Arsenic Trioxide With Cyclophosphamide in Patients With Relapsed/Refractory Acute Myeloid Leukemia: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Arsenic Trioxide With Cyclophosphamide in Patients With Relapsed/Refractory Acute Myeloid Leukemia (NCT03318016), a non-randomized phase 1 study. The primary outcome is Number of Participants That Reached Maximally Tolerated Dose (MTD) of Cyclophosphamide and ATO.

2. Clinical Question

This is a dose-finding question rather than a conventional efficacy comparison. The registry record describes a phase I trial in which cyclophosphamide dose levels were explored alongside a fixed arsenic trioxide dose. In a dose-finding study, observations about tolerability help characterize the dose levels under study; they do not by themselves establish comparative benefit.

The trial status is terminated. Its stated enrollment is 5, while the posted adverse-event records list participants at risk in Cohort 1 and Cohort 2 only. The registry record does not explain the circumstances of termination or provide a narrative account of recruitment, treatment completion, or follow-up. Those omissions limit what can be concluded about how fully the stated objectives were addressed.

3. Trial Design

The registry record identifies NCT03318016 as a phase I, non-randomized, unmasked trial with a sequential model. It lists the sponsor as University of Colorado, Denver. The recorded start date is 2017-12-15, and the primary completion date is 2020-01-15. The status is terminated, and enrollment is listed as 5.

The intervention descriptions specify arsenic trioxide at a fixed dose of 0.15 mg/kg/d IV for 3 consecutive days, followed by a single IV cyclophosphamide dose on day 4. The intervention list includes cyclophosphamide amounts of 500 MG, 1000 MG, 2000 MG, 3000 MG, and 4000 MG. The cohort descriptions repeat the treatment schedule but do not identify which listed cyclophosphamide amount was used in each cohort. The primary outcome description refers to a highest dose level of 1000 mg/m2, so the relationship between that dose statement and the intervention amounts is not clear from the registry record.

The primary outcome timeframe is 26 months. Its description calls the study a standard phase I, 3+3 design: the first 3 subjects would be assigned to Cohort 1, with the next 3 assigned to Cohort 2 if there were 0/3 dose-limiting toxicities in Cohort 1, and continued escalation until the stated MTD criterion was established. The record also describes MTD as the highest dose level of 1000 mg/m2 and says it is established when at least 6 participants within a cohort have responded without toxicity. The record does not report whether this criterion was met or clarify the wording about response without toxicity.

Because assignment was sequential and non-randomized, the cohorts are not randomized comparison groups. No separate control treatment is listed. Masking was none. Details of dose-limiting toxicity definitions, dose modifications, monitoring, and the operational conduct of escalation 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.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Patients With Relapsed/Refractory Acute Myeloid Leukemia

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: Relapsed/Refractory Acute Myeloid Leukemia

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants That Reached Maximally Tolerated Dose (MTD) of Cyclophosphamide and ATO, measured over 26 months.

The primary endpoint is the number of participants who reached the maximally tolerated dose of cyclophosphamide with arsenic trioxide. The registry record gives the unit as participants and the timeframe as 26 months. It describes MTD as the highest dose level of 1000 mg/m2 and states that MTD is established when at least 6 participants within a cohort have responded without toxicity.

A dose-finding endpoint is used in early-phase research to describe tolerability at dose levels under investigation and to identify a dose for further study. In general, dose-limiting toxicity information is central to interpreting an MTD endpoint, because the decision depends on how toxicity is defined and observed at each level. The registry record refers to dose-limiting toxicities in its 3+3 description but does not provide the detailed definition, observation window, or decision rules beyond the stated cohort progression.

The posted record does not give an observed primary endpoint count, a dose level shown to have met the MTD criterion, or an estimate of uncertainty. Therefore, the endpoint's definition and intended role can be described, but its observed result cannot be interpreted from the registry record. The wording also combines a dose-limiting-toxicity escalation description with a criterion framed as participants who “have responded without toxicity.” The record does not explain how response and toxicity jointly determined the endpoint, so the operational interpretation remains uncertain.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The record labels the trial phase I, non-randomized, unmasked, and sequential. These features describe how participants were assigned and how the study was intended to proceed; they do not specify a complete statistical analysis plan. The registry record describes a 3+3 dose-escalation approach, but it does not report a full analysis plan, a sample-size justification, or interim analyses.

What does sequential dose finding mean?

In general, a sequential dose-finding design uses information from participants already treated to guide which dose level is considered next. The registry description states that the first 3 subjects would enter Cohort 1 and that assignment would proceed to Cohort 2 if there were 0/3 dose-limiting toxicities in Cohort 1. The description says escalation would continue until MTD was established. These are the stated design intentions; the registry record does not document every decision made during conduct or provide a participant-level account of dose assignment.

The MTD description requires careful reading. The record states that MTD is the highest dose level of 1000 mg/m2 and that it is established when at least 6 participants within a cohort have responded without toxicity. It also discusses dose-limiting toxicities as the basis for the escalation rule. The record does not reconcile these descriptions or define how response and toxicity were combined in determining the endpoint. The cohort descriptions also do not map the listed cyclophosphamide amounts to individual cohorts.

Why does a non-randomized design matter?

In general, random assignment helps make treatment groups comparable with respect to both measured and unmeasured characteristics. Here, allocation is listed as non-randomized and the study is sequential, so differences between cohorts could reflect who entered at each stage, clinical circumstances, or other factors as well as dose. Cohort-to-cohort contrasts should not be interpreted as randomized estimates of comparative treatment effects. There is no listed control group receiving a different treatment or no study treatment.

How should event counts be interpreted?

The primary outcome is a count of participants reaching MTD, and the adverse-event information is also presented as participant counts. For a binary event, the count indicates how many participants were recorded with the event within the group at risk. General interpretation depends on the denominator, the event definition, and the observation period. Small denominators make each participant's status influential, and estimates based on sparse counts are imprecise. The registry record gives at-risk and affected counts for serious and other adverse events by cohort, but does not give event-level timing or exposure-adjusted rates.

General statistical methods for sparse binary outcomes may use exact or other small-sample approaches rather than rely on large-sample approximations. The registry record does not say that such methods were used, and it reports no inferential analysis for the posted outcomes. No p-values, confidence intervals, or adjusted effect estimates are reported. It would be inappropriate to attribute a particular statistical method to the trial.

What does the absence of reported analyses imply?

The registry lists 2 outcome measures and 0 analyses. This means the entry contains outcome definitions but no registered analysis results in the record. It does not show whether analyses were performed elsewhere, nor does it reveal how any unreported analysis was designed. Statistical details such as analysis populations, handling of missing observations, covariate adjustment, multiplicity procedures, and rules for evaluating response are not reported in the registry record.

General concepts can help frame the data without filling those gaps. A confidence interval communicates uncertainty around an estimate, while a p-value assesses compatibility with a specified null model under assumptions. Neither can be reconstructed from the posted counts without choosing a method, and no such recalculation is appropriate as a substitute for the sponsor's analysis. Over-dispersion matters in settings where variability is greater than a model assumes; the posted outcomes are counts, but no model for over-dispersion is reported or clearly indicated as relevant.

The registry record includes a sample-size-planning description for an illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. It says the effect to detect is a stated fraction of the observed effect, and distinguishes participant-per-arm quantities from total event counts for time-to-event outcomes. These are planning assumptions, not evidence about the trial's observed power. The registry record does not report a trial-specific sample-size justification. No planning values are available in the entry to interpret or repeat.

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("Cohort 1", "Cohort 2")
n      <- c(3, 2)
events <- c(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  Cohort 1  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Cohort 2  2  0  0.0  0.0  84.2  0.0  65.8  0.8  70.8

11. Multiplicity, Missing Data and Analysis Populations

The record lists 2 outcome measures: the primary count of participants reaching MTD and a secondary outcome for overall response rate using arsenic trioxide and cyclophosphamide. The brief summary also names response duration, event-free survival, overall survival, and the number of transplant-eligible subjects successfully bridged to stem cell transplantation or donor lymphocyte infusion as objectives. The registry record does not provide results for these additional outcomes.

Multiplicity arises in general when several outcomes, time points, groups, or analyses are tested, because repeated testing can increase the chance of a seemingly notable result occurring by chance. The record does not report a multiplicity adjustment, a hierarchy among efficacy outcomes, or a plan for interpreting multiple tests. It also lists 0 analyses, so no inferential results are available to assess for multiplicity.

Missing-data methods and analysis populations are not reported in the registry record. It does not state how participants with incomplete assessments, early discontinuation, or unavailable follow-up were handled. Nor does it define an intention-to-treat, treated, evaluable, or other analysis population. These omissions matter because the interpretation of counts and response outcomes depends on which participants are included and how missing outcomes are treated.

The enrollment is listed as 5, but the registry record does not provide participant-level disposition or explain how enrollment relates to the cohort safety denominators. It does not report the reason for termination, whether any participants were excluded from outcome assessment, or whether the outcomes were fully ascertained. Missing information should not be read as evidence that data were missing or that a particular method was used; the handling is simply not reported in the registry record.

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: pneumonia (33.3%), hypoxia (33.3%), chest pain (33.3%).

The serious adverse-event records are organized by cohort and distinguish participants at risk from participants affected. Cohort 1 lists 3 at risk and 1 affected; Cohort 2 lists 2 at risk and 0 affected. Cohort -1, Cohort 3, and Cohort 4 list no participants at risk and no affected participants. The record lists 0 deaths in each cohort.

The most frequent serious-event terms listed are Pneumonia, Hypoxia, and Chest Pain, each reported as 33.3%. These percentages are presented as term values in the registry record, but term-specific counts and their denominator are not reported. They therefore should not be used to infer a precise event rate or to assume that the terms occurred in distinct participants.

These are descriptive safety data from a small, non-randomized study. They do not estimate comparative risk against a control group. The registry record does not report exposure time, event onset, duration, resolution, severity grading details, or attribution to treatment. The separate other-adverse-event counts are 3 at risk and 3 affected in Cohort 1, and 2 at risk and 2 affected in Cohort 2. An affected count records participants, not necessarily the number of events.

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

The registry record documents a phase I dose-finding study of arsenic trioxide with cyclophosphamide in patients with relapsed or refractory acute myeloid leukemia. The combination schedule, sequential design, and intended MTD objective are described. The entry also provides a limited set of cohort-level adverse-event counts, including serious-event counts and a list of serious-event terms.

Those data do not establish the primary endpoint result. No observed count of participants reaching MTD or confirmed MTD dose is reported. The record does not say whether the stated criterion was met, and its descriptions of the criterion and escalation process are not fully reconciled. The five cyclophosphamide intervention amounts are listed, but their mapping to cohorts is not clear in the cohort descriptions.

The posted record also does not report results for overall response rate, response duration, event-free survival, overall survival, or transplant bridging. Although the record identifies overall response rate as a secondary outcome, the analysis count is 0. It is not possible to infer treatment efficacy or comparative benefit from the available registry information.

General interpretation of a small phase I study is constrained by sparse observations and the lack of randomization. The safety counts describe what was recorded among the listed participants at risk; they do not predict the frequency of events in another population. The absence of a control group means the record cannot isolate the treatment's effect from other possible influences.

The appropriate scope of interpretation is therefore limited: the entry describes what the trial intended to assess and reports selected safety counts, but it does not provide enough results to evaluate whether the MTD objective was achieved or whether the combination was associated with the named efficacy outcomes. The reason the trial was terminated is not reported in the registry record.

14. Why This Trial Matters Statistically

This trial illustrates why a phase I record needs to be read as a dose-finding study rather than as a randomized efficacy comparison. Its sequential, non-randomized design was intended to evaluate cyclophosphamide dose levels alongside a fixed arsenic trioxide schedule. The main statistical question concerns tolerability and the stated MTD criterion, not a between-group treatment effect.

It also demonstrates the importance of aligning endpoint definitions with the design. The registry describes escalation using dose-limiting toxicities, but defines MTD using a statement about participants who “have responded without toxicity.” It gives a highest dose level of 1000 mg/m2 while listing several cyclophosphamide amounts in MG, and the cohort descriptions do not resolve how these amounts correspond. Such ambiguities make it harder to interpret what was actually evaluated and how the primary endpoint would be determined.

Small cohort counts are informative as a record of observed events, but they carry substantial uncertainty and cannot support broad rate estimates. The lack of a randomized comparator also limits causal interpretation. These are design and reporting constraints, not proof that an outcome did or did not occur.

Finally, the registry entry lists outcome objectives but reports 0 analyses. The distinction between an outcome being named and a result being reported is important: without primary endpoint results, efficacy analyses, or participant disposition, the stated objectives cannot be evaluated from the registry record. Clear dose mapping, endpoint rules, analysis populations, and outcome reporting would be needed for a fuller statistical interpretation.

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 several trial-specific details unresolved. It gives a fixed arsenic trioxide schedule and lists five cyclophosphamide amounts, but does not map those amounts to the named cohorts. The cohort descriptions repeat the same treatment schedule without specifying a cohort-specific cyclophosphamide dose. The primary endpoint description uses 1000 mg/m2 for the highest dose level, while the intervention list expresses cyclophosphamide amounts in MG. The relationship between these descriptions is not clarified.

The primary endpoint criterion is also difficult to operationalize from the record alone. It refers to the highest dose level and to at least 6 participants within a cohort who “have responded without toxicity,” while the escalation description refers to dose-limiting toxicities. Definitions of response, toxicity, and the observation period for dose-limiting toxicity are not reported in the registry record.

The enrollment is listed as 5, and safety denominators are shown only for Cohort 1 and Cohort 2. The record does not provide a participant flow account, explain the absence of participants in other listed cohorts, or state whether all enrolled participants received treatment. It also does not describe the reason for termination or whether follow-up was complete.

There are no reported primary endpoint results, efficacy analyses, analysis populations, missing-data methods, or inferential estimates. The record does not report a trial-specific sample-size justification, a statistical analysis plan, or multiplicity handling. The posted adverse-event counts do not include exposure duration or detailed event-level information. These limits preclude conclusions about MTD attainment, comparative safety, efficacy, and the generalizability of the observed counts.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Arsenic Trioxide With Cyclophosphamide in Patients With Relapsed/Refractory Acute Myeloid Leukemia — NCT03318016.
• Registry record last updated 2024-08-01; status last verified 2024-02.
• Results first posted 2024-08-01.
• 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

NCT03318016 is a terminated, non-randomized, unmasked phase I trial sponsored by University of Colorado, Denver. It lists enrollment of 5 and a sequential design for arsenic trioxide with cyclophosphamide in relapsed or refractory acute myeloid leukemia. The recorded start date is 2017-12-15, with primary completion on 2020-01-15.

The stated primary outcome is the number of participants reaching MTD, with a 26-month timeframe. The registry record describes a 3+3 dose-escalation approach and lists overall response rate as a secondary outcome. It reports 0 analyses and does not give a primary endpoint result or efficacy results.

Safety records list serious adverse events in Cohort 1 and Cohort 2, with 0 deaths recorded in all cohorts. The reason for termination, cohort dose mapping, detailed analysis methods, and handling of missing data are not reported in the registry record.