Study to Determine the Maximum Tolerated Dose of the PARP Inhibitor CEP-9722 in Participants With Solid Tumors: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Determine the Maximum Tolerated Dose of the PARP Inhibitor CEP-9722 in Participants With Solid Tumors (NCT01311713), a non-randomized phase 1, phase 2 study. The primary outcome is Part 1: Maximum Tolerated Dose (MTD) of Oral CEP-9722.

2. Clinical Question

The central statistical task was dose finding, rather than estimating a treatment effect against a control. The outcome definition links the dose decision to specific toxicities considered related or potentially related to CEP-9722, along with treatment interruptions caused by possibly related toxicity. The record does not report the dose selected as the maximum tolerated dose, the number of evaluable participants for that decision, or a numerical summary of antitumor activity. Those omissions limit what can be concluded from the posted registry results about the study’s primary question.

3. Trial Design

The study is registered as Phase 1 and Phase 2, with a sequential model, non-randomized allocation, and no masking. Its title and stated primary purpose focus on determining the maximum tolerated dose of oral CEP-9722 in participants with advanced or metastatic solid tumors. The record lists 45 participants enrolled. It lists a start date of 2011-05-02 and a primary completion date of 2013-10-16, and the study status is terminated. The reason for termination is not reported in the registry record.

Seven CEP-9722 groups are described: Dose 1 once daily, Dose 1 twice daily, and Dose 2 through Dose 6 twice daily. Treatment was oral, with a standard meal, for up to 6 cycles of 28 days each. The milligram amounts corresponding to the dose labels are not reported in the registry record. The record does not describe a parallel control intervention. Since allocation was non-randomized, differences between dose groups should not be interpreted as if participants had been randomly assigned to comparable groups.

The study had two stated parts. Part 1 was intended to determine the maximum tolerated dose and included secondary measures of drug exposure, PAR concentration in peripheral blood cells, and overall response rate. Part 2 was intended to evaluate safety and tolerability at the selected dose and included change in QT interval among the listed outcomes. The registry record does not explain how the parts were operationally separated, how participants entered each part, or whether the Part 2 dose was selected using a prespecified rule beyond the primary outcome definition.

The primary completion date does not establish that every planned assessment was completed or that all outcomes were reported. The record lists seven outcome measures and zero analyses. A detailed statistical analysis plan, sample-size justification, interim analysis plan, and explanation of the termination 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: The study was planned to be conducted in 2 parts: Part 1 (to determine the maximum tolerated dose \[MTD\] of single agent oral CEP-9722) and Part 2 (to evaluate the safety and tolerability of the MTD of CEP-9722 identified in Part 1). The study was stopped before reaching its primary objective of determining the MTD of CEP-9722. The lowest dose of CEP-9722 administered was 150 milligrams (mg) and the highest dose was 1000 mg.

Only the first 6 of 7 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The MTD determination set included all participants who received at least 1 dose of the study drug during the first cycle. In addition, any participant who experienced a drug related DLT during cycle 1 was considered evaluable regardless of the number of doses received.

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 analysis set included participants who received at least 1 dose of CEP-9722.

Only the first 6 of 8 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Part 1: Maximum Tolerated Dose (MTD) of Oral CEP-9722, measured over Cycle 1 (28 days).

The primary endpoint is the maximum tolerated dose of oral CEP-9722, expressed in milligrams, during Cycle 1, which is defined as 28 days. The registry defines the maximum tolerated dose as the highest dose level at which 0 or 1 participant experiences a dose-limiting toxicity during that cycle. This is a dose-finding outcome: it uses early toxicity observations to identify a dose level for further evaluation, rather than measuring a difference in clinical outcome between randomized treatment groups.

The dose-limiting toxicity definition includes specified blood-related and non-blood-related adverse events considered by the investigator related or potentially related to CEP-9722. Examples in the definition include grade 4 hematologic adverse events, grade 3 or greater febrile neutropenia, and certain grade 3 or 4 nonhematologic events. It also includes QTcF greater than 500 milliseconds, confirmed by a repeat measurement on the same visit. A possibly treatment-related toxicity causing a cumulative dosing interruption of 7 or more days during Cycle 1 of Part 1 was also considered dose limiting.

This endpoint is used because dose escalation studies need a defined way to relate observed early toxicity to dose selection. Its interpretation depends on which participants are considered evaluable, how investigators attribute events, and the stated event criteria. The registry record describes the evaluability rule, but does not report the endpoint’s numerical result or identify a selected dose. The endpoint therefore cannot be used to determine from this record alone which dose met the stated definition.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Methods matter because a dose-finding study answers a different question from a randomized efficacy trial. The primary task described in this record is to identify a dose level meeting a Cycle 1 toxicity rule. The study is registered as sequential and non-randomized, with no masking. This design supports examining dose groups in sequence, but the record does not provide enough detail to reconstruct the dose-escalation procedure or its statistical operating characteristics. In particular, the registry does not report a dose-escalation algorithm, decision boundaries beyond the stated MTD definition, or a statistical analysis plan.

What does the primary outcome rule mean?

The registry defines the MTD as the highest dose level with 0 or 1 participant experiencing a DLT during Cycle 1. A DLT is not simply any adverse event: the definition specifies event types and severity, investigator attribution, and—in some cases—duration or confirmation. It includes specified hematologic events, specified nonhematologic events, QTcF greater than 500 milliseconds confirmed by repeat measurement on the same visit, and a cumulative interruption of dosing for 7 or more days caused by possibly related toxicity during Cycle 1 of Part 1. Applying this rule requires event timing and classification for each participant, not only an overall adverse-event count.

The primary outcome population includes participants who received at least 1 dose during the first cycle. It also includes any participant who experienced a drug-related DLT during Cycle 1 regardless of the number of doses received. This rule recognizes that a participant may have an informative toxicity even with limited exposure. The registry does not report how many participants met this evaluability definition at each dose level, how many were excluded, or how missing toxicity assessments were handled.

Why does the sequential, non-randomized design matter?

In general, sequential dose-finding designs use accumulating safety information to guide which dose is studied next. The registry identifies the model as sequential, but it does not describe the sequence of decisions or the escalation and de-escalation rules. Without those details, the statistical properties of the dose-selection process—such as how often it would select a dose under different underlying toxicity patterns—cannot be assessed. Since allocation was not randomized, comparisons across dose groups are descriptive and may reflect differences in who entered each group as well as differences in dose.

In general, randomization helps balance measured and unmeasured participant characteristics across treatment groups. That protection is absent in a non-randomized dose escalation study. This does not make a dose-finding design inherently unsuitable for its purpose, but it changes the interpretation: group contrasts should not be treated as randomized estimates of a dose effect. The registry does not report a comparator group, masking, or an adjusted analysis.

What can precision measures tell readers?

In general, a confidence interval describes a range of values compatible with the data and the assumptions of the analysis; wider intervals indicate less precision. A point estimate alone does not show how uncertain an estimate is. No confidence interval or other precision measure for the primary endpoint is reported in the registry record. For a toxicity proportion, precision also depends on the number of evaluable participants and observed events at the relevant dose. The registry’s adverse-event counts do not provide the DLT-specific numerator and evaluable denominator needed to assess precision for the MTD decision.

In general, over-dispersion occurs when observed variability is greater than assumed by a statistical model, and it can make standard errors and confidence intervals too small if ignored. The primary outcome is a dose-selection rule, not a reported fitted model with an estimated variance. The registry does not report a model-based toxicity analysis or information about over-dispersion. Thus, no model adequacy or variance assessment can be made from the record.

How should multiple outcomes be understood?

The registry lists one primary outcome and several secondary outcomes, including pharmacokinetic measures, PAR concentration, overall response rate, and change in QT interval. In general, when many outcomes or comparisons are tested, the chance of at least one apparently unusual result can increase. Multiplicity methods can address that issue, depending on the analysis goals. The registry record does not report a multiplicity adjustment or a testing hierarchy. It also lists zero analyses, so no set of reported statistical tests can be reviewed for multiplicity.

What is the role of planning illustrations?

In general, a sample-size calculation describes the number of participants needed under specified assumptions to target a chosen level of precision or power. A planning illustration based on an observed effect is not a description of the trial’s original design unless the registry documents that it was used prospectively. It is not observed power. The record does not report the trial’s sample-size justification or a numerical primary outcome effect from which to evaluate such a calculation. Any sample-size planning assumptions should therefore be distinguished from the actual study design and from observed results.

Overall, the registry gives a clinically interpretable DLT rule and a population definition, but does not report the outcome data and analysis needed to determine the MTD from that rule. The missing dose-specific DLT counts, evaluable denominators, and statistical analysis details prevent an assessment of the result’s precision or robustness.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary outcome and multiple secondary outcomes. The secondary outcomes include maximum observed plasma concentration and area under the concentration-time curve for CEP-8983, PAR concentration in peripheral blood monocyte or mononuclear cells, overall response rate, and change in QT interval. The record lists seven outcome measures in total. It does not report a hierarchy for testing those outcomes, a multiplicity adjustment, or which outcomes were intended to support confirmatory conclusions. Because the record lists zero analyses, no reported testing strategy can be assessed.

Missing-data handling is not reported in the registry record. The primary outcome population definition states which participants could enter the MTD determination set, including participants with a drug-related DLT even if they received few doses. It does not explain how participants without complete Cycle 1 toxicity observation were handled when no DLT had been recorded, how incomplete assessments were treated, or whether participants who discontinued early were followed for safety. The record also does not report missingness for the pharmacokinetic or other secondary outcomes.

The record describes a planned enrollment of 45 participants and lists 45 enrolled, but does not give the number evaluable for each outcome. It does not report analysis populations for the secondary endpoints or whether those populations differed from the MTD determination set. The detailed statistical analysis plan, interim analysis approach, and any procedures for controlling selective reporting are not reported in the registry record.

These omissions affect interpretation because the analyzed population and handling of incomplete observations can change both the denominator and the apparent frequency of events. Without outcome-specific denominators and analysis details, readers cannot determine whether the listed participants account for all enrolled participants in each result or how missing information influenced the reported summaries.

11. 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: pyrexia (33.3%), fistula (33.3%), lower gastrointestinal haemorrhage (20.0%), incoherent (20.0%), hypotension (20.0%).

The registry lists serious adverse event counts by dose group as participants at risk and participants affected. The Dose 1 QD group lists 3 at risk and 2 affected; Dose 1 BID lists 7 and 1; Dose 2 BID lists 8 and 1; Dose 3 BID lists 6 and 3; Dose 4 BID lists 5 and 2; Dose 5 BID lists 6 and 3; and Dose 6 BID lists 9 and 4. These are group-level counts in the registry record. They should be read as descriptive safety information, not as a randomized comparison or as counts of primary endpoint DLTs.

The record separately lists other adverse events, with all participants at risk in each group also listed as affected. The specific definition and event-level breakdown for that category are not reported in the registry record. Death counts are not reported for the groups.

Listed serious event terms include Pyrexia and Fistula at 33.3% each, Lower gastrointestinal haemorrhage, Incoherent, and Hypotension at 20.0% each, and Obstruction gastric at 16.7%. The denominator and basis for these percentages are not reported in the registry record. These figures should therefore not be assigned to a dose group or interpreted as overall participant-level risks without additional information. A serious adverse event is not automatically a DLT: the primary outcome requires the specified Cycle 1 timing, event criteria, and treatment attribution.

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

The study’s central statistical purpose was to identify a dose level using a predefined toxicity rule. The registry record explains that rule and describes seven dose groups, but it does not report a numerical MTD result. Consequently, the record does not establish which dose level was selected or whether any listed dose met the criterion of 0 or 1 DLT during Cycle 1. The dose labels do not give the milligram amounts.

The record does show that participants were enrolled across several CEP-9722 schedules and provides group counts for serious and other adverse events. Those summaries convey that adverse events were recorded in the groups, but they do not reveal whether each event satisfied the primary DLT definition, when it occurred, or whether investigators considered it related or potentially related to the drug. The serious event term percentages also lack a reported denominator in the registry record. These limitations prevent treating those summaries as a substitute for the primary dose-finding result.

The record does not report numerical findings for pharmacokinetic measures, PAR concentration, overall response rate, or change in QT interval. Although the study description includes an aim to investigate antitumor activity as a single agent, the registry does not provide an outcome estimate from which to assess that aim. The absence of a reported estimate is not evidence of a particular efficacy or safety outcome.

In general, a non-randomized sequential study can describe how a dose-finding program proceeded, but it does not provide the same type of treatment-versus-control estimate as a randomized trial. Here, the record does not report the dose-selection analysis, confidence interval, or detailed analysis plan. It is therefore not possible to judge the precision of the primary result, compare dose levels causally, or determine how robust the dose choice was. The stated results support a description of the study’s aims and the adverse-event counts, not a conclusion about treatment benefit or the selected MTD.

13. Why This Trial Matters Statistically

This trial is statistically notable because its primary question is a dose-selection problem rather than a conventional comparison of two treatments. The maximum tolerated dose definition turns Cycle 1 toxicity observations into a decision rule: the selected level is intended to be the highest dose with no more than 1 participant experiencing a DLT. That rule makes the timing, attribution, event criteria, and evaluability definition central parts of the endpoint, rather than incidental details.

The sequential design is also important. In general, a dose-finding study can use information from earlier participants to guide subsequent dose decisions. The record identifies a sequential model but does not report the operating rules, so readers cannot assess how the study balanced escalation with the chance of selecting a dose that met the toxicity target. The non-randomized allocation means dose-group counts are descriptive and do not form a controlled comparison.

The registry gives a clear DLT definition and an evaluability rule, which are necessary for interpreting the intended primary analysis. At the same time, it does not report the dose-specific DLT data or the primary outcome result. This illustrates a basic statistical distinction: a prespecified endpoint definition explains what a result would mean, but does not itself provide the result or its precision.

The study also lists several secondary outcomes spanning drug exposure, biological measurement, tumor response, and QT interval. Such breadth can be useful in early development, but interpretation depends on seeing outcome-specific results, denominators, and analysis choices. Those details are not reported in the registry record. The record therefore offers a useful example of why dose-finding design, endpoint definition, analysis population, and results reporting must be considered together when evaluating early-phase evidence.

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.

Several limitations specific to this record constrain statistical interpretation. The most important is that the primary outcome result is not reported. Although the record defines the MTD and describes the DLT criteria, it gives no selected dose, dose-specific DLT counts, or number of participants evaluable for the primary endpoint. The dose labels also lack corresponding milligram amounts, preventing interpretation of the dose range in physical units.

The design is sequential and non-randomized, and there is no masking. This is consistent with the stated dose-finding purpose, but it means that dose-group summaries are not randomized comparisons. The registry does not report the escalation procedure or decision rules, so the path from observed toxicities to dose selection cannot be reconstructed. It also does not report an analysis plan, interim analyses, or a sample-size justification.

For the safety summaries, the record lists participants at risk and affected, as well as serious adverse event terms and percentages. It does not report the denominator for the term percentages, the event-level timing, or a link between those counts and the primary DLT criteria. Death counts are not reported. These summaries therefore cannot establish the primary endpoint result or support a precise comparison across groups.

The record lists seven outcome measures and zero analyses. Numerical results for the primary endpoint and listed secondary outcomes are not reported in the registry record. Missing-data methods, outcome-specific analysis populations, and multiplicity procedures are also not reported. Finally, the study status is terminated, but the reason for termination is not reported. These are limitations of the registry information and leave key questions about conduct, analysis, and results unresolved.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Study to Determine the Maximum Tolerated Dose of the PARP Inhibitor CEP-9722 in Participants With Solid Tumors — NCT01311713.
• Registry record last updated 2024-01-30; status last verified 2024-01.
• Results first posted 2024-01-30.
• 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

The registry record describes a Phase 1 and Phase 2, open-label study of oral CEP-9722 in participants with advanced or metastatic solid tumors. It lists a sequential model, non-randomized allocation, no masking, and 45 participants enrolled. Seven dose groups are described, with one once-daily schedule and six twice-daily schedules. Treatment was planned for up to 6 cycles of 28 days each.

The primary outcome was the maximum tolerated dose during Cycle 1, defined as 28 days, using a rule based on the number of participants experiencing a dose-limiting toxicity. Secondary outcomes included drug exposure, PAR concentration, overall response rate, and change in QT interval. The record lists serious and other adverse-event counts by group and several serious event terms with percentages.

The study status is terminated. The primary outcome result, dose-specific DLT counts, numerical secondary outcome results, reason for termination, and detailed statistical analysis plan are not reported in the registry record. Accordingly, the registry describes the intended dose-finding question and some safety counts, but does not report the MTD selected or its statistical precision.