Trial of ICM With or Without AZD2281 (Olaparib) in Patients With Advanced Pancreatic Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Trial of ICM With or Without AZD2281 (Olaparib) in Patients With Advanced Pancreatic Cancer (NCT01296763), a na phase 1 study. The primary outcome is Number of Participants Who Experienced a Dose Limiting Toxicity to Determine the Maximum Tolerated Dose (MTD).

2. Clinical Question

The study’s stated rationale is that cancers with defects in specified DNA repair pathways might respond to olaparib combined with DNA-damaging drugs. That statement describes the study hypothesis, not a result. The endpoint is about treatment-related toxicity and dose selection, rather than a comparative estimate of tumor response or survival. A secondary outcome is time from Cycle 1, Day 1 on-study to date of death, expressed as number of years. The registry record does not report the observed primary endpoint count, response results, or an analysis comparing treatment strategies.

3. Trial Design

The registry identifies this as a phase I study of ICM, with or without olaparib, in advanced pancreatic cancer. Its title describes a randomized multi-center phase I/II trial, but the structured fields list allocation as NA, masking as none, and the model as single group. The record also flags that this is not a randomized comparison and that the arms are not a like-for-like control comparison. The title alone therefore should not be read as evidence of a randomized treatment contrast in the posted results.

The arm description outlines a 3+3 dose-escalation design starting with dose 1. It states that 3 patients per dose cohort are used and defines the maximum tolerated dose as the highest dose for which at most 1 out of 6 patients experiences a dose-limiting toxicity. The description is truncated after beginning to explain what follows if 0 of 3 patients have a toxicity, so the remaining escalation rules are not reported in the registry record. The listed intervention sequence describes irinotecan, cisplatin, and olaparib, followed by adding mitomycin C; the primary outcome description likewise refers to escalation from IC with olaparib to ICM with olaparib.

Enrollment is listed as 18. The phase is listed as PHASE1, and the record gives the status as completed. The listed start is 2011-01 and primary completion is 2014-01. Those registry fields describe the study record; they do not establish which participants completed treatment or had endpoint data available. The record does not report a statistical analysis plan, an enrollment target rationale, or a complete description of the dose cohorts and their treatment schedules.

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.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Number of subjects who experienced a dose limiting toxicity, as defined in the protocol.

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: Subject with advanced pancreatic cancer

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants Who Experienced a Dose Limiting Toxicity to Determine the Maximum Tolerated Dose (MTD), measured over 2 years.

The primary endpoint counts participants who experienced a dose-limiting toxicity (DLT), with the count intended to inform determination of the maximum tolerated dose. In dose escalation, this type of endpoint helps characterize whether toxicity at a treatment level is acceptable for considering further study. It is a safety and dose-selection measure, not a direct measure of tumor response or a comparison of clinical benefit.

The registry defines a DLT as a study-drug-related event during Cycle 1 meeting specified criteria. These include thrombocytopenia with platelets <25,000 x106/l for > 7 days; Grade 4 neutropenia lasting ≥7 days; Grade 3 or 4 febrile neutropenia; and Grade 3 or greater non-haematological toxicities, with stated exceptions for certain Grade 3 events despite adequate treatment. A delay of >2 weeks for the next scheduled IC/ICM for reasons of toxicity is also included.

The registry lists the primary outcome timeframe as 2 years, although its definition locates qualifying toxicity events during Cycle 1. The record does not explain how those entries relate to each other. It also does not report the observed number of participants meeting the DLT definition. Without that result, the endpoint’s observed frequency and its contribution to dose selection cannot be assessed from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry’s design fields identify a single-group study, no masking, and allocation listed as NA. The title uses the word randomized, but the structured record does not describe a randomized control comparison. This distinction is important: a trial title may summarize an intended project, while design fields and posted results determine what comparison can be interpreted. The record explicitly cautions that the listed arms are not a like-for-like control comparison.

What does a dose-escalation design estimate?

In general, dose escalation seeks information about tolerability across treatment levels. The stated 3+3 approach assigns participants in cohorts and uses observed DLTs to guide whether escalation proceeds. The registry defines the maximum tolerated dose as the highest dose for which at most 1 out of 6 patients experiences a DLT. This is a decision rule tied to the observed cohort experience, rather than a randomized estimate of treatment benefit. The arm description is incomplete, so the full rules for expansion, escalation, stopping, and cohort assignment are not reported in the registry record.

The cohort sizes described in the design are small, so each participant’s outcome can have substantial influence on the decision at a dose level. In general, this is a feature of early dose-finding designs: the aim is to guide subsequent dose selection, not to provide a precise estimate of how frequently an event would occur in a broad population. The registry’s enrollment figure is 18, but the record does not state how those participants were distributed across all dose levels or whether all enrolled participants were evaluable for the primary endpoint.

How should the primary endpoint be read?

The endpoint is a count of participants who experienced a protocol-defined DLT. As a binary outcome, each participant is classified according to whether the qualifying event occurred, and the endpoint count records those classified as having an event. The event definition is specific to treatment relationship, timing, severity, and exceptions. It should not be replaced by a looser interpretation of any toxicity, nor equated with the separate serious adverse event categories.

For a binary endpoint, a proportion or model-based estimate can be used in some analyses to describe event frequency. Such estimates usually have uncertainty, especially when groups are small. No primary count, proportion, confidence interval, or statistical test is reported in the registry record, so none can be interpreted. The endpoint timeframe is listed as 2 years, whereas the DLT definition refers to events during Cycle 1; the relationship between these entries is not reported.

What does a confidence interval contribute?

In general, a confidence interval communicates the range of values reasonably compatible with the data and the method used to calculate it. It describes precision, not whether a treatment is beneficial or clinically appropriate. With sparse event data, intervals can be wide, reflecting uncertainty even when an observed count appears clear. The record does not post an interval for the primary endpoint or a comparative effect, so the precision of those quantities cannot be assessed.

Why is over-dispersion relevant in general?

Over-dispersion occurs when observed variation is greater than a statistical model expects. For event counts, this can arise when events cluster or participant risks differ more than assumed. Accounting for it can affect standard errors and confidence intervals. That is a general statistical consideration, not a reported feature of this trial: the registry record does not identify an over-dispersion model or provide analysis details that would establish whether it was assessed.

What can planning illustrations say?

Sample-size calculations are planning illustrations, not trial outcomes. In general, they depend on assumptions about the effect to detect, significance level, allocation, and statistical method. The stated planning assumptions use a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and a target effect expressed as a fraction of the observed effect. The record cautions that these calculations are not the trial’s own design. For time-to-event calculations, the stated convention is a total event count; other calculations are expressed as participants per arm. Such planning values are not observed power and cannot substitute for the missing endpoint result.

No statistical analysis plan, model specification, interim analysis plan, or detailed analysis populations are reported in the registry record. The record lists 0 analyses. Accordingly, the statistical methods actually used to analyze the primary endpoint, handle incomplete observations, or support dose selection cannot be established from the posted 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("Dose Level 1", "Dose Level 2", "Dose Level 5")
n      <- c(7, 5, 6)
events <- c(0, 2, 2)
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  Dose Level 1  7  0  0.0  0.0  41.0  0.0  35.4  0.3  36.9
ARM  Dose Level 2  5  2  40.0  5.3  85.3  11.8  76.9  11.8  77.7
ARM  Dose Level 5  6  2  33.3  4.3  77.7  9.7  70.0  9.9  71.0

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 2 outcome measures, including the primary DLT count and a secondary time-to-death outcome. It does not report a multiplicity strategy, such as whether outcomes were tested in a hierarchy or whether any adjustment was planned. The presence of multiple outcomes does not by itself show that formal hypothesis tests were conducted. The record lists 0 analyses and does not post a primary statistical test or a family of test results.

Missing-data handling is not reported in the registry record. It does not describe how participants without complete Cycle 1 toxicity information were treated, whether any outcomes were imputed, or how missing time-to-death data were handled. The record also does not state the analysis populations used for the primary or secondary outcomes. Enrollment alone does not establish the number included in an endpoint analysis, and the adverse-event at-risk counts should not be assumed to define the primary analysis population.

The statistical analysis plan, interim analysis procedures, and any prespecified rules for censoring or participant exclusions are not reported in the registry record. Those omissions limit the ability to distinguish prespecified analyses from descriptive reporting or to evaluate how incomplete observations could affect conclusions. They also prevent assessment of whether multiple outcomes or repeated looks at accumulating data influenced inference. No specific procedure should be inferred from the phase I label or the 3+3 design description.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: myelodysplastic syndrome (28.6%), febrile neutropenia (28.6%), prolapsed colostomy (20.0%), anemia (20.0%), abdominal pain (20.0%).

The serious adverse event entries are descriptive group counts. At Dose Level 1, the record lists 7 participants at risk and 5 affected; at Dose Level 2, it lists 5 at risk and 4 affected; at Dose Level 5, it lists 6 at risk and 4 affected. These counts do not establish a comparative treatment effect, and the dose levels are not a randomized control comparison. The record does not explain whether these entries represent unique participants throughout the stated observation period or provide additional details about event timing or severity.

The listed serious-event terms include Myelodysplastic syndrome and Febrile Neutropenia, each at 28.6%, and prolapsed colostomy, anemia, abdominal pain, and atrial fibrilation, each at 20.0%. The record does not provide a dose-level breakdown for these listed terms. They should be read as registry safety listings, not as estimates of causal risk or as a substitute for the protocol-defined DLT endpoint.

The other adverse-event entries list 7 at risk and 7 affected at Dose Level 1, 5 at risk and 5 affected at Dose Level 2, and 6 at risk and 6 affected at Dose Level 5. These are separate from the serious-event entries. Definitions, collection details, and event-level summaries are not reported in the registry record, so the categories should not be combined or interpreted as interchangeable.

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

The record describes an early-phase study designed to assess safety while escalating IC with olaparib to ICM with olaparib. Its primary endpoint is a count of participants with protocol-defined DLTs, intended to inform determination of the maximum tolerated dose. That design can generate dose-selection information, but the registry record does not report the observed primary endpoint count or the selected dose. The stated study rationale is not a clinical result.

The serious adverse event entries give descriptive counts by dose level, along with a list of serious-event terms and percentages. They are not a randomized contrast and cannot establish that one dose level caused more or fewer events than another. Nor do they reveal whether an event met the DLT definition, which includes specified timing and criteria. The other adverse-event counts are a separate listing and should not be treated as DLT counts.

The record does not report tumor response results, an estimate of survival, a treatment effect, confidence intervals, or hypothesis tests. It therefore cannot support a conclusion about whether adding olaparib or mitomycin C changes outcomes. The trial title’s reference to randomization does not alter the structured record’s single-group designation and allocation listed as NA.

More generally, absence of a posted result is different from a result showing no effect or no harm. The registry record establishes what was planned at a broad level and includes some safety reporting, but it leaves key endpoint and analysis information unreported. Any interpretation should remain descriptive and should not extend beyond the reported design and safety entries.

14. Why This Trial Matters Statistically

This study illustrates the distinction between a dose-finding question and a treatment-comparison question. Its stated primary endpoint is dose-limiting toxicity, and its design description uses a 3+3 escalation rule to support dose selection. That is a different statistical task from estimating whether one regimen improves an outcome relative to a control group. The registry’s single-group designation and allocation listed as NA are therefore essential context for reading the record.

It also highlights the limits of interpreting small dose cohorts. In general, a few event observations can guide an early escalation decision but may provide imprecise estimates of toxicity frequency. The maximum-tolerated-dose rule is a design decision criterion, not proof that a selected dose is safe for all patients or suitable for every setting. Here, the observed DLT result and selected dose are not reported, so even the intended dose-selection conclusion cannot be recovered from the registry record.

The record further shows why endpoint definitions matter. The DLT definition includes treatment relationship, event timing, severity thresholds, and specified exceptions. Serious adverse event listings do not automatically answer the DLT question, because the categories have different definitions and purposes. The discrepancy between the listed 2-year outcome timeframe and the Cycle 1 DLT definition also calls for caution; the registry does not explain it.

Finally, a completed status and safety listings do not replace statistical reporting. With no posted primary count, analysis, or uncertainty estimate, readers cannot assess the precision of the main endpoint or infer a comparative effect. This makes the boundary between a study’s rationale, design, and demonstrated findings especially important.

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 most consequential limitation of the registry record is that it does not report the observed primary DLT count, despite identifying that count as the primary endpoint. It also does not report which dose was selected as the maximum tolerated dose. The endpoint timeframe is listed as 2 years, while the definition specifies events during Cycle 1, and the record does not explain the relationship.

Design information is incomplete and internally difficult to reconcile. The title calls the study randomized and phase I/II, but the structured fields identify PHASE1, a single-group model, and allocation as NA. The registry explicitly cautions that the arms are not a like-for-like control comparison. The arm description is truncated, leaving the complete dose-escalation rules and treatment schedules unreported.

The record lists serious adverse event counts and selected terms, but does not provide event-level timing, duration, severity detail, dose-level attribution for the listed terms, or an explanation of the observation periods. These descriptive entries cannot establish comparative risk. The record does not clarify which participants were evaluable for each endpoint, how missing observations were handled, or what analysis populations were used.

Finally, no statistical analysis plan, multiplicity approach, interim analysis details, confidence intervals, or hypothesis tests are reported. The brief summary gives a biological rationale, but the record does not establish that participants had the described repair defects or report outcomes by repair status. These limitations prevent conclusions about efficacy, comparative safety, precision, or generalizability beyond the stated registry information.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Trial of ICM With or Without AZD2281 (Olaparib) in Patients With Advanced Pancreatic Cancer — NCT01296763.
• Registry record last updated 2016-03-22; status last verified 2016-02.
• Results first posted 2016-03-22.
• 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

NCT01296763 is listed as a completed phase I study of ICM with or without olaparib in patients with advanced pancreatic cancer. The structured design fields identify a single-group model, no masking, and allocation as NA, despite the randomized wording in the title. Enrollment is listed as 18.

The primary endpoint is the number of participants experiencing a protocol-defined DLT, intended to help determine the maximum tolerated dose. The record describes a 3+3 dose-escalation approach and lists serious adverse event counts by dose level. However, the observed primary endpoint result, the selected dose, and statistical analyses are not reported in the registry record. The available safety entries are descriptive and do not establish a randomized comparison or treatment effect.