Phase 1b/2 Study of TTI-101 in Combination for Patients With Metastatic Hormone Receptor-Positive and HER2-Negative Breast Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase 1b/2 Study of TTI-101 in Combination for Patients With Metastatic Hormone Receptor-Positive and HER2-Negative Breast Cancer (NCT05384119), a non-randomized phase 1 study. The primary outcome is Phase 1b: Number of Participants Who Experience a Dose Limiting Toxicity (DLT).

2. Clinical Question

3. Trial Design

The registry describes a Phase 1b/2 study of TTI-101 added to treatment for metastatic hormone receptor-positive, HER2-negative breast cancer. It is listed as Phase 1, non-randomized, unmasked, and sequential. The study enrolled 6 participants and is marked terminated. Its recorded start date is 2023-01-09, and its primary completion date is 2024-05-06. The reason for termination is not reported in the registry record.

Phase 1b is described as dose escalation. Participants were to receive up to 3 dose levels of TTI-101 added to palbociclib and an aromatase inhibitor or fulvestrant, with the goal of determining a recommended Phase 2 dose. The registry’s safety results identify Dose Level 1 and Dose Level 2, each with 3 participants at risk. Those counts describe the reported safety groups; they do not establish that all planned dose levels or phases were completed.

Phase 2 is described as dose expansion at the recommended Phase 2 dose. It could commence with approval from the safety review committee, and its listed combinations include TTI-101 added to palbociclib or ribociclib and an aromatase inhibitor or fulvestrant. Whether the committee approved expansion, whether Phase 2 commenced, and whether a recommended dose was selected are not reported in the registry record.

Because allocation was non-randomized and the study was sequential, the dose groups do not provide a randomized comparison. The record does not report a concurrent control arm, masking, or a protocol-based statistical analysis plan. The stated study objectives distinguish Phase 1b safety and dose selection from Phase 2 anti-tumor activity; neither objective should be treated as a result merely because it appears in the study description.

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: 6 patients were enrolled in the Phase 1b.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All enrolled participants who receive at least one dose of TTI-101.

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: Phase 2 was not initiated, and thus no analyses were performed.

6. Primary Endpoint

The registry lists the primary outcome as Phase 1b: Number of Participants Who Experience a Dose Limiting Toxicity (DLT), measured over Day 1 to Day 28.

The primary endpoint is the number of participants who experience a dose-limiting toxicity, measured from Day 1 to Day 28. The specified population is all enrolled participants who receive at least one dose of TTI-101. The endpoint is a count of participants, not a measurement of tumor response or a time-to-event outcome. The registry record does not give the observed count of participants with a dose-limiting toxicity.

In general, dose-limiting toxicity is used in early-phase dose-escalation research to assess whether a treatment regimen can be given within the defined evaluation period and to inform dose selection. That general role aligns with the stated Phase 1b objectives: evaluating safety and tolerability and determining a recommended Phase 2 dose for TTI-101 when added to the specified regimens. The record does not report the criteria used to classify a toxicity as dose-limiting, how borderline cases were handled, or how the dose decision was made.

A count is most interpretable when its analysis population and observation window are clear. The registry identifies both, but the count itself and any supporting analysis are not reported. The separate adverse-event counts should not be substituted for the primary endpoint: the record does not state that all reported adverse events were dose-limiting toxicities.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What kind of outcome is the primary endpoint?

The primary endpoint is a participant count: the number who experience a dose-limiting toxicity during Day 1 to Day 28. In general, a count records how many people meet an event definition. It is not automatically a risk, rate, or treatment effect. A risk requires a defined denominator and observation period, while a comparative treatment effect also requires a suitable comparison. The record specifies the primary analysis population as enrolled participants receiving at least one dose of TTI-101, but it does not report the endpoint count or a corresponding estimate.

For a binary event such as whether a participant experienced an event, researchers may report both the number with the event and the number assessed. The numerator and denominator make the extent of observed information easier to interpret than a count alone. In general, uncertainty intervals can communicate how imprecise an estimate may be, particularly when groups are small. No primary-endpoint estimate or uncertainty interval is reported in the registry record, so none can be interpreted for this outcome.

Why does the study design matter?

This is a non-randomized sequential study, rather than a randomized comparison. In general, random allocation helps make treatment groups comparable with respect to both measured and unmeasured factors. Without randomization, groups may differ for reasons related to treatment assignment, clinical condition, or the sequence of enrollment. A difference between dose-level groups therefore cannot be attributed to dose alone on the basis of these counts.

The registry describes Phase 1b dose escalation followed by a possible Phase 2 dose expansion, contingent on safety review committee approval. The Phase 1b purpose is safety assessment and dose selection; the Phase 2 purpose is evaluation of anti-tumor activity. These are different questions and ordinarily call for different interpretations. The record does not report whether expansion began, whether a recommended dose was selected, or what statistical procedures were planned for either phase.

What do the safety counts say?

The reported counts are descriptive. For each dose-level group, the record gives the number at risk, the number with a serious adverse event, the number with another adverse event, and deaths. These entries should be read as the recorded counts for those groups, not as a formal comparison. With only 3 participants at risk in each listed group, the counts contain limited information about uncommon events or the range of possible outcomes. This is a general limitation of interpreting safety data from small groups, not a claim about an unreported event.

The record does not provide serious adverse-event terms, and no top serious-event terms are listed. It also does not give event-level descriptions, timing, duration, severity for other adverse events, or attribution to treatment. Those details are not reported in the registry record. The primary dose-limiting toxicity endpoint is distinct from the broader adverse-event counts; the record does not say that the latter were classified as dose-limiting.

How should statistical significance and intervals be understood?

In general, a hypothesis test evaluates data against a specified null hypothesis under assumptions about the design and analysis. A p-value does not measure the probability that a treatment works, and statistical significance alone does not establish clinical importance. A confidence interval describes a range of estimates compatible with the data and model at a stated confidence level; wide intervals indicate substantial uncertainty. Neither a p-value nor a confidence interval for the primary endpoint is reported in the registry record. There is therefore no inferential result to assess for statistical significance or precision.

The record states that there are 0 analyses. This means an analysis result is not available in the posted record for the listed outcomes. It does not establish that no analyses were conducted outside the registry record. The analysis plan, including any model, adjustment, or handling of repeated or correlated outcomes, is not reported in the registry record.

What are the planning illustrations?

General sample-size calculations depend on a target effect, outcome variability, allocation, significance level, and analysis method. The stated planning assumptions use 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. Such figures are planning illustrations, not observed power and not evidence about the probability that the trial detected an effect. The time-to-event convention is a total number of events, while other illustrations are expressed as participants per arm. These assumptions do not turn the non-randomized dose groups into a suitable control comparison. No sample-size justification for the trial itself is reported in the registry record.

What remains necessary for interpretation?

For a full evaluation, readers would need the primary endpoint count, the toxicity definition, the analysis population actually assessed, and the treatment of participants with incomplete observation. For efficacy, they would need outcome estimates and their precision, along with the analysis population and follow-up details. Those items are not reported in the registry record. General statistical principles can clarify what such information would mean, but they cannot replace missing trial results.

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 1b: Dose Level 1", "Phase 1b: Dose Level 2")
n      <- c(3, 3)
events <- c(0, 1)
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 1b: Dose Level 1  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Phase 1b: Dose Level 2  3  1  33.3  0.8  90.6  6.1  79.2  6.8  80.6

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 18 outcome measures, including outcomes focused on safety, tumor activity, pharmacokinetics, and pharmacodynamics. The listed secondary outcomes include PFS6 for Phase 1b; clinical benefit rate and overall response rate for both phases; and several measures of TTI-101 concentration and tumor-biopsy pharmacodynamics. Overall response rate appears twice in the outcome list. The reason for the repeated listing is not reported in the registry record.

When a study examines multiple outcomes, the chance of at least one apparently notable result can increase if many tests are performed. In general, a prespecified testing hierarchy or multiplicity adjustment can help control that issue. The registry record does not report a multiplicity strategy, a confirmatory hierarchy, or adjusted analyses. It lists 0 analyses, so no reported estimates or tests are available to evaluate across the outcomes.

The record identifies the primary endpoint population as all enrolled participants who receive at least one dose of TTI-101. It does not report how many participants met that definition or how incomplete observation, withdrawal, or missing endpoint information was handled. The missing-data approach is not reported in the registry record. Analysis populations for the secondary outcomes are also not reported.

These omissions matter because outcome definitions, analysis populations, and missing-data rules can affect both the estimate and its uncertainty. Without them, readers cannot determine whether the reported safety counts represent complete follow-up for each participant or how unobserved outcomes were treated. No assumptions about missingness, exclusions, imputation, or adjustment should be inferred from the registry listing.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent non-serious adverse event terms

The safety results give counts separately for Phase 1b Dose Level 1 and Dose Level 2. Each group has 3 participants at risk. The record reports 0 serious adverse events among 3 participants at Dose Level 1 and 0 among 3 at Dose Level 2. It reports other adverse events for 3 of 3 participants in each group. Deaths are recorded as 0 in each group. These figures are counts, not estimates of comparative risk.

A count of 0 serious adverse events in a small group does not establish that the regimen has no serious risks. In general, a small amount of observation provides limited information about events that may be uncommon or occur later. Likewise, the recorded other-adverse-event counts do not describe their types, severity, duration, or relationship to treatment. Those details are not reported in the registry record. No top serious adverse-event terms are listed.

These safety entries should not be confused with the primary endpoint. The primary endpoint is dose-limiting toxicity during Day 1 to Day 28, but its result is not reported. The registry does not specify that the serious and other adverse-event categories correspond to the dose-limiting toxicity definition. The two dose-level groups also are not randomized comparison arms, so their counts should not be used to estimate a causal difference between doses.

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

The posted information supports a limited descriptive account: 6 participants were enrolled, the trial is marked terminated, and safety counts are listed for two Phase 1b dose levels. Each listed group has 3 participants at risk. Serious adverse events are recorded for 0 participants in each group, other adverse events for 3 participants in each group, and deaths for 0 participants in each group.

Those observations do not answer whether TTI-101 met the study’s primary safety objective. The primary endpoint is the number of participants with a dose-limiting toxicity during Day 1 to Day 28, but that number is not reported in the registry record. The dose-limiting toxicity criteria and recommended-dose decision are not reported either. As a result, no conclusion about whether a Phase 2 dose was established can be drawn from the posted information.

The study description includes a Phase 2 objective to evaluate anti-tumor activity, with secondary outcomes such as clinical benefit rate and overall response rate. The record does not report efficacy estimates or their precision. It therefore does not establish whether tumor activity was observed or how reliable any such estimate would be. A study objective describes what researchers intended to evaluate; it is not evidence that the outcome was achieved.

The non-randomized design also limits causal interpretation. There is no randomized control group against which to compare outcomes, and dose-level groups are not like-for-like control arms. Differences across groups, if any, could reflect factors other than dose. The small enrolled sample further limits how much can be learned about the distribution of safety or efficacy outcomes.

The terminated status is a registry status, not an explanation of why the study ended. The reason for termination, whether planned objectives were completed, and whether additional results are available elsewhere are not reported in the registry record. Missing results should not be interpreted as either favorable or unfavorable findings. The defensible reading is restricted to the stated design, enrollment, status, and posted counts.

14. Why This Trial Matters Statistically

This trial illustrates why early-phase design and outcome reporting need to be read together. The stated Phase 1b aim is not simply to compare treatments: it is to assess safety and tolerability of adding TTI-101 and determine a recommended Phase 2 dose. The primary endpoint is therefore a dose-limiting toxicity count within a defined window, while the later phase is intended to evaluate anti-tumor activity. Distinguishing those objectives prevents a safety count from being mistaken for an efficacy result.

It also shows the limits of descriptive information from small, non-randomized dose groups. The registry reports 3 participants at risk at each of two dose levels, but these groups are not randomized comparison arms. Their counts can describe recorded events; they cannot by themselves isolate the effect of dose or of adding TTI-101. Precision and causal interpretation require more than the presence of a numerical result.

For clinical researchers, the record highlights the value of posting the primary endpoint result, its definition, the analysis population, and uncertainty around the estimate. A clear account of missing observations and the dose-selection decision would further explain how the study’s stated objectives were addressed. The record lists a broad set of secondary outcomes but 0 analyses, leaving those questions unresolved in the posted information.

The statistical lesson is not that a particular treatment conclusion follows from the available counts. Rather, it is that study purpose, allocation, endpoint definition, group size, and completeness of reporting jointly determine what can be inferred. An explicit distinction between observed safety counts, a primary dose-limiting toxicity result, and intended anti-tumor evaluation is essential to avoid overstating what this record establishes.

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 enrollment of 6 and the 3 participants at risk in each listed dose-level group mean that the posted safety counts describe a very small amount of observed information. Such counts cannot characterize the full range of possible adverse events, and they give limited information about uncommon events. The record does not report participant characteristics by dose level, so comparability of the groups cannot be assessed.

The study is non-randomized and sequential, and the registry explicitly does not treat its arms as a like-for-like control comparison. There is no randomized comparator reported. Consequently, the design does not support a direct causal comparison between TTI-101 and an alternative regimen or between dose levels. No adjustment strategy for baseline differences is reported.

The study is marked terminated, but the reason for termination is not reported in the registry record. It is also not reported whether Phase 2 began, whether safety review committee approval was given, or whether a recommended Phase 2 dose was selected. The primary dose-limiting toxicity result and efficacy results are not reported. These gaps prevent assessment of the stated objectives from the posted outcomes.

Further limitations include the absence of a reported statistical analysis plan, uncertainty estimates, and missing-data methods. The record does not provide details of adverse-event terms beyond the reported categories, nor does it explain the repeated overall-response-rate entry. The listed safety counts should therefore be interpreted as limited descriptive information, not as a comprehensive safety profile or an efficacy assessment.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Phase 1b/2 Study of TTI-101 in Combination for Patients With Metastatic Hormone Receptor-Positive and HER2-Negative Breast Cancer — NCT05384119.
• Registry record last updated 2026-09-24; status last verified 2026-08.
• Results first posted 2026-09-24.
• 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 record describes a non-randomized, sequential Phase 1b/2 study of TTI-101 added to palbociclib or ribociclib with an aromatase inhibitor or fulvestrant for metastatic hormone receptor-positive, HER2-negative breast cancer. Phase 1b was designed for dose escalation and assessment of dose-limiting toxicity; Phase 2 was intended to evaluate anti-tumor activity at a recommended dose, subject to safety review committee approval.

The study enrolled 6 participants, began on 2023-01-09, has a primary completion date of 2024-05-06, and is marked terminated. Safety counts are reported for Dose Level 1 and Dose Level 2, each with 3 participants at risk. The primary endpoint result, the reason for termination, and efficacy analyses are not reported in the registry record. The record lists 18 outcome measures and 0 analyses.