Randomized Phase 2 Trial of Axitinib and TRC105 Versus Axitinib Alone in Patients Renal Cell Carcinoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Randomized Phase 2 Trial of Axitinib and TRC105 Versus Axitinib Alone in Patients Renal Cell Carcinoma (NCT01806064), a randomized phase 1, phase 2 study. The primary outcome is Phase 1b: Number of Patients With DLT.

2. Clinical Question

3. Trial Design

NCT01806064 is described as a randomized phase 2 trial with a phase 1b dose-escalation portion. The registry lists both phase 1 and phase 2. Its overall enrollment is 173, and its status is terminated. The recorded start date is 2013-03-08 and the primary completion date is 2018-12-21. The reason for termination is not reported in the registry record.

The phase 1b portion evaluated safety and tolerability and sought a recommended phase 2 dose of TRC105 when added to axitinib. The posted primary outcome is phase 1b dose-limiting toxicity (DLT), with assessment over 12 Months. The reported phase 1b cohorts used different TRC105 doses or schedules alongside axitinib. These dose-escalation cohorts should not be treated as randomized comparisons against the axitinib-only group.

The phase 2 portion used a parallel-group randomized design. One group received axitinib 5 mg twice daily, and the other received TRC105 10 mg/kg weekly with axitinib 5 mg twice daily. Masking is listed as none. The registry summary describes the phase 2 population as patients with advanced or metastatic renal cell carcinoma following failure of one prior VEGF TKI. It states that the phase 2 objective was to estimate progression-free survival (PFS) by RECIST 1.1. Results for that objective are not reported in the registry record in the information.

The record lists six outcome measures and four posted secondary outcomes, but the number of reported analyses is zero. The allocation ratio, details of the randomization procedure, and the reason for termination are not reported in the registry record. Enrollment is a trial-level figure and should not be assumed to equal the analyzed population for any particular outcome.

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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Patients who discontinued the study prior to completing the DLT evaluation period were not evaluable.

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: All patients who received at least a portion of a dose of TRC105 or axitinib

6. Primary Endpoint

The registry lists the primary outcome as Phase 1b: Number of Patients With DLT, measured over 12 Months.

The posted primary endpoint counts phase 1b participants with dose-limiting toxicity. DLT is a safety measure used during dose-finding because it can help identify whether a regimen produces toxicities severe enough to limit the dose being evaluated. The registry says that DLT severity was classified using Common Terminology Criteria for Adverse Events version 4.0. This endpoint therefore concerns toxicity classification in the dose-escalation portion, not comparative tumor response or progression-free survival in phase 2.

The timeframe is 12 Months. Participants who discontinued before completing the DLT evaluation period were not evaluable, according to the registry description. That qualification matters: a count among evaluable participants is not necessarily a count among everyone who entered the phase 1b portion. The record does not provide the number excluded as not evaluable or further details about the handling of incomplete assessments.

The posted endpoint is a participant count, not a time-to-event measure or an average toxicity score. The registry reports zero participants with DLT in each of the three listed phase 1b dose cohorts. Those counts describe the posted observations in those cohorts; they do not by themselves establish that a regimen is free of toxicity or characterize all safety outcomes. The phase 1b endpoint also cannot answer the phase 2 question about comparative PFS, which is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

General: A randomized parallel-group trial assigns participants to different treatment groups and compares outcomes between those groups. Randomization is intended to reduce systematic differences between groups at the point of assignment, so that outcome differences can be interpreted more credibly as treatment contrasts. It does not ensure that every baseline characteristic is identical, and its value depends on how allocation and follow-up were carried out. The registry identifies this trial as randomized and parallel, but details of the randomization procedure and allocation ratio are not reported in the registry record.

This trial also includes a phase 1b dose-escalation portion. Its dose cohorts answer a different type of question from the phase 2 randomized comparison. Phase 1b evaluates tolerability across specified dosing approaches, while a randomized phase 2 comparison contrasts the combination regimen with axitinib alone. The phase 1b cohorts should not be combined conceptually with the two phase 2 arms as though they formed a single randomized comparison.

What does a participant count measure?

General: A participant count records how many people in a defined group experienced an event under the endpoint definition. Its interpretation depends on the denominator and on who was eligible for evaluation. Here, the endpoint is the number of phase 1b participants with DLT. The registry says participants who discontinued before completing the DLT evaluation period were not evaluable. The posted count is therefore not necessarily a count using every participant who began treatment. The record does not report how many participants were excluded from evaluation or provide a more detailed analysis population description.

The DLT endpoint uses a toxicity grading framework identified as CTCAE v4.0. Grading gives a structured way to classify severity, but a zero count for this specific endpoint does not mean there were no adverse events of any kind. Other event types and serious adverse events are reported separately in the safety information. Those measures have different definitions and should not be conflated with DLT.

How should the phase 2 response comparison be read?

The posted phase 2 secondary outcome is a binary response outcome by Choi criteria. A binary endpoint classifies participants into outcome categories, such as whether the defined response occurred. The registry reports the counts and group sizes for this outcome and an unadjusted risk difference. The risk difference expresses the absolute difference between the event proportions in the compared groups. The posted estimate is 0.0, with a confidence interval from -0.151 to 0.151.

General: A confidence interval represents uncertainty in an estimated effect under the statistical method used. An interval that includes zero for a risk difference is compatible with no difference, but it may also be compatible with effects in either direction. It does not establish equivalence. Demonstrating equivalence or noninferiority requires a prespecified margin and an analysis designed for that question; such a margin is not reported in the registry record. A p-value, including the posted unadjusted p-value of 1.0, is not the probability that the treatments are identical, nor does it measure the probability that a result occurred by chance.

The record describes the posted phase 2 response result as an unadjusted comparison. No adjusted analysis is listed among the reported analyses. Unadjusted estimates can be useful descriptions of the observed group contrast, but they do not account for covariates or other modeling choices. The registry record does not report a statistical analysis plan or further details about how the comparison was specified.

Why do study phases and endpoints matter?

The trial summary says phase 2 was intended to estimate PFS by RECIST 1.1. PFS is a time-to-event outcome, unlike a participant count at a defined response assessment. General time-to-event methods account for both the timing of events and follow-up that ends before an event is observed. However, the PFS endpoint results and its analysis details are not reported in the registry record. The response outcome by Choi criteria is a separate secondary endpoint and cannot substitute for the unreported PFS result.

Because the record lists multiple outcomes, results across them should be interpreted cautiously. Each additional outcome can create another opportunity for an apparently notable finding. Adjustment for multiple comparisons, a prespecified hierarchy, or another multiplicity strategy can help control the interpretation of repeated testing. Such a strategy is not reported in the registry record. The absence of a reported strategy does not establish that none was used; it means that the record does not document one in the information.

The sample-size illustrations accompanying the analysis are planning illustrations based on the observed effect under stated assumptions; they are not the trial’s original design justification and are not observed power. The registry record does not report the trial’s sample-size justification, interim analyses, or full statistical plan. Planning calculations based on an observed estimate cannot establish what the trial was designed to detect, and their interpretation depends on assumptions that may not match the actual design or data-generating process.

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("P1b: 8 mg/kg TRC105 Wkly + 5 mg Axitinib BID", "P1b: 10 mg/kg TRC105 Wkly + 5 mg Axitinib BID", "P1b: 10 mg/kg Wkly/15 mg/kg q2wks TRC105 + 5 mg Ax")
n      <- c(3, 15, 5)
events <- c(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  P1b: 8 mg/kg TRC105 Wkly + 5 mg Axitinib BID  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  P1b: 10 mg/kg TRC105 Wkly + 5 mg Axitinib BID  15  0  0.0  0.0  21.8  0.0  20.4  0.2  20.6
ARM  P1b: 10 mg/kg Wkly/15 mg/kg q2wks TRC105 + 5 mg Ax  5  0  0.0  0.0  52.2  0.0  43.4  0.4  45.9

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists six outcome measures and four posted secondary outcomes, while the reported number of analyses is zero. The response comparison included in the posted results is unadjusted. No multiplicity adjustment, testing hierarchy, or other strategy for interpreting multiple outcomes is reported in the registry record. This limits how confidently a reader can treat any secondary result as confirmatory. When several outcomes are examined, the chance of at least one apparently unusual result can increase; this is a general statistical concern, not evidence that a particular result in this trial is spurious.

Missingness also matters for the primary endpoint. The registry states that participants who discontinued before completing the DLT evaluation period were not evaluable. It does not report how many participants were not evaluable, the reasons for discontinuation, or how those participants were handled in other analyses. The primary DLT count should therefore be understood within the stated evaluability rule, not as proof that all participants who entered phase 1b completed the assessment.

For the phase 2 outcomes, the registry information does not report the analysis population, missing-data methods, treatment of participants with incomplete response assessments, or whether analyses followed intention-to-treat principles. These details are not reported in the registry record. The trial-level enrollment figure should not be assumed to be the denominator for any individual endpoint.

The registry also does not report the sample-size justification, interim analyses, or full statistical analysis plan in the information. The reason for termination is not reported in the registry record. Without those details, it is not possible to determine from this record whether the analyses followed a prespecified plan, whether early stopping affected interpretation, or whether missing outcomes were related to trial termination. These are documentation limits; they do not establish that a particular practice was or was not followed.

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: dehydration (40.0%), infusion related reaction (33.3%), diarrhoea (33.3%), abdominal pain (20.0%), colitis (20.0%).

The safety information separates serious adverse events, other adverse events, and deaths across phase 1b cohorts and phase 2 groups. These categories should be read as distinct summaries. A serious adverse event count is not the same as a DLT count: DLT has a specific phase 1b endpoint definition and grading framework, while the serious-event summaries describe a broader safety category. The figures are counts of participants with events in the listed groups, not estimates of comparative risk adjusted for follow-up or other factors.

Serious adverse events are reported for both phase 1b dose cohorts and the phase 2 groups. The registry also lists deaths by group. It does not state in the information whether the deaths were treatment-related, nor does it provide cause-specific explanations. A death count should not be interpreted as evidence of causation without that context. The serious-event terms and their percentages are also reported, but the denominator and method used for those percentages are not described; they should not be read as incidence rates without that information.

The phase 1b cohorts have different group sizes and dosing schedules, and phase 2 groups have different treatment assignments. Raw counts across these groups are therefore not a direct comparison of treatment safety. Follow-up duration, exposure, event definitions, and participant characteristics can affect comparisons; further details are not reported in the registry record. The safety figures describe what was recorded, but do not by themselves establish whether one regimen is safer than another.

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

The posted primary result means that no DLTs were recorded among the evaluable participants in each listed phase 1b cohort, under the registry’s stated endpoint and evaluation rules. It is a descriptive finding for the tested dose schedules and observed participants. It is not evidence that the regimens caused no toxicity of any kind, and it does not rule out uncommon or later events. The registry’s separate safety summaries include events beyond the DLT endpoint.

The phase 2 response result is an unadjusted comparison of a secondary binary outcome. Its point estimate is at zero difference, but its confidence interval includes values favoring either group. The result therefore does not establish that the treatments are equivalent or that their effects are identical. No equivalence or noninferiority margin is reported in the registry record.

The trial summary identifies phase 2 PFS as an objective, but PFS results are not reported in the registry record. As a result, the posted response comparison cannot answer whether the randomized groups differed in PFS. It also cannot establish a treatment effect on survival or other outcomes that are not reported. The phase 1b DLT result concerns safety in dose finding and is not a substitute for a randomized phase 2 efficacy analysis.

The record’s terminated status is important context, but the reason for termination is not reported in the registry record. It is not possible to infer whether the trial ended because of a safety concern, an efficacy finding, recruitment, operational constraints, or another reason. Likewise, the registry information does not document the sample-size rationale, interim analyses, or full statistical analysis plan.

In short, the available results support limited descriptive conclusions about DLT counts and the posted secondary response comparison. They do not provide the phase 2 PFS result identified in the trial summary, prove equivalence, or establish a comprehensive benefit-risk comparison. The uncertainty and reporting gaps should remain part of any interpretation.

14. Why This Trial Matters Statistically

This trial is statistically notable because it joins dose finding and randomized comparison within one study record. These phases address different questions and use different evidence structures. The phase 1b DLT endpoint describes tolerability within dose cohorts, whereas the phase 2 design compares a combination regimen with axitinib alone. Keeping those questions separate prevents safety observations in dose escalation from being mistaken for a randomized treatment effect.

The distinction between the phase 2 objective and the posted outcomes also matters. The trial summary identifies PFS as the phase 2 objective, yet the numerical phase 2 result described in the registry information is a secondary response outcome by Choi criteria. PFS and response are not interchangeable endpoints. A response comparison may provide relevant descriptive information, but it cannot fill the evidentiary role of an unreported PFS analysis.

The response estimate illustrates why uncertainty matters: a point estimate centered at no difference does not mean the data establish no difference, particularly when the confidence interval remains compatible with effects in either direction. The endpoint’s secondary status and the absence of a reported multiplicity strategy further support cautious interpretation rather than a definitive claim.

Finally, the trial is listed as terminated, while the reason is not reported in the registry record. Statistical interpretation depends not only on estimates but also on outcome definitions, analysis populations, missingness, and prespecification. The record leaves several of those details undocumented in the information. Recognizing what is available—and what is not—is essential to avoid making claims broader than the reported results can support.

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 is limited to DLT in phase 1b, not the randomized phase 2 comparison. The registry’s evaluability rule excludes participants who discontinued before completing the DLT evaluation period, but the number and characteristics of those not evaluable are not reported in the registry record. That makes it difficult to assess how complete the endpoint observation was.

The phase 2 PFS objective named in the trial summary has no result reported in the registry information. The posted phase 2 response outcome is secondary and uses Choi criteria. Its unadjusted estimate is accompanied by an interval that includes effects in either direction, and no equivalence margin is reported. The other listed secondary outcomes do not have numerical results, so the full outcome pattern cannot be assessed.

Although the phase 2 design is randomized, the registry information does not include the allocation ratio, randomization procedure, analysis population, missing-data methods, or further details of the statistical plan. Masking is listed as none. The record does not report whether analyses were adjusted for baseline characteristics or how deviations from treatment assignment were handled.

The trial’s status is terminated, but its reason is not reported in the registry record. The sample-size justification and interim analyses are also not reported. These gaps prevent assessment of whether termination affected planned analyses or whether the observed information was consistent with the trial’s original design goals.

Safety comparisons have additional constraints: the groups differ by phase, regimen, and group size, and the reported counts do not by themselves account for exposure or follow-up duration. The registry information does not establish causal attribution for deaths or detail the denominator for the listed serious-event term percentages. These limits argue against treating raw safety counts as a direct comparative estimate.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Randomized Phase 2 Trial of Axitinib and TRC105 Versus Axitinib Alone in Patients Renal Cell Carcinoma — NCT01806064.
• Registry record last updated 2020-10-19; status last verified 2020-10.
• Results first posted 2020-10-19.
• 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

NCT01806064 is a randomized, parallel, unmasked trial listed as phase 1 and phase 2, with a phase 1b dose-escalation portion and a phase 2 comparison of axitinib alone with TRC105 plus axitinib. The registry reports enrollment of 173, a start date of 2013-03-08, primary completion on 2018-12-21, and terminated status. The reason for termination is not reported in the registry record.

The posted primary outcome is the phase 1b count of participants with DLT over 12 Months; zero participants are reported in each of the three listed dose cohorts. The phase 2 summary objective is PFS by RECIST 1.1, but that result is not reported in the registry record. A secondary phase 2 response outcome by Choi criteria is posted, with an unadjusted risk difference of 0.0 and a confidence interval from -0.151 to 0.151. The registry information does not report the full statistical plan, sample-size justification, interim analyses, or reason for termination.