Sapanisertib and Ziv-Aflibercept in Treating Patients With Recurrent Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Sapanisertib and Ziv-Aflibercept in Treating Patients With Recurrent Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery (NCT02159989), a na phase 1 study. The primary outcome is Dose-limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD).

2. Clinical Question

This is a phase I study of a drug combination in patients with advanced cancers. Its central purpose, as described in the registry record, was to assess toxicities and identify a dose level for further study. The primary safety assessment was confined to Cycle 1, a 28-day cycle. The registry defines dose-limiting toxicities using adverse-event severity, duration, relation to the study agents, and specified hematologic and non-hematologic criteria.

The study also lists tumor response outcomes based on change in tumor size, including objective response rate and disease control rate per RECIST v1.1. Those outcomes concern tumor measurements, distinct from the primary dose-finding question. The registry record does not report numerical results for these outcomes. Without a separate comparison group, the design does not provide a randomized estimate of how the combination compares with another treatment or with no study treatment.

3. Trial Design

The registry describes NCT02159989 as a phase I, single-group study sponsored by the National Cancer Institute. Allocation is listed as not applicable and masking as none. The record reports enrollment of 83 and a completed status. The study began on 2014-06-18, and the primary completion date is 2021-06-29.

Participants received sapanisertib and ziv-aflibercept. Sapanisertib was taken by mouth once daily on days 2-4, 9-11, 16-18, and 23-25; ziv-aflibercept was administered intravenously over 60 minutes on days 1 and 15. Cycles repeated every 28 days unless disease progression or unacceptable toxicity occurred. The registry lists dose groups, including an expansion group, but these do not constitute randomized comparator arms.

The primary outcome was dose-limiting toxicities and maximum tolerated dose. DLT assessment took place during Cycle 1. The record says that participants in the dose-escalation phase had to receive at least 75% of planned doses of both agents to be evaluable for a DLT. It defines the MTD as the highest dose level at which no more than 1 of 6 evaluable patients had a DLT.

Secondary outcomes include objective response rate and disease control rate per RECIST v1.1. The registry lists 3 outcome measures. It does not report the protocol’s detailed dose-escalation procedure, the rationale for enrollment, or the statistical analysis plan. Those details are not reported in the registry record. Because the study is single-group and unmasked, its dose-level descriptions should not be read as a randomized comparison of treatment strategies.

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: Of the 83 patients, only 55 patients received at least 1 dose of the study agents. The remaining 28 patients screen failed and did not receive any dose of the study drugs. Per the protocol, all 55 patients who received one or more doses of drug were included in the analysis and the results are reported here.

Only the first 6 of 11 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Patients enrolled in the dose escalation phase must have received at least 75% of planned doses of both drugs to be evaluable for a DLT.

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.

Only the first 6 of 12 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Dose-limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD), measured over DLT was assessed during Cycle 1 (28-day cycle)..

The primary endpoint combines assessment of dose-limiting toxicities with determination of the maximum tolerated dose. A DLT is a qualifying adverse event attributed to the study agents and meeting the registry’s specified criteria for severity, duration, or treatment delay. The criteria include selected blood-related toxicities and non-hematologic toxicities, with stated exceptions for some events. DLTs were assessed during Cycle 1, defined as a 28-day cycle.

The registry says that a participant in the dose-escalation phase was evaluable for DLT only after receiving at least 75% of planned doses of both drugs. This eligibility rule matters to interpretation: the count of DLTs is tied to an evaluable population, which may differ from everyone enrolled or treated. The number of participants who met that rule is not reported in the registry record.

The MTD is defined in the record as the highest dose level at which no more than 1 of 6 evaluable patients had a DLT. In general, an endpoint of this kind is used in early-phase dose-finding to characterize tolerability and guide selection of a dose for later evaluation. It is not itself a measure of comparative efficacy. The registry record gives the definition and assessment window but does not report the observed DLT count by evaluable population or the resulting MTD. Therefore, the primary endpoint’s numerical result cannot be interpreted from the registry information described.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The study is described as single-group, with allocation listed as not applicable and masking listed as none. These design features determine what kinds of statistical conclusions are supported. A randomized comparison uses assignment to create groups intended for a direct comparison. Here, the dose-level groups are part of dose finding, not randomized arms. Differences in their observed event counts could reflect differences in dose, but also differences in group composition, treatment exposure, or other factors. The registry information does not permit those influences to be separated.

What does the primary endpoint capture?

A dose-limiting toxicity is a defined safety event within a specified period. The registry sets the assessment window at Cycle 1, a 28-day cycle, and lists criteria covering hematologic and non-hematologic events. The rule requiring receipt of at least 75% of planned doses of both drugs defines who is considered evaluable in dose escalation. In general, defining an evaluable population helps ensure that participants had sufficient exposure for the planned toxicity assessment. It also means that the evaluable population must be distinguished from the enrolled population. The number evaluable is not reported in the registry record.

The registry defines the MTD as the highest dose level at which no more than 1 of 6 evaluable patients had a DLT. This is a decision rule based on observed DLTs, not a guarantee that the selected dose has a particular toxicity probability in a broader population. In general, estimates based on small groups can be imprecise, and observed rates can vary substantially across studies. The registry record does not report the dose-escalation algorithm, uncertainty intervals, or the selected MTD.

How should counts and percentages be read?

Counts describe how many participants had an event in the population used for that count. A percentage expresses a count relative to a denominator, so its interpretation depends on who is included and how the event is defined. The adverse-event record lists group sizes and event counts, as well as percentages for selected serious adverse-event terms. The denominator for the term percentages is not reported in the registry record. They should therefore be read as the percentages displayed for those terms, not assumed to be rates among all enrolled participants or among a particular exposure-defined group.

Serious adverse events and DLTs are not interchangeable concepts. DLTs are defined by criteria that include timing, relation to study agents, and particular severity or duration rules. The serious-event listing is a separate safety description. An event can be serious without meeting the DLT definition, and the registry’s listed serious terms do not, by themselves, establish that an event was treatment-related. In general, causality and event classification require the study’s definitions and adjudication details.

What can a single-group study estimate?

In general, a single-group study can describe outcomes observed among participants meeting the relevant analysis definition. Without a comparator group, it cannot estimate a randomized between-group treatment effect. Comparisons across dose levels are also not equivalent to randomized comparisons: dose assignment processes and exposure can differ, and the registry record does not describe enough detail to assess those factors. The response outcomes named in the record are objective response rate and disease control rate per RECIST v1.1, but their numerical results are not reported in the registry record.

A confidence interval, in general, expresses statistical uncertainty around an estimate under the assumptions of the method used. It is not a guarantee that the true value lies within the interval, and it does not address biases caused by study design or missing data. No confidence intervals for the primary endpoint or tumor-response outcomes are reported in the registry information described. Consequently, the precision of those outcome estimates cannot be assessed.

How do the planning illustrations differ from observed results?

The registry’s sample-size assumptions describe planning illustrations computed from an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is defined as a stated fraction of the observed effect. For time-to-event outcomes, the assumptions describe total events using the Schoenfeld approach; other outcomes are expressed as participants per arm. These are planning illustrations, not the trial’s own design or observed power. Since this study is single-group rather than a randomized two-arm comparison, such hypothetical calculations should not be mistaken for the trial’s actual allocation or evidence about its precision. No numerical illustration values are reported in the registry record.

Overall, the statistical framework in the record supports describing the intended toxicity assessment and the available group-level adverse-event counts. It does not provide the primary endpoint result, tumor-response estimates, uncertainty intervals, or enough information to reconstruct an analysis. Those results and details are not reported in the registry 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 1b", "Dose Level 2", "Dose Level 3", "Dose Level 4", "Dose Level 5")
n      <- c(5, 4, 3, 3, 4, 3)
events <- c(0, 0, 0, 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  Dose Level 1  5  0  0.0  0.0  52.2  0.0  43.4  0.4  45.9
ARM  Dose Level 1b  4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2
ARM  Dose Level 2  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Dose Level 3  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Dose Level 4  4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2
ARM  Dose Level 5  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary outcome concerning DLTs and MTD, along with secondary outcomes for objective response rate and disease control rate per RECIST v1.1. It reports 3 outcome measures overall, but does not describe how the analyses were prioritized or whether any adjustment for multiple testing was planned. A multiplicity procedure is not reported in the registry record.

In general, when several outcomes or comparisons are examined, the chance of at least one apparently notable finding can increase unless the analysis plan accounts for the number and relationship of tests. This concern is especially relevant when outcomes are exploratory or when many dose groups and event types are examined. The registry record does not state whether formal hypothesis tests were conducted for the secondary outcomes, how any such tests were handled, or whether analyses were prespecified.

The registry provides a DLT evaluability rule requiring at least 75% of planned doses of both drugs during dose escalation. However, it does not report the number of participants evaluable for the primary endpoint, the handling of participants who did not meet the rule, or any broader missing-data procedure. It also does not state how missing tumor measurements or incomplete follow-up were treated. These details are not reported in the registry record.

The record lists 0 analyses. In the information reported, no adjusted or unadjusted effect estimates, confidence intervals, or hypothesis-test results are available for the primary or secondary outcomes. Therefore, multiplicity, missing-data handling, and the precise analysis populations cannot be assessed from the registry record. General statistical principles cannot determine which methods the investigators actually used.

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 1% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: anemia (50.0%), epistaxis (50.0%), platelet count decreased (50.0%), pancreatitis (40.0%), pruritus (40.0%).

The safety information is arranged by dose group and includes the number at risk, the number with serious adverse events, the number with other adverse events, and deaths. The record also lists selected serious adverse-event terms with percentages: anemia, epistaxis, and platelet count decreased are each listed at 50.0%; pancreatitis, pruritus, and rash maculo-papular are each listed at 40.0%. These are the percentages recorded for those terms; the denominator and fuller context are not reported in the registry record.

These figures are descriptive, not a randomized comparison. The dose groups are not like-for-like control arms, and the registry does not establish that the listed events were caused by study treatment. Serious adverse events should also not be read as synonymous with DLTs: the DLT definition adds timing, attribution, and specific severity or duration criteria. Death counts are listed by group, but the record excerpt does not state cause or relationship to treatment. The safety figures therefore describe reported events in the listed groups, without establishing comparative risk or causation.

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

The registry record supports a clear description of the study’s intended task: assess DLTs during Cycle 1 and identify an MTD for the combination of sapanisertib and ziv-aflibercept in patients with advanced solid tumors. It also provides the dosing schedule, DLT criteria, evaluability rule, dose-group safety counts, and selected serious adverse-event terms.

It does not report the primary endpoint result. In particular, it does not state the number of evaluable participants with DLTs or the MTD selected. Nor does it report numerical results for the secondary tumor-response outcomes. Without those findings, no conclusion about the observed frequency of DLTs, the dose selected, tumor response, or the precision of those outcomes can be drawn from the registry record.

Even if outcome estimates were reported, this single-group design would not provide a randomized comparison against another treatment. Its dose levels are not control arms, and descriptive variation between dose groups would not on its own identify a causal dose effect. The record’s safety counts also do not establish causality, and the listed percentages lack reported denominator context.

In general, phase I dose-finding and later comparative evaluation address different statistical questions. A dose-finding endpoint concerns toxicity under a defined early assessment window and a decision rule. Tumor-response outcomes concern observed tumor measurements. Neither type of result, without an appropriate comparative design and adequate reporting, establishes comparative effectiveness. The record establishes the study framework, but not the results needed to evaluate its primary or secondary outcomes.

14. Why This Trial Matters Statistically

This study illustrates why a trial’s design and its posted outcome reporting must be read together. Its stated primary purpose is dose finding, not a randomized efficacy comparison. The Cycle 1 DLT definition, the rule for evaluability, and the MTD decision criterion specify how the primary endpoint was intended to be interpreted. Those details are important because a toxicity count depends on the assessment window and the population counted.

The distinction between enrolled participants, participants at risk in a dose group, and participants evaluable for DLT is statistically important. The registry reports enrollment of 83 and gives dose-group safety counts, but the number meeting the DLT evaluability rule is not reported. Without that analysis population and the primary outcome counts, the MTD cannot be checked against the stated rule from the registry information.

The record also demonstrates the limits of interpreting safety descriptions across dose levels. Dose groups in a single-group dose-finding study are not randomized comparator arms. Descriptive event counts can help characterize what was recorded, but do not establish comparative risks or causality. For this study, the primary result and numerical tumor-response results are not reported in the registry record, so the design alone cannot answer whether any outcome was observed at a particular rate.

Statistically, the most consequential information is not only which endpoint was planned, but also the outcome values, analysis population, and uncertainty around estimates. Those results are not reported in the registry record. This limits the conclusions that can be drawn even though the study is marked completed.

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 registry record leaves important trial-specific details unavailable. It does not report the primary DLT counts among evaluable participants, the resulting MTD, or numerical results for objective response rate and disease control rate. It also does not report uncertainty intervals for those outcomes. The listed enrollment figure cannot resolve these omissions because the registry does not state how many participants were evaluable for each endpoint.

The record does not describe the dose-escalation algorithm, the sample-size justification, or a detailed statistical analysis plan. It does not report how missing assessments, incomplete exposure, or participants who failed the DLT evaluability rule were handled. The analysis populations for the response outcomes are not reported in the registry record.

The study is single-group and unmasked, with no separate comparator. Dose levels should not be interpreted as randomized arms. The registry’s serious adverse-event terms include percentages, but the denominator and details of their analysis population are not reported. It also does not provide enough information in the listed terms to attribute events to treatment. These limitations restrict assessment of the primary endpoint, the safety profile, and any tumor-response findings from the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Sapanisertib and Ziv-Aflibercept in Treating Patients With Recurrent Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery — NCT02159989.
• Registry record last updated 2025-10-20; status last verified 2025-09.
• Results first posted 2025-10-20.
• 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

NCT02159989 is a completed phase I, single-group study sponsored by the National Cancer Institute. It evaluated sapanisertib with ziv-aflibercept in patients with advanced solid tumors. The primary outcome concerned DLTs during Cycle 1 and MTD determination, with a rule requiring at least 75% of planned doses of both drugs for dose-escalation participants to be evaluable.

The record lists enrollment of 83, dose-level safety counts, and selected serious adverse-event terms and percentages. It also names objective response rate and disease control rate per RECIST v1.1 as secondary outcomes. The primary endpoint result, selected MTD, numerical tumor-response results, and detailed analysis methods are not reported in the registry record. The single-group design does not provide a randomized comparator.