Study to Evaluate Efficacy, Safety, Tolerability, and Pharmacodynamics of Entospletinib in Adults With Relapsed or Refractory Hematologic Malignancies: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Evaluate Efficacy, Safety, Tolerability, and Pharmacodynamics of Entospletinib in Adults With Relapsed or Refractory Hematologic Malignancies (NCT01799889), a randomized phase 2 study. The primary outcome is Progression-Free Survival (PFS) Rate of Participants With CLL After BCR Targeted Therapy, MCL, and DLBCL at Week 16.

2. Clinical Question

This question concerns a fixed-time progression-free survival (PFS) rate, not the length of time until progression for every participant. The endpoint counts participants who had not experienced definitive progression or death by Week 16, according to the registry definition. For NHL, the assessment used standardized 2007 Cheson criteria; for CLL, it used International Workshop on Chronic Lymphocytic Leukemia criteria.

The study enrolled participants with several distinct malignancies and treatment histories. Those groups differ in disease type and, in CLL, prior BCR inhibitor exposure and transformation status. The registry describes random allocation at the overall study level, but the posted primary results do not present a single treatment-versus-control contrast within a shared population. The results therefore address cohort-specific PFS estimates, rather than establishing a comparative treatment effect across the whole study population.

3. Trial Design

The registry describes a Phase 2, randomized, open-label, parallel study of entospletinib in adults with relapsed or refractory hematologic malignancies. The study included CLL, MCL, DLBCL, FL, and non-FL indolent non-Hodgkin lymphoma. Enrollment was 326, and the study status is terminated. The registry lists a start date of 2013-03-14 and a primary completion date of 2017-09-14.

Entospletinib was used in the original mono-mesylate formulation or the spray dried dispersion formulation. The arm descriptions indicate that the formulation and dose varied over the course of the study, with the new formulation described after amendment 8. Separate groups are also listed for CLL participants who were prior BCR inhibitor naive, participants with non-Richters CLL previously exposed to a BTK or PI3K inhibitor, and participants with Richters or Richters-like CLL previously exposed to those inhibitor classes. Most listed treatment descriptions state that treatment continued until disease progression or unacceptable toxicity.

Although the study is described as randomized, the registry record does not report the randomization sequence, allocation ratio, stratification factors, or how allocation was implemented. It also does not report a masked assessment of participants or treating staff; masking is listed as none. The primary result groups are not a conventional set of treatment and control arms: they represent different diseases or prior-treatment subgroups, and all are entospletinib groups. The record does not report a common placebo or active-control arm for the primary endpoint results.

The full original design assumptions, including any sample-size justification or planned interim analyses, are not reported in the registry record. The posted results include several separate outcome measures, but no reported analyses are listed for the secondary outcomes. These limitations matter when interpreting differences between groups: disease-specific cohort contrasts should not be read as randomized comparisons of entospletinib against a shared control.

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: 444 participants were screened.

Only the first 6 of 12 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Full Analysis Set included all enrolled participants who took at least one dose of study drug with treatment group designated according to the planned treatment. Only participants with CLL after BCR target therapy (including CLL non-Richters, and CLL Richters participants), SDD, MCL, and DLBCL were analyzed for this outcome measure.

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: The Full Analysis Set included all enrolled participants who took at least one dose of study drug with treatment group designated according to the planned treatment.

Only the first 6 of 13 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Progression-Free Survival (PFS) Rate of Participants With CLL After BCR Targeted Therapy, MCL, and DLBCL at Week 16, measured over Week 16.

The primary endpoint is the percentage of participants with CLL after BCR targeted therapy, MCL, and DLBCL who were progression-free at Week 16. PFS was defined as not experiencing definitive disease progression or death. An independent review committee assessed disease status using standardized 2007 Cheson criteria for NHL and International Workshop on Chronic Lymphocytic Leukemia criteria for CLL.

The progression definitions include new disease or worsening of existing disease, with disease-specific features. For NHL, the criteria include worsening of index lesions, non-index disease, or organs such as the liver or spleen, as well as specified changes in IgM measures. For CLL, the criteria include new or worsening disease and specified decreases in platelet count or hemoglobin attributable to CLL. The registry reports that the PFS rate was analyzed with Kaplan-Meier estimates.

In general, a fixed-time PFS rate is useful because it describes the estimated proportion remaining alive and without progression at a chosen time point. It combines progression and death into a clinically interpretable outcome, while the disease-specific assessment rules define what qualifies as progression. It does not by itself describe when events occurred before or after that time point, nor does it show how long an individual participant remained progression-free. The Week 16 estimates should therefore be read as time-specific cohort summaries, with their uncertainty intervals and the small sizes of some groups taken into account.

7. Results Posted in the Registry

• MCL: Entospletinib MM/SDD: 64.1% (25/39) versus 4.7% (2/43) on control; risk difference 59.5 percentage points (95% CI 43.1 to 75.8), risk ratio 13.78 (3.49–54.43); unadjusted two-proportion z-test p = <0.001.
• CLL (Non-Richters) Prior BTK Inhibitor: Entospletinib SDD: 63.6% (21/33) versus 4.7% (2/43) on control; risk difference 59.0 percentage points (95% CI 41.4 to 76.6), risk ratio 13.68 (3.45–54.26); unadjusted two-proportion z-test p = <0.001.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Objective Response Rate (ORR), as Assessed by IRC Per Standardized Criteria (2007 Cheson Criteria) (for NHL) and IWCLL Criteria (for CLL)

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • FL: Entospletinib MM/SDD: 17.1% (7/41) versus 53.7% (22/41) on control; risk difference -36.6 percentage points (95% CI -55.7 to -17.5), risk ratio 0.32 (0.15–0.66); unadjusted two-proportion z-test p = <0.001.
  • DLBCL: Entospletinib MM/SDD: 0.0% (0/43) versus 53.7% (22/41) on control; risk difference -53.7 percentage points (95% CI -68.9 to -38.4); unadjusted two-proportion z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically lower for FL: Entospletinib MM/SDD than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically lower for DLBCL: Entospletinib MM/SDD than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Time to Response (TTR), as Assessed by IRC Per Standardized Criteria (2007 Cheson Criteria) (for NHL) and IWCLL Criteria (for CLL)

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Non-FL iNHL: Entospletinib MM/SDD: mean 2.80 versus 3.20 on control; difference -0.40 (95% CI -1.79 to 0.99), standardized effect d = -0.18; z-test p = 0.574.
  • CLL, Prior BCR Inhibitor Naive: Entospletinib SDD 400 mg: mean 6.80 versus 3.20 on control; difference 3.60 (95% CI 0.99 to 6.21), standardized effect d = 1.17; z-test p = 0.007.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Non-FL iNHL: Entospletinib MM/SDD and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for CLL, Prior BCR Inhibitor Naive: Entospletinib SDD 400 mg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary outcomes provide several kinds of context, but they answer different questions from Week 16 PFS. Objective response rate records the proportion meeting response criteria; time to response describes timing among those who responded; duration of response concerns how long a response persisted. Adverse-event outcomes describe harms observed during treatment. Taken together, these measures can complement a PFS estimate by describing response and tolerability, but they are not interchangeable endpoints.

The response percentages vary across malignancy and treatment-history groups. Time-to-response summaries are available only where responses occurred, so those means describe a selected subset rather than every participant assigned to a group. The patterns across these secondary outcomes do not provide a single consistent comparison across all cohorts: populations, disease criteria, and available observations differ. They therefore should be interpreted within their own group and outcome definitions, not treated as a unified ranking of treatment effects.

These secondary results relate to the primary result by offering additional descriptions of disease response and treatment experience. A response does not necessarily mean that a participant remained progression-free at Week 16, and time to response does not measure PFS. Conversely, a PFS rate at a fixed time does not specify the rate of tumor response. The outcomes may tell related but distinct parts of the clinical story.

The registry does not list reported analyses for the secondary outcomes. Multiple outcomes and multiple cohorts create opportunities for chance findings, especially if results are interpreted after examining the data. Unless a testing hierarchy or adjustment for multiplicity is specified, unadjusted secondary comparisons carry less evidential weight than a clearly prespecified primary analysis. The registry record does not report a multiplicity plan, so the secondary results are best read as descriptive. They can motivate questions for further study, but they do not independently confirm a treatment effect.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Percentage of Participants Experiencing Treatment-Emergent Adverse Events
• Percentage of Participants With Hematology Postbaseline Toxicity Grade 3 or Higher
• Percentage of Participants With Serum Chemistry Toxicity Postbaseline Grade 3 or Higher
• Objective Response Rate (ORR), as Assessed by IRC Per Standardized Criteria (2007 Cheson Criteria) (for NHL) and IWCLL Criteria (for CLL)
• Duration of Response (DOR), as Assessed by IRC Per Standardized Criteria (2007 Cheson Criteria) (for NHL) and IWCLL Criteria (for CLL)
• Time to Response (TTR), as Assessed by IRC Per Standardized Criteria (2007 Cheson Criteria) (for NHL) and IWCLL Criteria (for CLL)

9. Statistical Interpretation

10. Statistical Methods Explained

What does the Week 16 PFS rate represent?

The primary measure is a percentage: the estimated proportion of participants who had not experienced definitive progression or death by Week 16. PFS is a time-to-event outcome because progression or death can occur at different times during follow-up. A rate at a fixed time point condenses that follow-up into an estimate at a particular time, so it should not be interpreted as the average duration of PFS.

The registry says that Kaplan-Meier estimates were used. In general, the Kaplan-Meier method estimates the probability of remaining event-free over time while accounting for participants whose event status is not observed for the full follow-up period. Such participants may be censored, meaning their observed follow-up ends without an event being recorded at that time. How censoring was handled in detail, including the operational rules for censoring and any sensitivity analyses, is not reported in the registry record.

Why use disease-specific progression criteria?

Progression does not have an identical definition across all hematologic malignancies. The registry describes use of the standardized 2007 Cheson criteria for NHL and IWCLL criteria for CLL. The criteria combine evidence such as new disease, worsening lesions, organ changes, or disease-specific laboratory measures. Applying criteria defined for the relevant disease makes the endpoint more interpretable than using an unspecified clinical judgment, but it also means the event definition is not identical across every cohort. The record states that an independent review committee assessed the outcome; additional details about committee procedures are not reported.

How should the confidence intervals be read?

A confidence interval expresses statistical uncertainty around an estimated quantity. In general, a wider interval indicates less precision: the data are compatible with a broader range of underlying rates. The posted intervals vary substantially in width. This is especially important for the smaller CLL subgroups, where a high or low point estimate can coexist with substantial uncertainty. The intervals describe uncertainty under the methods used; they do not account for every possible source of bias, such as differences between disease cohorts or the open-label design.

The primary results are presented as percentages with 95% confidence intervals. Those intervals are the appropriate context for reading the point estimates. A point estimate alone can give a misleading impression of certainty, especially when the group is small or the observed rate lies near an extreme. The 100.0% estimate in one subgroup, for example, should be read with the group size and the stated interval, not as proof that the underlying rate is exactly 100.0%.

What do the recalculated comparisons test?

The posted risk differences and p-values are unadjusted recalculations from summary statistics. In general, a risk difference compares two observed proportions, and an unadjusted p-value measures how incompatible the observed difference is with a specified no-difference model, under the assumptions of that calculation. These recalculations do not replace the sponsor's analysis. The registry record does not report a corresponding sponsor analysis for these comparisons, and the comparisons cross disease or treatment-history groups rather than comparing randomized arms within a common population. Therefore, small unadjusted p-values do not establish that the treatment caused the difference.

The comparison estimates have confidence intervals as well as p-values. A confidence interval helps show the range of differences compatible with the data under the calculation, whereas a p-value does not measure the size or clinical importance of a difference. Neither summary resolves confounding created by comparing populations with different malignancies or prior therapies. The registry does not report adjustment for those differences in these recalculations.

Why do the secondary outcomes use different summaries?

Objective response rate is a binary outcome: participants are classified according to whether they meet response criteria. The registry defines response using the disease-specific Cheson or IWCLL criteria and includes CR or PR, with VGPR or MR for participants with LPL/WM. Its reported percentages and confidence intervals describe response frequency within each group.

Time to response is measured in months and is summarized as a mean and standard deviation among the reported groups. It concerns the time from the first dose to the first documented response, not the time until progression or death. In groups with no responding participants, a mean time to response is not available; a missing value in that setting does not mean that response time was zero. Because time to response is only observed for responders, it is also conditional on having a response and should not be compared as if it represented the whole group.

The registry lists treatment-emergent adverse events, severe hematology and chemistry toxicities, duration of response, objective response, and time to response among the secondary measures. The outcome list includes 8 measures, but the record does not provide reported analyses for the secondary results. The analysis populations, missing-data rules, and any adjustments for multiple testing are not fully reported in the registry record. General statistical interpretation therefore needs to remain separate from conclusions about a prespecified testing strategy.

11. Confidence Intervals and Precision

The confidence intervals show how uncertain the cohort-specific PFS estimates are. The MCL estimate of 63.9% has a 95% CI from 45.0% to 77.8%, and the non-Richters CLL prior BTK inhibitor estimate of 64.0% has a 95% CI from 43.2% to 78.9%. These intervals cover a substantial range of plausible rates, so the close point estimates should not be treated as proof that the two populations have the same underlying PFS rate. They are different clinical groups, and no direct randomized comparison between them is reported.

The DLBCL estimate of 3.6% has a 95% CI from 0.3% to 15.2%. The CLL Richters groups have especially broad intervals: 0.8% to 58.2% for prior BTK inhibitor exposure and 0.6% to 91.0% for prior PI3K inhibitor exposure. The latter estimates are based on 6 and 3 participants, respectively. Such intervals reflect limited precision; they do not indicate that every value within the interval is equally likely or that the endpoints should be read as exact bounds on the true rate.

The non-Richters CLL prior PI3K inhibitor group has a 100.0% estimate and a 95% CI of 100.0% to 100.0%, based on 8 participants. A boundary estimate from a small group should be interpreted cautiously. The reported interval does not remove uncertainty arising from the small sample or from the selected clinical population.

In general, confidence intervals quantify sampling uncertainty under the analysis method. They do not address possible selection effects, differences in disease prognosis, measurement issues, or the implications of an open-label study. Nor do overlapping or non-overlapping intervals alone provide a substitute for a suitable prespecified comparison. The registry record does not report a sponsor analysis comparing all of these primary endpoint groups.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The sample-size figures are planning illustrations based on the observed effects in the posted comparisons, not the trial's original design assumptions. The original design assumptions are not reported in the registry record. For binary outcomes, the figures are participants per arm, not a total across arms. The planning assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the target effect is a stated fraction of the observed effect.

For each assumed effect size, the 80% power column gives the illustrative number of participants per arm for a design with an 80% chance of detecting an effect of that size under the listed assumptions, if that effect and the model assumptions are correct. The 90% power column uses a higher probability of detection and therefore generally calls for more participants per arm. The rows describe planning for 100%, 75%, or 50% of the observed effect. Smaller effects are harder to distinguish from random variation, so planning for a smaller effect requires more participants.

These calculations are not observed power. They are not a retrospective measure of how convincing the trial result is, and they do not account for the differences between the disease cohorts used in the posted recalculations. The actual study's enrollment and allocation plan cannot be inferred from these illustrations. The results are most useful as a demonstration of how sample-size requirements change under stated hypothetical planning choices, rather than as evidence that the original study was designed to detect those effects.

For time-to-event outcomes, the planning convention would be total events; for the binary outcomes discussed in these comparisons, it is participants per arm. No time-to-event planning figures are posted for the primary Week 16 rate. The planning estimates should therefore be read as assumptions-based illustrations linked to the recalculated comparisons, not as a replacement for an original protocol-based sample-size justification.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.047; treatment proportion p₁ = 0.641; average p̄ = 0.344.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6717 = 1.3165.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5239 = 0.4409.
4. n = (1.3165 + 0.4409)² / (0.5945)² = 8.7, rounded up to 9 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.0465116279069767                          # control proportion
p1 <- 0.641025641025641                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(1799889)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 9 (80% power), 12 (90% power)
 75% of observed effect: n per arm = 15 (80% power), 19 (90% power)
 50% of observed effect: n per arm = 27 (80% power), 36 (90% power)
power.prop.test: 8.7 
Simulated power at n = 9 per arm: 0.858 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Multiplicity, Missing Data and Analysis Populations

The study reports a primary endpoint and multiple secondary endpoints across several malignancies and treatment-history subgroups. This creates a multiplicity issue: when many outcomes or comparisons are examined, some results can appear statistically notable by chance even if there is no underlying effect. In general, a prespecified testing hierarchy or an adjustment for multiple testing can help control that risk. Neither a multiplicity adjustment nor a testing hierarchy is reported in the registry record.

The posted comparisons include unadjusted p-values. They should not be treated as confirmatory evidence, particularly because the comparisons span different diseases or prior-treatment groups. The number and timing of any interim analyses are not reported in the registry record. The full statistical analysis plan, including any planned subgroup analyses and control of type I error, is also not reported.

The primary analysis population is described as the Full Analysis Set, including enrolled participants who took at least one dose of study drug, with treatment group assigned according to planned treatment. The description identifies CLL after BCR targeted therapy, including non-Richters and Richters groups, as well as MCL and DLBCL for the primary measure. Detailed eligibility rules for this endpoint population and any further analysis-population qualifications are not reported in the registry record.

Missing-data handling is only partly described. Kaplan-Meier estimation is reported for PFS and, in general, this method accommodates censoring when an event has not been observed by the end of available follow-up. The registry does not report the detailed censoring rules, the amount or pattern of missing outcome data, or sensitivity analyses addressing missingness. The method used to handle missing data for the other outcomes is not reported in the registry record.

These omissions do not establish that appropriate procedures were absent; they mean the registry record does not allow those procedures to be evaluated. The interpretation should remain anchored to the analyses and population descriptions that are actually reported.

15. 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: atrial fibrillation (33.3%), abdominal pain lower (33.3%), haematemesis (33.3%), haematochezia (33.3%), pneumonia (33.3%).

The registry lists serious adverse events and other adverse events by treatment group. The serious-event counts vary across the listed groups; for example, the reported counts include 16 in the DLBCL group, 16 in the MCL group, and 22 in the non-FL iNHL group. Other event counts are also reported by group. These are counts, not rates of risk across a common follow-up period, and the groups differ in size and clinical composition. They should not be added together to create an overall figure.

Deaths are also listed by group, including 13 in the DLBCL group, 6 in the MCL group, and 5 in the non-FL iNHL group. The registry does not provide enough detail in these figures to attribute deaths to treatment or to determine their timing or cause. The listed serious-event terms each have a reported frequency of 33.3%: atrial fibrillation, lower abdominal pain, haematemesis, haematochezia, pneumonia, and respiratory failure. These terms describe reported events, not comparative risks or evidence of causation.

In general, safety counts require context about exposure duration, event definitions, severity, and whether events were considered treatment-related. The registry record does not report all such details in the posted safety summaries, so the counts should be read as descriptive rather than as a comparison of safety between treatments.

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

The results show that the reported Week 16 PFS estimates differed across the posted groups of participants receiving entospletinib. They also show varying response percentages and safety-event counts across disease and treatment-history groups. The confidence intervals indicate that precision differs by group, with several estimates remaining uncertain. These observations describe the participants included in the registry's analyses; they do not establish what would happen in a different population.

The study is described as randomized, but the posted primary endpoint groups are not presented as a common randomized treatment-versus-control comparison. The contrasts recalculated from the posted summaries compare DLBCL with MCL or with non-Richters CLL previously exposed to a BTK inhibitor. Differences between these groups may reflect the underlying malignancy, prior therapy, participant characteristics, or other factors, as well as any treatment-related differences. The unadjusted calculations cannot separate those explanations.

A Week 16 PFS percentage is not the same as a measure of long-term survival, symptom change, or quality of life. The registry record does not report those outcomes in the results. A response percentage also does not by itself establish the duration of response or a causal effect. The secondary outcome summaries should be interpreted according to their own definitions and populations.

The terminated status is a factual feature of the record, but the reason for termination is not reported in the registry record. It is not possible to infer the reason from the outcome values, adverse-event counts, or the study status alone. Similarly, the registry record does not provide the full protocol or statistical analysis plan needed to assess every intended analysis.

Overall, the findings are descriptive evidence about selected cohorts in this study. They are not a basis for medical advice, and they do not by themselves establish that entospletinib is effective or ineffective. Any broader conclusion would require appropriate comparative evidence and complete information about the study's analysis plan and conduct.

17. Why This Trial Matters Statistically

This study illustrates why trial-level labels and result-level comparisons need to be distinguished. The registry describes a randomized, parallel phase 2 study, yet the posted primary results are organized into groups defined by malignancy and prior treatment. A randomized label does not make every comparison between those groups a randomized contrast. Statistical interpretation depends on whether the groups being compared were assigned to different treatments within a shared eligible population.

The endpoint also illustrates the value and limits of a fixed-time survival estimate. A PFS rate at Week 16 gives a concise summary of remaining free from progression or death at that time, while Kaplan-Meier estimation accounts for differing observed follow-up in general. However, the endpoint still depends on disease-specific progression criteria and the handling of censored observations. Those details shape what the estimate means.

The range of group sizes and confidence intervals demonstrates the relationship between data volume and precision. Some subgroup estimates have broad intervals, while an extreme point estimate can occur in a relatively small group. Reporting uncertainty alongside the point estimate is essential; a single percentage can make limited evidence look more definitive than it is.

Finally, the posted outcomes span PFS, response, time to response, and safety. Each contributes different information, but multiple outcomes and subgroup comparisons raise multiplicity concerns. Without a reported analysis hierarchy or adjustment plan, unadjusted results should be interpreted cautiously. The record is a useful example of how statistical meaning depends not just on a p-value or point estimate, but on the population, comparator, endpoint definition, precision, and transparency of the analysis plan.

18. 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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

Several features specific to this record limit interpretation. The primary endpoint results combine neither one disease nor one treatment-history population: the groups include DLBCL, MCL, and CLL subgroups defined by Richters status and prior inhibitor exposure. These populations can differ in prognosis and clinical history. The reported recalculated comparisons therefore do not provide a clean estimate of a treatment contrast within a single population.

The registry describes the study as randomized, but the randomization details and the allocation ratio are not reported. The primary endpoint groups are all entospletinib groups, and no shared comparator is listed for the posted results. Masking is listed as none. The registry record does not provide enough information to determine how randomization related to the reported cohort structure or whether any planned comparisons were conducted as intended.

Several primary endpoint groups are small, including the Richters CLL groups and the non-Richters CLL prior PI3K inhibitor group. The associated estimates have limited precision, as reflected in broad or boundary confidence intervals. The study is terminated, but its reason for termination is not reported. This prevents readers from connecting the status to the observed efficacy or safety findings.

Other limitations include the absence of reported sponsor analyses for the posted secondary outcomes, no reported multiplicity plan, and incomplete detail about missing data, censoring, and the analysis populations. The study-specific original sample-size assumptions and any interim analyses are not reported in the registry record. These gaps do not prove that such procedures were not used; they constrain what can be verified from the record.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Study to Evaluate Efficacy, Safety, Tolerability, and Pharmacodynamics of Entospletinib in Adults With Relapsed or Refractory Hematologic Malignancies — NCT01799889.
• Registry record last updated 2020-11-19; status last verified 2020-11.
• Results first posted 2020-09-23.
• 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.

22. Record Summary

This Phase 2 study evaluated entospletinib in adults with relapsed or refractory hematologic malignancies. It is listed as randomized, open-label, and parallel, with enrollment of 326 and status terminated. The primary outcome was the Week 16 PFS rate in selected CLL after BCR targeted therapy, MCL, and DLBCL groups, assessed by an independent review committee using disease-specific criteria.

The posted PFS estimates vary by disease and treatment-history group, with substantial uncertainty in several groups. Secondary results describe response, response timing, and adverse events, but the registry lists no reported analyses for the secondary outcomes. The posted recalculated comparisons are unadjusted and compare different clinical cohorts, limiting causal interpretation. The registry record does not report the reason for termination, the original sample-size justification, detailed missing-data procedures, or a multiplicity plan.