PAK4 and NAMPT in Patients With Solid Malignancies or NHL (PANAMA): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for PAK4 and NAMPT in Patients With Solid Malignancies or NHL (PANAMA) (NCT02702492), a non-randomized phase 1 study. The primary outcome is Maximum Tolerated Dose (MTD) for KPT-9274.

2. Clinical Question

The study was designed to assess safety, tolerability, and efficacy in patients with advanced cancers. Its primary endpoint focused on tolerability at different doses rather than a direct comparison of treatment effects between randomized groups. The listed treatment groups cover KPT-9274 alone, KPT-9274 with niacin ER, and KPT-9274 with nivolumab. The registry does not report the allocation process among these treatment groups or provide results for the primary endpoint.

The question therefore has two parts: whether an MTD could be identified using the specified Cycle 1 DLT rule, and what safety and other outcome information was recorded across the treatment groups. The posted record does not provide an MTD estimate. It also does not give a randomized comparison of clinical efficacy. The record states that the study was terminated prematurely due to lack of efficacy, but it does not report a numerical efficacy result in the information.

3. Trial Design

PANAMA (NCT02702492) was a Phase 1, open-label, non-randomized, single-group study sponsored by Karyopharm Therapeutics Inc. Its official title describes a study of the safety, tolerability, and efficacy of KPT-9274 in patients with advanced solid malignancies or non-Hodgkin's lymphoma. The registry lists enrollment as 60. The study started on 2016-06-08, had a primary completion date of 2021-01-26, and is listed as terminated.

The treatment groups were organized into Parts A, B, and C. Part A evaluated KPT-9274 alone at oral doses of 10mg, 20mg, 30mg, and 40mg three times a week every other day during each 28 day cycle, as well as a 40mg biweekly schedule. Part B paired KPT-9274 doses of 30mg, 40mg, 60mg, 80mg, or 100mg with a starting dose of 500mg niacin ER, given orally three times a week every other day during each 28-day cycle. Part C paired KPT-9274 at 20mg, 30mg, or 40mg with 480mg nivolumab by intravenous infusion on Day 1 of each cycle, once every 4-week cycle. The registry does not report whether these parts were conducted sequentially or how participants were assigned to the listed groups.

Because allocation was non-randomized and masking was absent, these treatment groups do not constitute randomized, blinded comparisons. Differences between groups could reflect factors other than the treatments, and the registry does not provide details that would allow adjustment for such factors. The record lists pharmacokinetic secondary outcomes, including maximum plasma concentration, time-to-peak concentration, terminal half-life, volume of distribution, and apparent plasma clearance. Results for those outcomes are not reported in the 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: A total of 60 participants were enrolled and randomized to receive treatment in 2 phases, Dose Escalation (Part A \[23 participants\] and Part B \[27 participants\]; and Dose Expansion Phases (Part C \[10 participants\]). Study was terminated prematurely due to a lack of efficacy during primary analysis and therefore, efficacy, pharmacokinetic (PK) and pharmacodynamics (PDn) assessments were not determined.

Only the first 6 of 13 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Study was terminated prematurely due to a lack of efficacy. Therefore, the data were not determined due to insufficient number of participants with events.

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 consisted of all participants who had received at least 1 dose of the study treatment. Participants were analyzed according to the treatment they received.

Only the first 6 of 14 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Maximum Tolerated Dose (MTD) for KPT-9274, measured over From start of study drug administration up to 44 weeks.

The primary endpoint was the maximum tolerated dose (MTD) for KPT-9274, measured as a count of participants. The registry defines the MTD as the highest dose at which less than or equal to (≤) 1 participant experienced a dose-limiting toxicity (DLT) in Cycle 1. A DLT was an adverse event or abnormal laboratory value occurring within the first 28 days of KPT-9274 treatment, unless it was clearly caused by underlying disease, disease progression, or external factors. The stated timeframe for the endpoint was from the start of study drug administration up to 44 weeks.

In general, an MTD endpoint is used in early-phase dose-finding research to identify a dose meeting a prespecified tolerability rule. It is not itself a measure of comparative efficacy. The endpoint depends on both the observed DLTs and the dose levels evaluated, and its interpretation requires enough participants with relevant events to apply the rule meaningfully. Here, the registry states that the study was terminated prematurely due to lack of efficacy and that the data were not determined because of an insufficient number of participants with events. It therefore does not identify an MTD. No dose can be designated as meeting the endpoint from the posted primary result.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Several statistical ideas help clarify what can and cannot be inferred from the registry record. The study's primary outcome is a dose-finding endpoint, while the safety results are descriptive counts. Neither should be interpreted as if the trial were a randomized comparison of treatment effects.

What does the MTD rule mean?

The registry defines the MTD as the highest dose at which less than or equal to (≤) 1 participant experienced a DLT in Cycle 1. A rule of this kind translates early tolerability observations into a dose-selection criterion. A DLT is not simply any adverse event: the definition restricts the time window to the first 28 days of treatment and excludes events clearly attributed to underlying disease, disease progression, or external factors. Applying the rule requires enough evaluable participants and event information at the doses being considered. The registry explicitly says the MTD data were not determined because there were too few participants with events. No MTD should be inferred from the available record.

Why does the study design matter?

Random allocation can help make groups comparable at baseline, on average, by reducing systematic differences in who receives each treatment. This study was non-randomized and single-group, with no masking. It includes distinct regimens across Parts A, B, and C, rather than a randomized control arm. Consequently, differences in observed counts across cohorts could reflect dose, co-treatment, patient characteristics, follow-up, or other factors. The record does not report a statistical adjustment intended to separate those influences. The arms therefore should not be treated as if they were balanced, like-for-like controls.

Open-label means treatment masking was absent according to the registry. In general, knowledge of assigned treatment can affect reporting or assessment, especially for outcomes involving clinical judgment. The registry does not state whether outcome assessment was independently blinded or whether other safeguards were used. Such details are not reported in the registry record.

How should counts and percentages be read?

The outcome kind is binary, described as participants with an event (counts). A count tells how many participants in a specified group had an event; it is not a rate unless the relevant denominator and time at risk are also considered. The adverse-event data list participants at risk and affected by serious and other adverse events, as well as deaths. These figures are descriptive. They do not by themselves estimate a treatment effect, and they do not establish causation.

General statistical context: a confidence interval expresses the range of effect values reasonably compatible with data under the model used. Wider intervals generally indicate less precision. No confidence interval for the primary endpoint or efficacy is reported in the registry record, so the precision of those results cannot be assessed. The record also does not give a numerical primary estimate to which an interval could be attached.

General statistical context: over-dispersion occurs when observed variability is greater than a statistical model assumes. It can make uncertainty estimates too narrow if the model does not account for the extra variability. No over-dispersion model or other fitted statistical model is reported for the outcomes, so this is a general consideration rather than a claim about the trial's analysis.

What do planning illustrations mean?

The sample-size planning assumptions describe an illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is specified as a fraction of the observed effect. For time-to-event outcomes, the stated method uses the total number of events; for other outcomes, the figures are participants per arm. Such calculations are planning illustrations, not observed power and not evidence that the trial had adequate power. They do not replace the trial's own design justification, which is not reported in the registry record. In addition, the study is non-randomized and does not have the equal-allocation two-arm comparison described by those assumptions, so the illustration should not be mistaken for the study's actual design.

The record reports zero analyses. It does not describe the statistical models, analysis populations, missing-data methods, interim analyses, or sample-size justification. Without those details and without reported primary or efficacy estimates, inferential conclusions cannot be reconstructed from the descriptive record. General methods can explain the role of such procedures, but their use in this trial cannot be assumed.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 14 outcome measures, including the MTD primary outcome and pharmacokinetic secondary outcomes. It reports zero analyses. A multiplicity strategy for interpreting several outcomes or repeated tests is not reported in the registry record. In general, when many outcomes are examined, the chance of observing an apparently notable result by chance can increase unless the analysis accounts for the number and structure of tests. No particular adjustment, hierarchy, or testing procedure should be attributed to this study from the available information.

The registry does not report the analysis populations or explain how participants with incomplete outcome information were handled. It also does not describe missing-data assumptions, imputation, sensitivity analyses, or exclusions from particular analyses. These details matter because the interpretation of an endpoint depends on who is included and how unavailable measurements are treated. Their absence means the reader cannot assess whether missingness could have affected the results.

The primary endpoint itself was not determined because the study was terminated prematurely due to lack of efficacy and there were too few participants with events. The registry does not report interim analyses or a formal stopping rule, so neither should be inferred from the termination statement. It also does not report whether any secondary outcome results were analyzed or selectively omitted. The record's statement of zero analyses and absence of results leave those questions unresolved.

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: small intestinal obstruction (100.0%), pleural effusion (100.0%), haematoma (100.0%), anaemia (50.0%), gastrointestinal haemorrhage (33.3%).

The safety record reports serious adverse events and other adverse events by treatment group, with the number at risk and the number affected. It also gives death counts. For example, in Part A: KPT-9274 20mg, 2 participants were affected by serious adverse events among 3 at risk; the other-adverse-event count was 2 among 3 at risk, and the death count was 2. In Part B: KPT-9274 60mg + Niacin 500mg, 6 participants were affected by serious adverse events among 12 at risk, and 12 were affected by other adverse events among 12 at risk; the death count was 6.

These counts are not treatment-effect estimates. The groups were non-randomized and included different doses and combinations, so direct comparisons could be confounded. The registry does not provide exposure-adjusted rates or causal attribution for the deaths and events. It lists serious adverse-event terms including small intestinal obstruction, pleural effusion, and haematoma at 100.0%, as well as anaemia at 50.0%, gastrointestinal haemorrhage at 33.3%, and Klebsiella bacteraemia at 33.3%. The denominator details for those percentages are not reported in the registry record. They should be read as the listed term summaries, not as evidence of treatment causation or population-wide risk.

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

The posted record establishes that PANAMA was a Phase 1, open-label, non-randomized study of KPT-9274 in patients with advanced solid malignancies or NHL. It describes treatment groups involving KPT-9274 alone and combinations with niacin ER or nivolumab. It also defines the primary endpoint as an MTD based on DLTs in Cycle 1. These are useful details for understanding the study's aim and the kind of evidence it was designed to collect.

The primary endpoint result, however, was not determined. The registry attributes this to premature termination due to lack of efficacy and an insufficient number of participants with events. No MTD estimate is reported. The registry also does not provide a numerical efficacy result in the record, so the magnitude and precision of any efficacy outcome cannot be assessed from this information.

The descriptive safety counts document events in the listed groups, but they do not show that treatment caused an event or that one dose or combination was safer than another. Non-randomized treatment groups may differ for reasons beyond the regimen, and the record does not provide adjusted comparative analyses. A death count is not evidence that a death was treatment-related. Likewise, percentages attached to serious-event terms need their denominator and analysis context for interpretation, which are not reported in the registry record.

In general, an absent or undetermined result is not equivalent to a finding of no effect, and lack of a reported estimate does not establish benefit or harm. The record supports describing the trial's design, endpoint definition, termination status, and available safety counts. It does not support a definitive conclusion about the MTD, efficacy, or comparative safety.

13. Why This Trial Matters Statistically

This trial illustrates why early-phase dose-finding and efficacy questions should be kept distinct. The primary MTD endpoint was defined through a DLT rule in Cycle 1, while the registry's stated reason for termination was lack of efficacy. Because the MTD outcome was not determined, the record does not resolve the dose-finding question even though it describes multiple dose levels and combinations.

It also shows the limits of interpreting descriptive safety counts across non-randomized groups. The groups vary in KPT-9274 dose and in whether niacin ER or nivolumab was included. Their counts can help describe what was recorded, but do not provide an unbiased comparison of regimens. The absence of reported analyses and outcome estimates further limits the ability to quantify uncertainty or separate treatment effects from other influences.

From a statistical perspective, transparent endpoint definitions are valuable, but a definition alone is not a result. Readers also need outcome data, analysis methods, and information about who contributed to each analysis to judge how precise and robust a finding is. In this record, the primary outcome is unavailable and the analysis plan details are not reported. That makes careful separation of documented details, descriptive counts, and unanswerable questions especially important.

The registry also lists pharmacokinetic outcomes and several treatment parts, underscoring that a clinical trial can address multiple kinds of questions. Without reported results for those measures, their contribution cannot be evaluated. The trial therefore matters statistically as an example of why design, outcome availability, and reporting detail jointly determine what conclusions the evidence can support.

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 primary limitation for interpreting the study is that its MTD outcome was not determined. The registry states that the trial was terminated prematurely due to lack of efficacy and that there were too few participants with events. This leaves the endpoint's defined DLT rule without a reported result.

The non-randomized, single-group design and lack of masking limit comparative interpretation. Although multiple dose groups and combinations are listed, the record does not explain how participants were allocated among them, whether the groups were intended for formal comparisons, or how any differences were adjusted. Thus, their event counts should not be interpreted as causal contrasts.

The registry lists enrollment as 60, but the record does not provide participant flow or explain the relationship between that enrollment figure and the group-specific safety denominators. It does not report baseline characteristics, follow-up completeness, analysis populations, missing-data handling, or outcome-specific denominators for the serious-event percentages. These omissions make it difficult to assess comparability, precision, or potential selection effects.

The record does not report efficacy estimates, confidence intervals, statistical models, multiplicity procedures, interim analyses, or a sample-size justification. It also gives no results for the listed pharmacokinetic outcomes. The stated termination reason is available, but the numerical findings and decision process behind it are not reported in the registry record. These limitations prevent a full assessment of efficacy, the MTD, and comparative safety.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: PAK4 and NAMPT in Patients With Solid Malignancies or NHL (PANAMA) — NCT02702492.
• Registry record last updated 2024-11-25; status last verified 2024-10.
• Results first posted 2024-11-25.
• 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

PANAMA (NCT02702492) was a Phase 1, open-label, non-randomized, single-group study sponsored by Karyopharm Therapeutics Inc. It evaluated KPT-9274 in patients with advanced solid malignancies or NHL, with treatment groups involving KPT-9274 alone or combined with niacin ER or nivolumab. The registry lists enrollment as 60 and status as terminated.

The primary endpoint was the MTD for KPT-9274, defined by the number of participants with DLTs in Cycle 1. The registry says the outcome was not determined because the study was terminated prematurely due to lack of efficacy and there were too few participants with events. Safety counts are reported by group, but they are descriptive and do not establish causal differences among regimens. The registry lists pharmacokinetic secondary outcomes, but their results and numerical efficacy estimates are not reported in the record.