorts can be affected by changes in who enters the study, how participants are monitored, or other features of conduct over time. A pattern across listed cohorts can be described, but it is not equivalent to a randomized dose-response estimate. The record does not report a formal dose-response model, an escalation algorithm, or an analysis adjusting for participant characteristics.

The reported cohort sizes are small, ranging from cohorts with one participant to cohorts with three participants. General statistical context: with few observations, a single event can substantially change a cohort's descriptive event proportion, and the absence of an event provides limited information about uncommon harms. The cohort counts are therefore best treated as a record of what was observed in these participants, not precise estimates for a broader population.

What do inferential statistics add?

General statistical context: a confidence interval communicates uncertainty around an estimate under stated assumptions; it is not a guarantee that the true value lies within the interval. A p-value, when used appropriately, summarizes how unusual data would be under a specified null model. Neither statistic substitutes for a clear endpoint definition, a relevant comparison, or complete reporting. The registry record reports no primary analyses and no p-values, confidence intervals, or adjusted estimates for the outcomes. No statistical conclusion about a treatment difference can be drawn from absent inferential results.

The record states assumptions for planning illustrations: a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect set as a stated fraction of the observed effect. These are generic planning assumptions, not descriptions of this trial's nonrandomized sequential design. General statistical context: sample-size calculations depend on the chosen endpoint, assumed effect, variability, allocation, significance level, and target power. A planning illustration based on an observed effect does not show that the trial had a particular observed power, and does not recover the original design rationale. The registry record does not report the trial's own sample-size justification or a planned power calculation.

Over-dispersion is a general concern for count data when observed variability exceeds what a simple model assumes. It can make uncertainty estimates too narrow if the model does not account for extra variability. This study's primary outcome is a participant count over a defined period, and no model-based analysis is reported. There is therefore no basis in the registry record to evaluate whether over-dispersion was assessed or whether a model was fitted.

What can be inferred from the safety listings?

The adverse event information gives counts of participants at risk and affected in each cohort, as well as deaths. These are descriptive safety summaries. General statistical context: an adverse event recorded during a study is not automatically an event caused by the intervention. Causal attribution requires clinical assessment and a suitable design and analysis; the registry's event counts alone do not settle causation. The primary dose-limiting toxicity definition includes a relatedness judgment, whereas the event listings should not be assumed to use the same endpoint definition or time window.

The record does not report a statistical analysis plan, a missing-data strategy, interim analyses, or the method used to handle participants who did not complete cycle 1. These details are important because analysis decisions can affect the denominator and interpretation of a safety count. They are not recoverable from the endpoint definition alone. The record also does not describe whether analyses were prespecified or selected after data collection.

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("PU-H71, 10 mg/m^2", "PU-H71, 20 mg/m^2", "PU-H71, 40 mg/m^2", "PU-H71, 60 mg/m^2", "PU-H71, 80 mg/m^2", "PU-H71, 110 mg/m^2")
n      <- c(1, 1, 1, 1, 2, 3)
events <- c(0, 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  PU-H71, 10 mg/m^2  1  0  0.0  0.0  97.5  0.0  79.3  1.3  84.2
ARM  PU-H71, 20 mg/m^2  1  0  0.0  0.0  97.5  0.0  79.3  1.3  84.2
ARM  PU-H71, 40 mg/m^2  1  0  0.0  0.0  97.5  0.0  79.3  1.3  84.2
ARM  PU-H71, 60 mg/m^2  1  0  0.0  0.0  97.5  0.0  79.3  1.3  84.2
ARM  PU-H71, 80 mg/m^2  2  0  0.0  0.0  84.2  0.0  65.8  0.8  70.8
ARM  PU-H71, 110 mg/m^2  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary endpoint and several secondary outcomes, including best response, days on treatment, and pharmacokinetic measures. It does not report how many formal hypotheses were tested, whether any outcomes were designated exploratory, or whether an adjustment for multiple comparisons was planned. When many outcomes are examined, general statistical context, the chance of at least one apparently unusual result can increase if each is tested separately. Without a reported analysis plan, the role of multiplicity control cannot be evaluated. The number of listed outcomes alone does not establish that formal tests were performed.

Missing-data handling and analysis populations are not reported in the registry record. It is not stated how participants with incomplete cycle 1 follow-up would be treated in the primary endpoint, whether all enrolled participants were included in each outcome analysis, or how unavailable pharmacokinetic or response assessments were handled. For a count endpoint, the number assessed is essential context; a missing result should not be treated as absence of toxicity unless the analysis definition says so.

Interim analyses, stopping rules, and any prespecified boundaries for dose escalation are also not reported in the registry record. The record describes sequential treatment and lists a terminated status, but does not state why the study ended or whether a formal stopping criterion was met. No assumptions about these decisions should be inferred from the status alone. The absence of these details limits assessment of selective reporting, analysis flexibility, and completeness of outcome ascertainment.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: lung infection (100.0%), nausea (100.0%), vomiting (100.0%), atrioventricular block first degree (33.3%), sinus bradycardia (33.3%).

The serious adverse event summary lists participants at risk and affected within each dose cohort, along with deaths. For serious adverse events, the record lists zero affected among one at risk at 10 mg/m^2; one among one at 20 mg/m^2; zero among one at 40 mg/m^2; zero among one at 60 mg/m^2; zero among two at 80 mg/m^2; zero among three at 110 mg/m^2; zero among one at 150 mg/m^2; zero among two at 200 mg/m^2; zero among one at 266 mg/m^2; one among three at 354 mg/m^2; and one among one at 470 mg/m^2. The death counts are listed separately in the registry, and should not be read as automatically attributable to study treatment.

Serious event terms listed include Lung Infection, Nausea, and Vomiting, each with 100.0%, and Atrioventricular block first degree and Sinus bradycardia, each with 33.3%. The record excerpt does not make the denominator or counting basis for these term percentages clear, so they should be interpreted as reported terms rather than cohort-specific incidence estimates. General statistical context: small cohort counts are imprecise, and an event recorded during a trial does not by itself establish causation. These serious adverse event entries are not the same as the primary cycle 1 dose-limiting toxicity endpoint.

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

The record establishes that a phase I study of PU-H71 enrolled 17 participants with refractory solid tumors or lymphoma and used a sequential, nonrandomized design across dose levels. It defines a primary safety endpoint for cycle 1 and describes the dosing schedule and monitoring procedures. These registry entries explain the study's focus on early tolerability and the way treatment was administered.

The record does not report the observed primary endpoint count. It also does not provide numerical results for listed secondary outcomes such as best response, days on treatment, or pharmacokinetic measures. Therefore, the registry information does not support a numerical conclusion about the frequency of dose-limiting toxicity, tumor response, duration of treatment, or drug exposure. A defined outcome is not the same as a reported result.

The serious adverse event counts show that some events were recorded in some of the small dose cohorts, while no serious adverse events were recorded in other listed cohorts. These observations describe the participants in the record; they do not estimate the safety experience precisely for a wider population. Nor do the counts establish that the drug caused each event. The study has no randomized comparator, and the cohort sizes are small.

General statistical context: an uncontrolled early-phase study can provide descriptive information, but it cannot by itself establish that an intervention is more effective or safer than an alternative. This record also does not report a comparative effect estimate, confidence interval, or p-value. Its terminated status does not explain why the study ended; the reason is not reported in the registry record. Any conclusion about the reason for termination, the success of dose escalation, or the overall benefit-risk balance would go beyond the posted information.

14. Why This Trial Matters Statistically

Statistically, this study illustrates the distinction between a carefully defined endpoint and an analyzable reported result. The registry gives a detailed definition of cycle 1 dose-limiting toxicity, including the timing, relatedness condition, toxicity criteria, and dose-reduction response. Yet the observed primary count and its denominator are not reported in the registry record. Without those values, readers cannot estimate the endpoint frequency or its uncertainty, even though the endpoint is clearly described.

The design also demonstrates why dose cohorts should not be mistaken for a controlled comparison. Participants received PU-H71 in sequential, nonrandomized cohorts, and the cohorts contain very few participants. Descriptive differences across dose levels can be recorded, but they cannot be separated confidently from differences in the people enrolled or other features of the study. The record does not report an analysis that addresses these potential sources of variation.

Finally, the record distinguishes between outcomes named in the protocol summary and results actually available for interpretation. A long list of response and pharmacokinetic outcomes does not itself convey what was observed. Reporting estimates with denominators and uncertainty would support more informative interpretation; in their absence, the appropriate statistical conclusion is limited. The case is a reminder that registry status, endpoint definitions, and adverse event listings each answer different questions and should not be treated as substitutes for complete outcome reporting.

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 registry record does not report the observed result for the primary endpoint, its analysis denominator, or a statistical analysis. It also does not provide numerical values for the listed secondary outcomes. This prevents assessment of the primary safety outcome and limits interpretation of response and pharmacokinetic outcomes. The record does not report confidence intervals or other measures of uncertainty.

The study was nonrandomized, unmasked, and sequential, with no control group. The listed dose cohorts are small, so adverse event counts are highly descriptive and cannot support precise comparisons between doses. Participant characteristics by cohort and the rules for assigning participants to dose levels are not reported in the registry record. Potential differences across cohorts therefore cannot be assessed.

The study status is terminated, but the reason is not reported in the registry record. The record also does not report the planned enrollment target, sample-size justification, dose-escalation rules, interim analyses, or stopping criteria. Missing-data procedures, analysis populations, and the handling of incomplete follow-up are not reported. The scope and completeness of outcome reporting therefore remain uncertain.

The adverse event summary includes serious event counts and deaths, but these counts do not establish causality. The basis for the percentages attached to serious event terms is not clear from the record information. The serious adverse event listings should not be equated with the primary endpoint, which has a separate definition and cycle 1 time window. Together, these limitations mean that the registry record supports description of design and reported event entries, but not broad claims about efficacy, comparative safety, or the precision of event risks.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: PU-H71 in Patients With Solid Tumors and Low-Grade Non-Hodgkin's Lymphoma That Have Not Responded to Standard Treatment — NCT01581541.
• Registry record last updated 2017-10-04; status last verified 2017-09.
• Results first posted 2017-10-04.
• 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

NCT01581541 is a terminated phase I study of PU-H71 in participants with refractory solid tumors or low-grade non-Hodgkin's lymphoma. The record describes a nonrandomized, unmasked, sequential design and reports enrollment of 17. PU-H71 was administered intravenously over one hour on days 1 and 8 of each 21-day cycle, with dose cohorts listed from 10 mg/m^2 to 470 mg/m^2.

The primary endpoint was the number of participants with dose-limiting toxicities during cycle 1, defined as 21 days. The endpoint definition is reported, but its observed result is not reported in the registry record. Serious adverse event counts are listed by dose cohort, while numerical results for the listed response and pharmacokinetic outcomes are not reported in the registry record. The reason for termination, sample-size justification, detailed statistical plan, and missing-data procedures are also not reported.