A Study to Evaluate the Safety and Antitumor Activity in Subjects With Advanced Solid Tumors: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Evaluate the Safety and Antitumor Activity in Subjects With Advanced Solid Tumors (NCT01248949), a na phase 1 study. The primary outcome is Number of Participants With Dose Limiting Toxicities (DLTs).

2. Clinical Question

3. Trial Design

NCT01248949 is recorded as a completed phase 1 study. Its official title describes a phase 1/1b, open-label, dose-escalation and expansion study of MEDI3617 as a single agent or in combination therapy in adults with advanced solid tumors. The registry lists enrollment as 162 and the study dates as starting 2010-10, with primary completion in 2015-07. The registry status is COMPLETED.

The design is classified as single-group, with no masking and no randomized allocation. It included a MEDI3617 single-agent group and groups receiving MEDI3617 with bevacizumab, paclitaxel, or carboplatin/paclitaxel. The regimen descriptions specify different infusion schedules and cycle lengths: some use 21-day cycles and others 28-day cycles. Treatment was described as continuing until specified events such as unacceptable toxicity or documented disease progression, with the stopping conditions varying by regimen.

The study's stated purpose was to determine the maximum tolerated dose or optimal biological dose and to characterize the safety profile of MEDI3617, alone or with other agents. These aims fit an early-phase dose-escalation and expansion design. Such a design can describe observed tolerability and activity within the studied groups, but without random allocation it does not provide a randomized comparison of the regimens.

The registry lists 21 outcome measures. It records no analysis entries. The statistical analysis plan, dose-escalation decision rules, expansion criteria, and sample-size justification are not reported in the registry record. Consequently, the record does not establish how dose decisions were made or how each analysis was prespecified.

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 162 participants were screened, of which 46 did not meet eligibility criteria and were considered as screen failures; the remaining 116 participants entered into the study and treated with MEDI3617.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: DLT Evaluable population included all participants enrolled in dose-escalation, who received at least 1 full assigned dose of single-agent MEDI3617 or full assigned doses of MEDI3617 and standard therapeutic agents on Cycle 1 and completed safety follow-up or experienced a DLT at any point during the 21-day or 28-day DLT evaluation period.

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: Safety population included all participants who receive any treatment with MEDI3617.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Dose Limiting Toxicities (DLTs), measured over From the time of first administration of MEDI3617 single agent or MEDI3617 combination therapy through the first 21-day or 28-day cycle (Cycle 1).

The primary endpoint is the number of participants with dose-limiting toxicities. A DLT was defined as a treatment-related toxicity of grade 3 or higher under NCI CTCAE version 4.0, occurring during the first 21 or 28 days after the initial MEDI3617 administration. The endpoint timeframe is Cycle 1, whose duration depends on the regimen.

In an early-phase dose-escalation study, DLTs are used to assess the tolerability of treatment at the doses and schedules under study. The stated aim was to determine the maximum tolerated dose or optimal biological dose and characterize safety. Counting participants who meet a specified toxicity definition within a defined period makes the endpoint directly relevant to that aim. However, the endpoint count alone does not describe all safety outcomes, later toxicities, or antitumor activity.

The registry describes the DLT-evaluable population as including participants enrolled in dose escalation who received at least a full assigned dose of single-agent MEDI3617 or full assigned doses of MEDI3617 and standard therapeutic agents in Cycle 1, and who completed safety follow-up or experienced a DLT. The remaining text of the population definition is not reported in the registry record. Most importantly, the DLT endpoint's observed count is not reported in the registry record. The endpoint definition and analysis result must therefore be distinguished: the definition is available, but the number of participants meeting it is not.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical methods help distinguish what the observed data can describe from what they can support as an inference. For this study, the central design feature is the absence of random allocation and a like-for-like control group. The registry classifies the study as single-group and open-label. Treatment groups can be described separately, but a difference between their outcomes is not equivalent to a randomized estimate of treatment effect.

What does a count endpoint represent?

The primary endpoint is a count of participants meeting the DLT definition during Cycle 1. It is not a measure of the total number of toxicity episodes, nor does it capture every possible safety outcome over the full treatment period. The registry defines a qualifying DLT as treatment-related toxicity of grade 3 or higher under NCI CTCAE version 4.0 during the stated initial period. The count is meaningful only when interpreted alongside the population used for the endpoint and the timeframe. The registry describes a DLT-evaluable population, but the full population definition is not reported in the registry record.

For a binary outcome, a participant either meets the specified event definition or does not, for purposes of that endpoint. In general, the event count and the number of people assessed are both needed to understand the observed frequency. Here the primary endpoint result itself is not reported in the registry record, so no DLT frequency or uncertainty estimate can be described.

Why does the design limit comparisons?

In general, random allocation helps make treatment groups comparable with respect to measured and unmeasured characteristics, on average. This trial did not use random allocation, and its groups received different regimens. Consequently, group differences in adverse events cannot be attributed to the treatment regimen alone. They can also reflect differences in the enrolled participants, treatment schedules, follow-up, or other features. Descriptive counts remain useful for understanding what was recorded in each group, but they are not a substitute for a controlled comparison.

The open-label design means masking was absent. In general, knowledge of treatment can affect subjective reporting or assessment, although the registry record does not describe whether or how such effects occurred in this study. The toxicity endpoint uses a defined grading framework, which clarifies its event definition; it does not by itself remove all possible assessment or reporting differences.

What do uncertainty estimates tell readers?

In general, a confidence interval expresses the range of estimates compatible with the data under a specified statistical method. A narrow interval indicates greater precision than a wide interval, while neither interval alone establishes clinical importance or causality. The registry record does not report confidence intervals or a statistical analysis for the primary endpoint. No precision estimate for DLT frequency can therefore be stated.

In general, a p-value assesses how unusual data would be under a specified null hypothesis and analysis assumptions. It is not the probability that a treatment works, nor does it measure the size or importance of an effect. The registry record lists no analysis entries and does not report p-values for the primary endpoint. There is no basis to describe a significance test or its result.

What should be made of the planning illustrations?

The stated assumptions for sample-size planning illustrations refer to a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The illustrations are described as based on a fraction of the observed effect. They are planning illustrations, not the study's original design and not observed power. The registry record does not report the study's sample-size justification. The illustrations should not be interpreted as evidence that the study was designed around a particular effect or that a result has a particular probability of detection.

In general, over-dispersion refers to variability greater than a statistical model expects. It matters when a model's assumed variability is too small, because uncertainty can then be understated. The primary endpoint is described as a participant count with an event, rather than a repeated event count model, and the registry record does not report an over-dispersion analysis. It would not be appropriate to infer that such an analysis was conducted.

What analyses are documented?

The registry lists 21 outcome measures but no analysis entries. The analysis population for the primary endpoint is partially described; other analysis populations, missing-data methods, model specifications, and any adjustment for multiple testing are not reported in the registry record. The endpoint definitions and descriptive safety counts can be read as recorded, but the missing analysis detail prevents a fuller assessment of prespecification and statistical uncertainty.

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("MEDI3617 SINGLE AGENT TOTAL", "MEDI3617 + BEVACIZUMAB Q3W ESCALATION TOTAL", "MEDI3617 + BEVACIZUMAB Q2W TOTAL", "MEDI3617 + PACLITAXEL TOTAL", "MEDI3617 + CARBOPLATIN/PACLITAXEL TOTAL")
n      <- c(23, 15, 22, 11, 6)
events <- c(1, 1, 2, 1, 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  MEDI3617 SINGLE AGENT TOTAL  23  1  4.3  0.1  21.9  0.8  21.0  1.0  21.1
ARM  MEDI3617 + BEVACIZUMAB Q3W ESCALATION TOTAL  15  1  6.7  0.2  31.9  1.2  29.8  1.6  30.2
ARM  MEDI3617 + BEVACIZUMAB Q2W TOTAL  22  2  9.1  1.1  29.2  2.5  27.8  2.8  28.0
ARM  MEDI3617 + PACLITAXEL TOTAL  11  1  9.1  0.2  41.3  1.6  37.7  2.1  38.5
ARM  MEDI3617 + CARBOPLATIN/PACLITAXEL TOTAL  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 21 outcome measures, including pharmacokinetic measures, anti-drug antibodies, objective response rate, and time to response. With multiple outcomes, there can be more than one opportunity to observe a result that appears noteworthy by chance. In general, multiplicity procedures can address that issue by adjusting how results are evaluated. Whether any such procedure was planned or used is not reported in the registry record. No analysis entries are listed, so the record does not establish which outcomes were formally tested or how they were prioritized beyond identifying the primary endpoint.

The registry provides a partial description of the DLT-evaluable population. It specifies dose-escalation enrollment and receipt of full assigned doses during Cycle 1, along with completion of safety follow-up or experiencing a DLT. The full population criterion is not reported in the registry record. The missing-data approach, the handling of participants who did not complete the relevant follow-up, and the numbers excluded from the primary endpoint analysis are also not reported. It is therefore not possible to assess whether the analysis could be affected by missing observations or exclusions.

The record does not report a statistical analysis plan, model details, confidence intervals, or inferential tests for the primary endpoint. It also does not report the DLT result itself. These omissions limit the assessment of precision and the ability to determine how the reported endpoint was analyzed. No assumptions about planned interim analyses, missing-data procedures, or multiplicity control can be made from the available registry information.

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 3% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: confusional state (15.4%), ascites (14.3%), anaphylactic reaction (14.3%), drug hypersensitivity (14.3%), pneumonia (14.3%).

The serious adverse-event counts are reported by treatment group as participants at risk and participants affected. In group order, the registry records 18 of 42 for MEDI3617 single agent, 4 of 16 for MEDI3617 with bevacizumab Q3W escalation, 18 of 38 for MEDI3617 with bevacizumab Q2W, 7 of 13 for MEDI3617 with paclitaxel, and 4 of 7 for MEDI3617 with carboplatin/paclitaxel. Counts for other adverse events are 40 of 42, 16 of 16, 34 of 38, 13 of 13, and 7 of 7, respectively. These are descriptive group-level figures, not randomized comparisons.

The listed serious adverse-event terms include confusional state at 15.4%; ascites, anaphylactic reaction, drug hypersensitivity, pneumonia, and infusion related reaction are each listed at 14.3%. The denominators for these percentages are not reported in the registry record. The terms and percentages should therefore be read as recorded, without assuming they share a denominator or represent group-specific risks. Death counts are not reported in the registry record.

These adverse-event summaries are distinct from the primary DLT endpoint. DLTs had a specific treatment-related grade and Cycle 1 timeframe, whereas the serious adverse-event counts are presented as safety outcomes without that same endpoint definition. Neither set of figures alone describes the full safety profile over every treatment cycle.

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

The record establishes that MEDI3617 was studied as a single agent and in several combination regimens in an open-label, dose-escalation and expansion study of adults with advanced solid tumors. It defines the primary endpoint as the number of participants with a qualifying DLT in Cycle 1 and gives descriptive adverse-event counts by treatment group. It also identifies secondary outcomes related to pharmacokinetics, anti-drug antibodies, objective response rate, and time to response.

The record does not report the primary DLT count, the outcomes for objective response rate or time to response, or statistical analyses of those endpoints. It cannot therefore support a statement about the observed DLT frequency, the precision of an efficacy estimate, or whether the study met its aims. The listed adverse-event counts describe what is recorded in the groups, but do not establish that a regimen caused more or fewer events than another.

In general, a single-group early-phase study can provide descriptive information about a treatment regimen and help characterize outcomes within the study population. Without random allocation and a like-for-like control group, differences across the listed regimens cannot be interpreted as unbiased causal treatment effects. The groups also differ in treatment combinations and schedules, further limiting direct comparison.

The registry's COMPLETED status describes the study's status, not the direction or strength of its findings. Likewise, the stated goal of assessing antitumor activity does not itself demonstrate antitumor benefit. The registry record does not report a sample-size justification, full analysis plan, missing-data methods, multiplicity approach, or analysis entries. These limits should remain part of any reading of the posted information.

14. Why This Trial Matters Statistically

This study illustrates the role of early-phase research in evaluating dose and safety when a treatment is given alone or in combinations. Its stated goals were to determine the maximum tolerated dose or optimal biological dose and assess the safety profile of MEDI3617. The primary endpoint's focus on treatment-related grade 3 or higher toxicity during Cycle 1 is aligned with an initial tolerability assessment.

Statistically, the record also illustrates why design and endpoint definitions matter. The endpoint specifies an event threshold, grading framework, and time window, while the DLT-evaluable population identifies key eligibility conditions for the endpoint analysis. Those definitions help readers understand what a reported DLT count would mean. But the registry record does not report that count or the analysis result, so the endpoint's intended role cannot be matched to an observed primary outcome.

The different treatment groups provide descriptive safety information for MEDI3617 alone and in combinations. Yet the single-group, nonrandomized structure means those groups are not interchangeable controls. Their adverse-event counts can be presented as observations, but a direct ranking of regimens would risk treating differences in participants, schedules, or other factors as if they were caused by treatment alone.

Finally, the record makes visible the distinction between a study's purpose and its evidence. Listing antitumor outcomes does not report their results; a completed status does not answer the efficacy question; and planning illustrations do not describe observed power or the original design. These distinctions are central to careful interpretation of early-phase clinical data.

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 endpoint result is not reported in the registry record. Although its definition and a partial description of the DLT-evaluable population are available, the record does not provide the number of participants meeting the DLT definition, an uncertainty estimate, or the remaining population criteria. This prevents assessment of the primary endpoint's observed frequency.

The study was open-label, single-group, and nonrandomized. It had no like-for-like control comparison, and its groups received different regimens and schedules. The group-level adverse-event counts therefore support description but not a causal comparison among regimens. The registry's serious adverse-event term percentages lack reported denominators, and death counts are not reported in the registry record.

The registry lists 21 outcome measures but no analysis entries. It does not report the statistical analysis plan, sample-size justification, analysis models, multiplicity procedures, missing-data handling, or whether interim analyses were conducted. The secondary outcome names do not substitute for their results. As a result, neither antitumor activity nor the precision of efficacy estimates can be assessed from the registry record.

Enrollment is recorded as 162, but this does not by itself identify the number assessed for each outcome or explain the group-specific safety denominators. The registry's DLT-evaluable population description is incomplete, and the treatment groups have different listed numbers at risk. These details limit the ability to connect the overall enrollment figure with each endpoint analysis.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study to Evaluate the Safety and Antitumor Activity in Subjects With Advanced Solid Tumors — NCT01248949.
• Registry record last updated 2017-03-29; status last verified 2017-02.
• Results first posted 2017-03-29.
• 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

NCT01248949 is recorded as a completed, open-label phase 1 study with a dose-escalation and expansion design. The official title describes MEDI3617 as a single agent or in combination therapy for adults with advanced solid tumors. The registry lists enrollment of 162, a start date of 2010-10, and primary completion in 2015-07.

The primary endpoint was the number of participants with DLTs during Cycle 1, using a treatment-related grade 3 or higher toxicity definition under NCI CTCAE version 4.0. The registry record does not report the primary endpoint result. It lists serious and other adverse-event counts by treatment group, but these are descriptive findings in a nonrandomized study, not controlled comparisons.

Secondary outcomes include pharmacokinetic measures, anti-drug antibodies, objective response rate, and time to response. Their results, the statistical analysis plan, and missing-data and multiplicity methods are not reported in the registry record.