This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Randomized Trial of Topotecan With M6620, an ATR Kinase Inhibitor, in Small Cell Lung Cancers and Small Cell Cancers Outside of the Lungs (NCT03896503), a randomized phase 2 study. The primary outcome is Progression-free Survival (PFS) Reported With 80% Confidence Interval.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT03896503 |
| Phase | Phase 2 |
| Condition | Extensive Stage Lung Small Cell Carcinoma, Extrapulmonary Small Cell Neuroendocrine Carcinoma, Limited Stage Lung Small Cell Carcinoma |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | None (open label) |
| Enrollment | 104 |
| Arms in the primary outcome | 5 |
| Lead sponsor | National Cancer Institute (NCI) |
| Results posted | Yes |
2. Clinical Question
Population
Participants with relapsed small-cell lung cancer were eligible for the randomized comparison. The registry also lists an exploratory cohort of participants with small-cell cancer arising outside the lungs. The conditions include platinum-sensitive and platinum-resistant lung small-cell cancer, as well as recurrent, limited-stage and extensive-stage disease.
Intervention
The combination arm received topotecan hydrochloride and berzosertib, also called M6620 or VX-970. Topotecan was given intravenously on days 1-5, and berzosertib intravenously on days 2 and 5. Treatment cycles repeated every 21 days while there was no disease progression or unacceptable toxicity.
Comparator
The randomized comparator was topotecan hydrochloride alone, given intravenously on days 1-5, with cycles repeating every 21 days while there was no disease progression or unacceptable toxicity. Participants in the topotecan-alone arm could cross over to the combination at progression.
Primary question
The primary question was whether progression-free survival differed between the combination and topotecan-alone groups in relapsed small-cell lung cancer. The registry describes Kaplan-Meier curves and a one-tailed log-rank test for this comparison. The posted outcome values are group-specific medians and 80% confidence intervals; a hazard ratio or test result is not reported in the registry record.
3. Trial Design
NCT03896503 is a randomized, open-label, parallel-group phase II trial sponsored by the National Cancer Institute. The registry lists enrollment of 104. The study began on 2019-12-30, and its primary completion date is 2022-12-19. Its status is active, not recruiting.
The main comparison assigns participants with relapsed small-cell lung cancer to topotecan alone or topotecan plus berzosertib. The reported groups are divided by platinum response: sensitive and resistant. A separate exploratory cohort received the combination; it is not presented as a randomized topotecan-alone comparison. The registry record also allows participants assigned to topotecan alone to cross over to the combination at disease progression, which matters when interpreting treatment exposure and subsequent outcomes.
In the listed schedules, topotecan is administered intravenously over 30 minutes on days 1-5. Berzosertib is administered intravenously over 60 minutes on days 2 and 5. Cycles repeat every 21 days in the absence of progression or unacceptable toxicity. CT scans, biopsy procedures and biospecimen collection appear among the listed interventions, but further procedural details are not reported in the registry record.
The primary outcome is progression-free survival. The registry describes follow-up from treatment start until progression or death, whichever occurs first, with assessment at 6 months after the last participant enrolled; it also gives maximum follow-up periods of up to 2 years for the pulmonary cohort and up 31.5 months for the exploratory cohort. The registry lists objective response rate and overall survival as secondary outcomes. Further details of the statistical design, including a sample-size justification, 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.
Before assignment: 104 participants were enrolled, and 82/104 participants were treated as shown in the Participant Flow table.
Only the first 6 of 8 groups are shown.
Initial Subgroup and Arm Enrollment
| Stage | Platinum Response - Sensitive: Topotecan Monotherapy | Platinum Response - Sensitive: Topotecan & M6620 (VX-970) Combination Therapy | Platinum Response - Sensitive: Enrolled But Not Treated | Platinum Response - Resistant: Topotecan Monotherapy | Platinum Response - Resistant: Topotecan & M6620 (VX-970) Combination Therapy | Platinum Response - Resistant: Enrolled But Not Treated |
|---|---|---|---|---|---|---|
| STARTED | 10 | 20 | 10 | 11 | 23 | 9 |
| Not Treated | 1 | 0 | 10 | 1 | 2 | 9 |
| Off Treatment | 7 | 17 | 0 | 10 | 0 | 0 |
| COMPLETED | 7 | 18 | 0 | 10 | 20 | 0 |
| NOT COMPLETED | 3 | 2 | 10 | 1 | 3 | 9 |
Reasons for not completing this period:
| Reason | Platinum Response - Sensitive: Topotecan Monotherapy | Platinum Response - Sensitive: Topotecan & M6620 (VX-970) Combination Therapy | Platinum Response - Sensitive: Enrolled But Not Treated | Platinum Response - Resistant: Topotecan Monotherapy | Platinum Response - Resistant: Topotecan & M6620 (VX-970) Combination Therapy | Platinum Response - Resistant: Enrolled But Not Treated |
|---|---|---|---|---|---|---|
| Disease progression before treatment | 1 | 0 | 1 | 0 | 1 | 0 |
| No treatment per protocol | 0 | 0 | 1 | 0 | 0 | 1 |
| Late determination of ineligibility | 0 | 0 | 1 | 0 | 0 | 1 |
| Declined to participate | 0 | 0 | 1 | 1 | 1 | 1 |
| Not treated; participate found ineligible | 0 | 0 | 4 | 0 | 0 | 0 |
| Not treated; screen failure | 0 | 0 | 2 | 0 | 0 | 3 |
| Refused further treatment | 2 | 1 | 0 | 0 | 0 | 0 |
| Off treatment? other reasons withdrew consent | 0 | 1 | 0 | 0 | 0 | 0 |
| Not treated; death before treatment | 0 | 0 | 0 | 0 | 1 | 0 |
| Not treated; participate found ineligible | 0 | 0 | 0 | 0 | 0 | 2 |
| Off treatment; screen failure | 0 | 0 | 0 | 0 | 0 | 1 |
Crossover Participants
| Stage | Platinum Response - Sensitive: Topotecan Monotherapy | Platinum Response - Sensitive: Topotecan & M6620 (VX-970) Combination Therapy | Platinum Response - Sensitive: Enrolled But Not Treated | Platinum Response - Resistant: Topotecan Monotherapy | Platinum Response - Resistant: Topotecan & M6620 (VX-970) Combination Therapy | Platinum Response - Resistant: Enrolled But Not Treated |
|---|---|---|---|---|---|---|
| STARTED | 0 | 5 | 0 | 0 | 6 | 0 |
| Not Treated | 0 | 0 | 0 | 0 | 0 | 0 |
| Off Treatment | 0 | 0 | 0 | 0 | 0 | 0 |
| COMPLETED | 0 | 5 | 0 | 0 | 6 | 0 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 |
Analysis population for the primary outcome, as defined in the registry: Participants enrolled but not treated are not reported for this outcome measure. Six participants from the groups reported below were not evaluable for this outcome measure. Participants who have results reported were placed into categories per initial randomization. Exploratory cohort consists of participants with extrapulmonary disease and were not randomized to treatment.
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: Baseline data was collected and is reported here for participants enrolled but not treated.
Only the first 6 of 9 groups are shown.
| Characteristic | Unit | Platinum Response - Sensitive: Topotecan Monotherapy | Platinum Response - Sensitive: Topotecan & M6620 (VX-970) Combination Therapy | Platinum Response - Sensitive: Enrolled But Not Treated | Platinum Response - Resistant: Topotecan Monotherapy | Platinum Response - Resistant: Topotecan & M6620 (VX-970) Combination Therapy | Platinum Response - Resistant: Enrolled But Not Treated |
|---|---|---|---|---|---|---|---|
| Participants analysed | 10 | 20 | 10 | 11 | 23 | 9 | |
| Age, Categorical: <=18 years | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Age, Categorical: Between 18 and 65 years | Participants | 7 | 12 | 6 | 7 | 15 | 6 |
| Age, Categorical: >=65 years | Participants | 3 | 8 | 4 | 4 | 8 | 3 |
| Age, Continuous | years | 56 (SD 9.53) | 61.65 (SD 9.05) | 63 (SD 8.17) | 61.72 (SD 7.00) | 60.60 (SD 7.57) | 58.33 (SD 8.83) |
| Sex: Female, Male: Female | Participants | 6 | 7 | 5 | 5 | 10 | 3 |
| Sex: Female, Male: Male | Participants | 4 | 13 | 5 | 6 | 13 | 6 |
| Ethnicity (NIH/OMB): Hispanic or Latino | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Ethnicity (NIH/OMB): Not Hispanic or Latino | Participants | 10 | 20 | 10 | 11 | 22 | 9 |
| Ethnicity (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 | 0 | 1 | 0 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): Asian | Participants | 0 | 0 | 0 | 0 | 2 | 0 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): Black or African American | Participants | 0 | 4 | 0 | 0 | 1 | 1 |
| Race (NIH/OMB): White | Participants | 10 | 15 | 10 | 11 | 20 | 7 |
| Race (NIH/OMB): More than one race | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 0 | 1 | 0 | 0 | 0 | 1 |
| Region of Enrollment: United States | participants | 10 | 20 | 10 | 11 | 23 | 9 |
6. Primary Endpoint
The registry lists the primary outcome as Progression-free Survival (PFS) Reported With 80% Confidence Interval, measured over From start of treatment to time of progression or death, whichever occurs first, assessed at 6 months after last participant has enrolled; up to 2 years for pulmonary cohort and up 31.5 months for Exploratory Cohort..
| Element | Registry entry |
|---|---|
| Result type | Median |
| Measure of spread | 80% Confidence Interval |
| Unit | Months |
| Endpoint classification | Time-to-Event Analysis |
Progression-free survival (PFS) measures the time from the start of treatment until disease progression or death, whichever occurs first. It combines these events into a time-to-event endpoint: a participant’s follow-up ends at the first of the two events, rather than only when death occurs. The registry says progression was assessed using RECIST version 1.1. It describes progression as at least a 20% increase in the sum of target-lesion diameters, using the smallest sum on study as the reference, and/or the appearance of one or more new lesions.
The registry reports PFS as a median in months with an 80% confidence interval. A median time-to-event estimate describes the point at which the estimated proportion remaining free of progression or death reaches one half. It is not an average duration and does not describe every participant’s experience. The confidence interval conveys uncertainty around the estimated median; it does not show the range of individual outcomes.
PFS is used in trials because it captures the timing of progression as well as death and can be analyzed while participants have different lengths of follow-up. The registry’s stated primary comparison is between the combination and topotecan alone in relapsed small-cell lung cancer. The results also include platinum-response subgroups and an exploratory cohort, so those group estimates should be read in the context of their distinct roles in the study.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The posted PFS medians differ across the reported groups, but these values alone do not establish whether the randomized treatments differ. For platinum-sensitive disease, the median was 5.5 months with topotecan monotherapy (80% CI 2.6 to 6.0) and 4.4 months with topotecan plus M6620 (80% CI 3.4 to 5.5). For platinum-resistant disease, the median was 2.1 months with monotherapy (80% CI 1.3 to 3.0) and 2.7 months with the combination (80% CI 2.0 to 4.0). The exploratory combination cohort had a median of 1.5 months (80% CI 1.4 to 1.8).
These are separate group estimates, not a single overall treatment contrast. The sensitive and resistant groups are clinically distinct registry categories, and the exploratory cohort is not shown with a randomized monotherapy comparator. The medians should therefore be read within their stated groups rather than compared as if they came from one common population. The registry’s specified primary comparison concerns relapsed small-cell lung cancer; the available outcome values do not include a hazard ratio, log-rank result or other formal test result for that comparison.
Confidence intervals communicate uncertainty in each median estimate. Their limits indicate that the estimate is not exact, but the intervals do not themselves test the treatment difference. Whether intervals overlap or do not overlap is not a substitute for the prespecified comparison of time-to-event data. No conclusion about statistical significance can be drawn from the listed medians and intervals alone.
The reported group sizes are 9 and 20 for the platinum-sensitive monotherapy and combination groups, and 11 and 20 for the platinum-resistant monotherapy and combination groups. The exploratory combination cohort has 16 participants reported for this outcome. Six participants from the groups described were not evaluable for PFS, and participants who were not treated are not reported for this outcome. These details constrain how broadly the estimates can be interpreted.
The registry describes a one-tailed log-rank test as a primary analysis method, but its numerical result is not reported in the registry record. A sponsor-reported hazard ratio is also not available among the posted results. Thus, the posted figures describe estimated PFS medians by group; they do not independently answer the formal randomized treatment-comparison question.
9. Statistical Methods Explained
The registry describes a time-to-event analysis for PFS, with Kaplan-Meier curves and a one-tailed log-rank test as the primary methods. The posted outcome is the median PFS in months with an 80% confidence interval. No numerical log-rank result or hazard ratio is reported in the registry record.
What does Kaplan-Meier estimation do?
General explanation: Kaplan-Meier estimation uses each participant’s observed follow-up time and event status to estimate the probability of remaining free of the endpoint over time. For PFS, the event is progression or death, whichever occurs first. Participants who have not had either event by the end of their observed follow-up can still contribute information up to that point. They are then censored, rather than treated as if they had experienced an event at the end of follow-up.
The estimated survival curve is a step function: it changes when events occur. The median is read from this curve as the time at which the estimated event-free proportion reaches one half. A median is only estimable when the curve reaches that point; the registry reports estimates for the groups listed. A median compresses the curve into one summary, so it does not describe all differences in event timing or the shape of the curves.
What does the log-rank test assess?
General explanation: A log-rank test compares the observed timing of events across groups over the follow-up period. It uses information from participants still under observation at each event time, rather than comparing only the medians. The registry specifies a one-tailed test for the primary comparison. A one-tailed test assesses a difference in the direction specified by the analysis plan; the direction and additional details of that plan are not reported in the registry record.
A test result would usually be interpreted alongside an effect estimate and its uncertainty. Here, a numerical test result and a hazard ratio are not reported. The group medians and confidence intervals therefore remain descriptive outcome estimates and should not be treated as a replacement for the formal time-to-event comparison.
How should the confidence intervals be read?
General explanation: A confidence interval represents uncertainty in an estimated quantity under the method used to construct it. The reported 80% intervals accompany the median PFS estimates; they do not describe the range of participant-level PFS times and do not mean that a stated proportion of participants had outcomes within the interval.
An 80% confidence interval is less stringent, and generally narrower, than a 95% confidence interval calculated from the same data using comparable methods. The registry also lists overall survival as a secondary outcome with 80% and 95% confidence intervals, but no numerical overall-survival results are reported in the record described. The PFS intervals should be interpreted as uncertainty around each group median, not as a direct interval for the difference between treatments.
Why do follow-up and censoring matter?
General explanation: Time-to-event methods can include participants whose follow-up ends before an event is observed. Their information is retained up to the last time they are known to be event-free. This approach relies on assumptions about censoring and on sufficiently complete and accurate event-time information. The registry record does not report details about censoring patterns or how those assumptions were assessed.
The stated PFS timeframe is from treatment start to progression or death, with assessment at 6 months after the last participant enrolled; the registry also lists follow-up of up to 2 years for the pulmonary cohort and up 31.5 months for the exploratory cohort. The posted estimates should be read in light of these cohort-specific follow-up descriptions. Further information about assessment schedules and completeness is not reported in the registry record.
What do the group estimates permit?
The posted estimates permit description of median PFS within the reported platinum-sensitive, platinum-resistant and exploratory groups. They do not, on their own, estimate an adjusted treatment effect or establish a difference between randomized arms. The registry record does not report an adjusted model, a stratified analysis, or a numerical treatment-effect estimate. The one-tailed log-rank test is the stated primary method, but its result is not posted.
Separate subgroup estimates also do not show whether treatment effects differ by platinum response. That question requires a formal comparison of effects across subgroups, and such an analysis is not reported in the registry record. The exploratory cohort has no monotherapy comparator in the posted results, so its median is descriptive rather than a randomized contrast.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists objective response rate and overall survival as secondary outcomes, with overall survival identified for reporting with both 80% and 95% confidence intervals. A total of three secondary outcomes are posted, but numerical results for these outcomes are not included in the registry record described. No multiplicity adjustment or strategy for interpreting multiple outcomes is reported in the registry record. Without that information, the degree to which the primary and secondary analyses were treated as confirmatory cannot be established.
For PFS, participants who enrolled but were not treated are not reported for the outcome. The record states that six participants from the groups reported were not evaluable. Participants whose results are reported were assigned to categories according to their initial randomization. The record does not give further detail about reasons for non-evaluability, the handling of missing assessments, or an analysis population definition beyond these statements. The remaining description of the exploratory cohort’s outcome population is not reported in the registry record.
These omissions matter because missing outcome data can affect the amount and pattern of available follow-up. General explanation: if participants with missing assessments differ systematically from those with observed outcomes, estimates may be affected; the direction and extent depend on why data are missing and how the analysis handles them. No missing-data method or sensitivity analysis is reported in the registry record.
Crossover from topotecan alone to the combination was permitted at progression. The posted PFS groups are categorized by initial randomization, but further details about crossover handling in analyses are not reported. The record also does not report an interim-analysis plan, analysis populations such as intention-to-treat, or additional statistical-analysis details.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Platinum Response - Sensitive: Topotecan Monotherapy | 6 | 9 | 66.7% |
| Platinum Response - Sensitive: Topotecan & M6620 (VX-970) Combination Therapy | 12 | 20 | 60.0% |
| Platinum Response - Resistant: Topotecan Monotherapy | 9 | 11 | 81.8% |
| Platinum Response - Resistant: Topotecan & M6620 (VX-970) Combination Therapy | 11 | 20 | 55.0% |
| Exploratory Cohort: Topotecan & M6620 (VX-970) Combination Therapy | 9 | 16 | 56.2% |
| Platinum Response - Sensitive: Topotecan & M6620 Combination Therapy -Cross-over From Cohort 1 Arm I | 4 | 5 | 80.0% |
| Platinum Response -Resistant: Topotecan & M6620 Combination Therapy - Cross-over From Cohort 2 Arm 1 | 4 | 6 | 66.7% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Platinum Response - Sensitive: Topotecan Monotherapy | 9 of 9 |
| Platinum Response - Sensitive: Topotecan & M6620 (VX-970) Combination Therapy | 19 of 20 |
| Platinum Response - Resistant: Topotecan Monotherapy | 11 of 11 |
| Platinum Response - Resistant: Topotecan & M6620 (VX-970) Combination Therapy | 19 of 20 |
| Exploratory Cohort: Topotecan & M6620 (VX-970) Combination Therapy | 15 of 16 |
| Platinum Response - Sensitive: Topotecan & M6620 Combination Therapy -Cross-over From Cohort 1 Arm I | 5 of 5 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Platinum Response - Sensitive: Topotecan Monotherapy | 8 of 9 |
| Platinum Response - Sensitive: Topotecan & M6620 (VX-970) Combination Therapy | 20 of 20 |
| Platinum Response - Resistant: Topotecan Monotherapy | 11 of 11 |
| Platinum Response - Resistant: Topotecan & M6620 (VX-970) Combination Therapy | 19 of 20 |
| Exploratory Cohort: Topotecan & M6620 (VX-970) Combination Therapy | 16 of 16 |
| Platinum Response - Sensitive: Topotecan & M6620 Combination Therapy -Cross-over From Cohort 1 Arm I | 5 of 5 |
Most frequent serious adverse event terms
| Event term | Organ system | Platinum Response - Sensitive: Topotecan Monotherapy | Platinum Response - Sensitive: Topotecan & M6620 (VX-970) Combination Therapy | Platinum Response - Resistant: Topotecan Monotherapy | Platinum Response - Resistant: Topotecan & M6620 (VX-970) Combination Therapy | Exploratory Cohort: Topotecan & M6620 (VX-970) Combination Therapy | Platinum Response - Sensitive: Topotecan & M6620 Combination Therapy -Cross-over From Cohort 1 Arm I |
|---|---|---|---|---|---|---|---|
| Lung infection | Infections and infestations | 5 of 9 | 1 of 20 | 3 of 11 | 2 of 20 | 0 of 16 | 3 of 5 |
| Platelet count decreased | Investigations | 2 of 9 | 1 of 20 | 3 of 11 | 4 of 20 | 2 of 16 | 2 of 5 |
| Anemia | Blood and lymphatic system disorders | 0 of 9 | 1 of 20 | 3 of 11 | 4 of 20 | 2 of 16 | 0 of 5 |
| Disease progression | General disorders | 1 of 9 | 1 of 20 | 2 of 11 | 3 of 20 | 0 of 16 | 1 of 5 |
| White blood cell decreased | Investigations | 1 of 9 | 2 of 20 | 1 of 11 | 1 of 20 | 1 of 16 | 1 of 5 |
| Sepsis | Infections and infestations | 0 of 9 | 0 of 20 | 1 of 11 | 1 of 20 | 4 of 16 | 0 of 5 |
| Neutrophil count decreased | Investigations | 0 of 9 | 1 of 20 | 1 of 11 | 2 of 20 | 1 of 16 | 0 of 5 |
| Respiratory failure | Respiratory, thoracic and mediastinal disorders | 1 of 9 | 0 of 20 | 2 of 11 | 0 of 20 | 1 of 16 | 1 of 5 |
| Confusion | Psychiatric disorders | 1 of 9 | 0 of 20 | 2 of 11 | 0 of 20 | 1 of 16 | 0 of 5 |
| Death NOS | General disorders | 0 of 9 | 1 of 20 | 1 of 11 | 1 of 20 | 1 of 16 | 0 of 5 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Platinum Response - Sensitive: Topotecan Monotherapy | Platinum Response - Sensitive: Topotecan & M6620 (VX-970) Combination Therapy | Platinum Response - Resistant: Topotecan Monotherapy | Platinum Response - Resistant: Topotecan & M6620 (VX-970) Combination Therapy | Exploratory Cohort: Topotecan & M6620 (VX-970) Combination Therapy | Platinum Response - Sensitive: Topotecan & M6620 Combination Therapy -Cross-over From Cohort 1 Arm I |
|---|---|---|---|---|---|---|---|
| Platelet count decreased | Investigations | 7 of 9 | 20 of 20 | 11 of 11 | 16 of 20 | 14 of 16 | 4 of 5 |
| Anemia | Blood and lymphatic system disorders | 8 of 9 | 18 of 20 | 9 of 11 | 16 of 20 | 12 of 16 | 5 of 5 |
| White blood cell decreased | Investigations | 6 of 9 | 14 of 20 | 7 of 11 | 12 of 20 | 11 of 16 | 3 of 5 |
| Lymphocyte count decreased | Investigations | 5 of 9 | 15 of 20 | 8 of 11 | 11 of 20 | 10 of 16 | 3 of 5 |
| Fatigue | General disorders | 4 of 9 | 13 of 20 | 9 of 11 | 11 of 20 | 10 of 16 | 2 of 5 |
| Neutrophil count decreased | Investigations | 4 of 9 | 10 of 20 | 6 of 11 | 11 of 20 | 9 of 16 | 3 of 5 |
| Nausea | Gastrointestinal disorders | 4 of 9 | 9 of 20 | 6 of 11 | 10 of 20 | 6 of 16 | 3 of 5 |
| Hyponatremia | Metabolism and nutrition disorders | 3 of 9 | 9 of 20 | 6 of 11 | 7 of 20 | 7 of 16 | 2 of 5 |
| Alkaline phosphatase increased | Investigations | 6 of 9 | 10 of 20 | 6 of 11 | 3 of 20 | 3 of 16 | 4 of 5 |
| Hypocalcemia | Metabolism and nutrition disorders | 3 of 9 | 6 of 20 | 7 of 11 | 4 of 20 | 6 of 16 | 2 of 5 |
Serious events with the highest arm-level rate: lung infection (60.0%), platelet count decreased (40.0%), anemia (33.3%), confusion (33.3%), sepsis (25.0%).
The safety figures count participants at risk and participants affected in each reported group. For serious adverse events, the registry lists 6 of 9 in the platinum-sensitive topotecan-alone group, 12 of 20 in the platinum-sensitive combination group, 9 of 11 in the platinum-resistant topotecan-alone group, 11 of 20 in the platinum-resistant combination group, and 9 of 16 in the exploratory combination cohort. Separate crossover groups are also listed: 4 of 5 in the sensitive combination crossover group and 4 of 6 in the resistant combination crossover group.
The registry separately lists other adverse events: 8 of 9, 20 of 20, 11 of 11, 19 of 20, 16 of 16, 5 of 5 and 6 of 6, respectively, across the seven safety groups. These are counts of affected participants, not event totals or rates per treatment exposure. Death counts are also listed for the groups, but whether deaths were attributed to treatment is not reported in the registry record.
The listed serious adverse-event terms include lung infection (60.0%), platelet count decreased (40.0%), anemia (33.3%), confusion (33.3%), sepsis (25.0%) and acidosis (20.0%). The denominator and selection details for these displayed percentages are not reported in the registry record. Adverse-event counts should be read as descriptive safety reporting; they do not establish that treatment caused an event or support a direct causal comparison between groups.
12. What the Result Does, and Does Not, Mean
The posted PFS data describe the median time to progression or death in each reported group, together with uncertainty intervals. The estimates show variation across the platinum-response categories and the exploratory cohort. They are useful for understanding what was observed in these groups, but they are not, by themselves, a formal estimate of the difference between randomized treatments.
The randomized design makes the topotecan-alone and combination groups the relevant basis for the trial’s primary comparison. However, the registry record does not report a numerical result from the planned one-tailed log-rank test or a hazard ratio. The group medians cannot be substituted for those missing results. Nor can a formal conclusion be drawn from comparing the separate confidence intervals.
The exploratory cohort should be interpreted separately because the posted results do not include a randomized topotecan-alone comparator for that cohort. The crossover option also means some participants initially assigned to monotherapy could later receive the combination; details of how crossover was addressed in any analysis are not reported in the registry record.
These results do not establish how the treatments compare for every person with small-cell cancer, nor do they identify a causal explanation for the observed group values. The reported outcome groups, evaluability information and follow-up descriptions define the scope of the data. Missing formal comparison results, information about analysis populations and details of missing-data handling limit further interpretation.
In short, the registry reports group-level PFS medians and 80% confidence intervals, along with descriptive safety counts. It does not report the primary inferential comparison needed to quantify the treatment difference or its statistical uncertainty. The posted findings should be read as a record of estimated outcomes in the stated groups, not as a definitive treatment-effect conclusion.
13. Why This Trial Matters Statistically
This trial is statistically informative because its design and reporting bring together randomized treatment groups, platinum-response categories, an exploratory cohort and permission to cross over after progression. These features make it important to distinguish the randomized primary comparison from subgroup descriptions and exploratory results. A single set of medians cannot represent all of those questions.
The primary endpoint is time-to-event, so estimates use both whether an event occurred and when it occurred. Kaplan-Meier curves and a log-rank test are appropriate tools for describing and comparing such outcomes under their assumptions. Reporting medians with confidence intervals gives readers an estimate and an indication of uncertainty, while the absence of a numerical test result or hazard ratio leaves the formal treatment contrast unavailable in the registry record.
Subgroup estimates also illustrate why context matters. Platinum-sensitive and platinum-resistant groups have separate outcome values and different reported group sizes. The exploratory cohort has no posted randomized monotherapy comparison. These categories should not be collapsed into an overall conclusion without a reported analysis that supports doing so.
Finally, crossover, six participants not evaluable for PFS, and the lack of reported detail on analysis populations and missing-data methods all affect how confidently the estimates can be interpreted. The statistical importance of the study is therefore not only in its observed medians, but also in recognizing which questions those medians answer and which require results or analysis details not reported in the registry record.
14. 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 a numerical result for the stated primary log-rank test, a hazard ratio, or an adjusted treatment-effect estimate. Consequently, the posted PFS medians and intervals do not supply a formal randomized comparison. The record also does not report the direction specified for the one-tailed test or a full statistical analysis plan.
Six participants from the reported groups were not evaluable for PFS, while participants enrolled but not treated are not reported for this outcome. Reasons for non-evaluability, missing-data procedures and sensitivity analyses are not reported in the registry record. The outcome population description for the exploratory cohort is incomplete in the record.
Group estimates are presented separately for platinum-sensitive and platinum-resistant participants, as well as for an exploratory cohort. No formal treatment-by-subgroup assessment is reported, and the exploratory group has no posted randomized comparator. Crossover to the combination after progression was allowed, but the record does not explain how crossover was handled in any treatment-effect analysis.
Details about censoring patterns, assessment completeness, multiplicity control, interim analyses, and analysis populations are not reported in the registry record. The registry lists secondary outcomes, but numerical results for those outcomes are not included in the record described. The safety summary includes counts and selected event terms, but attribution of deaths and the denominator for the displayed serious-event percentages are not reported. These limitations restrict what can be concluded from the posted group summaries.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Randomized Trial of Topotecan With M6620, an ATR Kinase Inhibitor, in Small Cell Lung Cancers and Small Cell Cancers Outside of the Lungs — NCT03896503.
- Registry record last updated 2026-07-31; status last verified 2026-06.
- Results first posted 2024-11-13.
- 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.
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Use this trial's endpoint as a starting point for deeper study of effect measures, confidence intervals, and sample-size planning.
18. Record Summary
NCT03896503 is a randomized, open-label, parallel-group phase II trial sponsored by the National Cancer Institute. The registry lists enrollment of 104 and a status of active, not recruiting. Its primary outcome is PFS, reported as a median in months with an 80% confidence interval.
The posted PFS estimates are separated by platinum response for the randomized topotecan-alone and topotecan-plus-M6620 groups, with an additional exploratory combination cohort. Six participants were not evaluable for the outcome, and crossover from monotherapy to combination treatment was permitted at progression. Serious and other adverse-event counts are also listed.
The registry describes Kaplan-Meier curves and a one-tailed log-rank test for the primary comparison, but does not report a numerical test result or hazard ratio. Further details about the analysis plan, missing-data handling, multiplicity and analysis populations are not reported in the registry record.