Venetoclax and Vincristine in Treating Patients With Relapsed or Refractory T-cell or B-cell Acute Lymphoblastic Leukemia: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Venetoclax and Vincristine in Treating Patients With Relapsed or Refractory T-cell or B-cell Acute Lymphoblastic Leukemia (NCT03504644), a non-randomized phase 1, phase 2 study. The primary outcome is Number of Participants With Dose Limiting Toxicity (Phase I).

2. Clinical Question

The study’s stated purpose was to assess side effects and the best dose of venetoclax when combined with vincristine, as well as how well the combination works in relapsed or refractory disease. These are related but distinct questions: dose-finding focuses on toxicity at specified dose levels, while assessment of activity requires outcomes such as response, progression-free survival, or overall survival.

The registry lists progression-free survival, overall survival, toxicities, and minimal residual disease negativity as phase II secondary outcomes. Their results are not reported in the registry record. The record therefore supports a description of the study question and design, but not a conclusion about the combination’s antileukemia activity.

3. Trial Design

This is a phase Ib/II, nonrandomized, parallel-group study sponsored by ECOG-ACRIN Cancer Research Group. The registry lists enrollment as 40 and study status as active, not recruiting. The recorded start date is 2018-08-13, and the primary completion date is 2025-07-22. The registry does not report a randomized allocation process or masking; masking is listed as none.

The phase Ib portion used dose-level arms with venetoclax and liposomal vincristine. The described schedule gives venetoclax orally once daily on days 1-42 of cycle 1 and days 43-70 of cycle 2. Liposomal vincristine was given intravenously over 1 hour weekly for 4 weeks starting on day 15 of cycle 1. Further treatment could continue for patients with at least stable disease response at the treating clinician’s discretion, but additional details are not reported in the registry record.

The phase II description pairs venetoclax with either liposomal vincristine or vincristine sulfate. Venetoclax was given orally once daily on days 1-28 of each cycle. The record describes weekly liposomal vincristine for 4 weeks on day 1 of each cycle, or vincristine sulfate on days 1, 8, 15, and 22 of cycle 1 and once every 4 weeks on day 1 of each subsequent cycle. The full cycle description is not reported in the registry record.

Allocation was nonrandomized, so differences between arms may reflect factors other than the vincristine formulation or dose. The registry itself cautions that the arms are not a like-for-like control comparison. The record does not report the rationale for the phase II sample size, the process for assigning participants to treatment groups, or additional design details beyond those stated.

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: Phase I treatment employed a standard 3 + 3 dose escalation design, starting at dose level 1. The phase II portion of this trial was a single arm, open-label study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: If a patient never starts the study drug, withdraws prior to Day 42 of cycle 1 for non-DLT reasons, is lost to follow up prior to Day 42, or dose not receive 75% of study medications, this slot would be made available for replacement. In total 6 patients were replaced, all were assigned to Arm B.

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: Patients met the eligibility criteria and started protocol treatment

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Dose Limiting Toxicity (Phase I), measured over From start of treatment up to 42 days.

The primary endpoint is the number of phase I participants with a dose-limiting toxicity. The registry defines a dose-limiting toxicity as a protocol-listed toxicity meeting CTCAE version 5.0 criteria and considered possibly, probably, or definitely related to study medication or the combination during the first cycle, up to 42 days after the first dose of study drug.

This endpoint is used in dose-finding because toxicity at a dose level helps guide whether escalation should continue or whether a lower dose should be selected. The phase I portion is described as using a 3+3 design. Escalation would continue until more than 33% of a particular dose arm experienced a dose-limiting toxicity; the next lower dose arm would then be considered the maximum tolerated dose. The registry gives a separate rule for Arm C: if fewer than two participants experienced a dose-limiting toxicity in that arm, its dose would be considered the maximum tolerated dose.

The endpoint is a participant count, not a measure of how often all adverse events occurred or how severe every toxicity was. Its specified time window is limited to the first cycle. It is also distinct from the phase II efficacy outcomes listed in the record, including progression-free survival, overall survival, and minimal residual disease negativity. The number of participants with dose-limiting toxicity is not reported in the registry record, so the endpoint’s observed result cannot be described from this record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The record describes two related stages of investigation. Phase Ib uses a 3+3 dose-finding design and records the number of participants with dose-limiting toxicity. Phase II lists secondary outcomes, including progression-free survival, overall survival, incidence of toxicities, and minimal residual disease negativity. The registry does not report the detailed statistical methods for phase II analyses, so the phase I dose-finding description should not be treated as a complete analysis plan for all outcomes.

What does the 3+3 design do?

The registry says that dose escalation would continue until more than 33% of a particular dose arm experienced a dose-limiting toxicity, with the next lower dose arm considered the maximum tolerated dose. It also states that if fewer than two participants experienced a dose-limiting toxicity in Arm C, the Arm C dose would be considered the maximum tolerated dose. In general, a 3+3 approach uses observed toxicity counts at dose levels to guide escalation decisions. It is a rule-based dose-finding method, not a randomized comparison of treatment efficacy. The registry does not report additional operating characteristics, such as the chance of selecting a particular dose under different underlying toxicity patterns.

What does a participant count convey?

The primary measure is a count of participants who met the protocol definition of dose-limiting toxicity within the stated time window. A count is directly interpretable as the number of people meeting that endpoint, but it does not communicate uncertainty on its own. General statistical explanation: an interval estimate can show the range of values compatible with the observed data under specified assumptions. No interval estimate for the primary endpoint is reported in the registry record, and its observed count is also not reported there.

The safety entries distinguish participants at risk from participants affected for serious and other adverse events. These counts describe whether participants in a group were recorded as having an event in the relevant category. They do not disclose the number of separate events per person, event duration, severity distribution, or attribution for every event. The registry lists serious adverse event terms with percentages, but the denominator and calculation details for those percentages are not reported in the registry record.

How should arm comparisons be understood?

The study is nonrandomized and the registry warns that its arms are not like-for-like controls. General statistical explanation: random allocation can help balance measured and unmeasured participant characteristics across groups, whereas nonrandomized allocation does not ensure that balance. Therefore, observed differences between these arms could reflect differences in participants, treatment schedules, or other factors, as well as any treatment-related effect. The record does not report an adjusted comparative analysis that would address such differences.

The phase Ib groups represent dose levels, while the phase II group uses venetoclax with liposomal vincristine or vincristine sulfate. The available registry entries do not establish that participants were assigned to these groups in a way that supports causal comparison. No comparative effect estimates for the treatment groups are reported in the registry record.

What do the planning illustrations represent?

The registry’s planning assumptions describe illustrations based on an observed effect, not the trial’s own design. The stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is specified as a fraction of the observed effect. For time-to-event outcomes, the planning quantity is total events using the Schoenfeld approach; for other outcomes, it is participants per arm. Such calculations describe hypothetical planning requirements under stated assumptions. They are not observed power, do not show the power achieved by this study, and do not establish what sample-size justification the investigators used. The trial’s own sample-size justification is not reported in the registry record.

The record does not state whether interim analyses were planned or conducted, what hypothesis tests were used for phase II outcomes, how confidence intervals were constructed, or how any model assumptions were checked. General statistical explanation: for count or binary outcomes, methods should reflect the outcome definition and the amount of information in each group; for repeated or clustered observations, dependence between observations may also matter. The registry does not report whether such complications were relevant or how they were handled. These methodological details should not be inferred from the endpoint names or the design label alone.

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("Phase Ib Arm A (Dose Level 1)", "Phase Ib Arm B (Dose Level 2)", "Phase Ib Arm C (Dose Level 3)")
n      <- c(3, 6, 3)
events <- c(0, 0, 2)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Phase Ib Arm A (Dose Level 1)  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Phase Ib Arm B (Dose Level 2)  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Phase Ib Arm C (Dose Level 3)  3  2  66.7  9.4  99.2  20.8  93.9  19.4  93.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists multiple outcomes, including the phase I dose-limiting-toxicity count and phase II outcomes for progression-free survival, overall survival, incidence of toxicities, and minimal residual disease negativity. It also reports 12 outcome measures and 3 analyses. The statistical plan for these outcomes, including which are primary or secondary in each analysis, is not reported in the registry record beyond the stated phase I primary endpoint and the phase II secondary outcome labels.

When multiple outcomes or analyses are examined, the chance of a false-positive finding can increase if each is interpreted independently. General statistical explanation: a multiplicity plan can specify which outcomes are confirmatory and whether significance thresholds or interpretation will be adjusted across tests. The registry does not report whether multiplicity adjustments were planned or used. No p-values or comparative efficacy estimates for these outcomes are reported in the registry record.

Missing-data rules and analysis populations are also not reported in the registry record. The phase I description says that a participant could be replaced if they never started study drug, withdrew before Day 42 of cycle 1 for reasons other than dose-limiting toxicity, were lost to follow-up before Day 42, or did not receive 75% of study medications. It states that 6 patients were replaced and all were assigned to Arm B. This replacement rule concerns the phase I endpoint assessment; it does not specify the analysis population for other outcomes or explain how missing observations were handled in phase II.

The record does not state whether outcome analyses included all enrolled participants, treated participants, or another defined population. It also does not describe imputation, censoring rules, or sensitivity analyses for missing outcome data. Without those details, the influence of incomplete follow-up or replacement on reported estimates cannot be assessed from 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: febrile neutropenia (100.0%), white blood cell decreased (66.7%), anemia (33.3%), cardiac disorders - other, specify (33.3%), fever (33.3%).

The serious adverse event figures are group-level participant counts. The registry lists 3 at risk and 2 affected in Phase Ib Arm A; 12 at risk and 9 affected in Arm B; 3 at risk and 3 affected in Arm C; and 21 at risk and 12 affected in Phase II. The corresponding counts for other adverse events are 3 and 3, 12 and 12, 3 and 3, and 21 and 21, respectively. The record lists deaths as 0, 2, 0, and 17 across those same groups.

These are descriptive safety counts, not estimates from a randomized comparison. They do not establish that a treatment caused an event or death, and they do not show the number of separate events experienced by each participant. The record does not report event timing, individual severity, attribution, or reasons for death in the information available for this analysis.

The registry also lists febrile neutropenia at 100.0%, white blood cell decreased at 66.7%, and anemia, cardiac disorders - Other, specify, fever, and non-cardiac chest pain at 33.3% each among the top serious adverse event terms. The denominator and details of the percentage calculation are not reported in the registry record. These percentages should therefore be read as registry-listed term summaries, not as arm-specific rates or evidence that the listed events occurred in all participants across the study.

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

The record shows that a phase Ib/II study was designed to examine venetoclax in combination with vincristine in relapsed or refractory T-cell or B-cell acute lymphoblastic leukemia. Its phase I primary endpoint concerns dose-limiting toxicity during the first cycle, while phase II lists additional safety and disease-related outcomes. The registry also documents selected serious and other adverse event counts by treatment group.

These details do not show whether the regimen achieved a particular response rate, improved progression-free or overall survival, or produced minimal residual disease negativity. Although those outcomes are listed, their results are not reported in the registry record. The observed result for the primary dose-limiting-toxicity endpoint is also not reported, so the record does not support a conclusion about the dose-finding result.

The safety counts describe what was recorded in each group, but they do not establish a causal effect. The study was nonrandomized, and the registry cautions that its arms are not a like-for-like control comparison. Group differences in the counts therefore cannot be interpreted as evidence that one regimen is safer or less safe than another. The available information also does not provide event-level details or the denominators behind the listed serious adverse event term percentages.

General statistical explanation: a treatment effect is best interpreted using an estimate, its uncertainty, and a design that supports the intended comparison. In this record, comparative efficacy estimates and uncertainty intervals are not reported. The absence of these results from the registry record is not evidence that an outcome did or did not occur; it means that the outcome cannot be evaluated from the recorded information.

The record supports a careful account of study design, endpoint definitions, and selected safety counts. It does not support medical advice, a claim that the combination works or does not work, or a definitive comparison between the nonrandomized groups.

14. Why This Trial Matters Statistically

This study is statistically notable because it combines an early dose-finding stage with a later phase II stage, while asking questions that require different kinds of evidence. The phase Ib endpoint counts participants with protocol-defined dose-limiting toxicity during the first cycle. That measure is intended to inform dose escalation and selection of a maximum tolerated dose. The phase II outcomes listed in the registry instead include time-to-event, toxicity, and minimal residual disease outcomes.

Keeping these questions distinct matters. A dose-finding result would describe toxicity under the phase I rules; it would not, by itself, establish clinical activity. Likewise, a safety count does not answer whether a treatment changes progression-free survival or overall survival. The registry does not report the primary endpoint result or phase II efficacy results, so these questions remain unresolved in the information available from the record.

The nonrandomized design also matters for interpretation. The registry warns that the arms are not like-for-like controls. This means that simple differences in counts across phase Ib dose levels or between the phase II group and other groups cannot be treated as unbiased treatment comparisons. The design and allocation information should shape any interpretation of the reported safety data.

Finally, transparent reporting of analysis populations, missing-data handling, multiplicity, and uncertainty would help readers assess the strength and precision of outcome estimates. Those details are not reported in the registry record. The statistical importance of this study therefore lies in its stated dose-finding framework and the need to distinguish descriptive safety reporting from evidence of comparative efficacy.

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 does not report the observed count for the primary dose-limiting-toxicity endpoint. It also does not report results for the listed phase II outcomes, including progression-free survival, overall survival, and minimal residual disease negativity. This limits interpretation to design features and selected safety summaries.

Allocation was nonrandomized, and the record explicitly cautions that the arms are not a like-for-like control comparison. The group counts therefore cannot establish comparative treatment effects. The record also does not describe baseline characteristics that would help assess differences among groups, or report adjusted analyses to account for potential differences.

The arm descriptions give some treatment schedules but do not provide a complete account of all treatment details. The registry does not report additional information about the phase Ib continuation decision beyond stating that treatment could continue at the treating clinician’s discretion for patients with at least stable disease response. It also does not report the full phase II cycle description.

Safety reporting is limited to group-level participant counts, listed deaths, and selected serious adverse event terms. The registry does not report event-level timing, attribution, severity detail, or the denominator and calculation method for the listed term percentages. It also does not report how missing data were handled for outcomes other than the phase I replacement rule, or define the phase II analysis populations.

The record does not report the investigators’ sample-size justification, detailed phase II statistical methods, interim analyses, or multiplicity approach. These omissions prevent assessment of the planned precision and inferential framework from the registry record alone.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Venetoclax and Vincristine in Treating Patients With Relapsed or Refractory T-cell or B-cell Acute Lymphoblastic Leukemia — NCT03504644.
• Registry record last updated 2026-10-06; status last verified 2026-09.
• Results first posted 2026-02-25.
• 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

The registry describes a nonrandomized phase Ib/II study of venetoclax combined with liposomal vincristine or vincristine sulfate in patients with relapsed or refractory T-cell or B-cell acute lymphoblastic leukemia. Enrollment is listed as 40, and the study status is active, not recruiting. The recorded study start date is 2018-08-13, with primary completion dated 2025-07-22.

The phase I primary endpoint is the number of participants with dose-limiting toxicity during the first cycle, up to 42 days from the first dose. The phase I portion uses a 3+3 dose-finding design. Phase II secondary outcomes include progression-free survival, overall survival, toxicities, and minimal residual disease negativity.

The record reports selected serious and other adverse event counts, deaths, and serious adverse event terms. It does not report the primary endpoint result or phase II efficacy results in the registry record. Because allocation was nonrandomized, the study groups are not a like-for-like control comparison.