This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record.
1. Trial at a Glance
LIBRETTO-001 is a phase 1/2, single-group study evaluating selpercatinib (LOXO-292) in participants with advanced solid tumors, RET fusion-positive solid tumors, and medullary thyroid cancer. The registry identifies three primary endpoints spanning dose determination and objective tumor response.
| Feature | LIBRETTO-001 |
|---|---|
| Trial name | LIBRETTO-001 |
| NCT ID | NCT03157128 |
| Brief title | A Study of Selpercatinib (LOXO-292) in Participants With Advanced Solid Tumors, RET Fusion-Positive Solid Tumors, and Medullary Thyroid Cancer (LIBRETTO-001) |
| Phase | 1/2 |
| Status | ACTIVE_NOT_RECRUITING |
| Start | 2017-05-02 |
| Primary completion | 2025-02-14 |
| Lead sponsor | Eli Lilly and Company |
| Sponsor type | INDUSTRY |
| Therapeutic area | Oncology |
| Allocation | NA |
| Design model | SINGLE_GROUP |
| Masking | NONE |
| Primary purpose | TREATMENT |
| Enrollment | 857.0 |
| Intervention | LOXO-292 (drug) |
2. Clinical Question
The clinical question changes across the two phases of the study. In Phase 1, the principal statistical task is dose escalation and identification of a maximum tolerated dose and recommended Phase 2 dose. In Phase 2, the registered primary question is whether selpercatinib produces an objective response, based on Independent Review Committee assessment, in the studied participant population.
Population
Participants with advanced solid tumors, RET fusion-positive solid tumors, and medullary thyroid cancer. The registered conditions include Non-Small Cell Lung Cancer; Medullary Thyroid Cancer; Colon Cancer; Any Solid Tumor.
Intervention
LOXO-292, also identified in the registry as selpercatinib.
Comparator
No concurrent comparator arm is identified in the registry design. Allocation is listed as NA and the design model is SINGLE_GROUP.
Primary questions
What dose level satisfies the registered MTD definition, what dose is selected as the RP2D, and what is the Phase 2 objective response rate based on IRC assessment?
3. Trial Design
the ClinicalTrials.gov record identifies 16 arms. The serious-adverse-event data reported with the registry record identify several Phase 1 dose groups, including 20 mg Selpercatinib QD, 20 mg Selpercatinib BID, 40 mg Selpercatinib BID, 60 mg Selpercatinib BID, 160 mg Selpercatinib QD, 80 mg Selpercatinib BID, and 120 mg Selpercatinib BID. The registry-reported safety string ends during the description of another 160 mg Selpercatinib group and therefore does not provide a complete arm-by-arm safety inventory.
4. Registered Primary Endpoints
| Endpoint | Time frame | Registry definition |
|---|---|---|
| Phase 1: Maximum Tolerated Dose (MTD) | Cycle 1 (cycle length = 28 days) | The MTD is defined as the highest dose level at which none of the first 3 treated patients, or not more than 1 of the first 6 treated patients, experiences a DLT. A DLT is any adverse events that starts on or after first administration of study drug, as defined by National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. * Any Grade(G) ≥3 nonhematologic toxicity, excluding * G3 AST, ALT, and/or total bilirubin elevation for \<7 days. * G3 neutropenia \<7 days * G3 thrombocytopenia without clinically significant bleeding * G3 or G4 lymphopenia. * First occurrence of G3 or G4 electrolyte abnormalities * G3 fatigue, weakness, nausea; other manageable constitutional symptom * G3 or G4 vomiting or diarrhea that lasts for \<48hours with antiemetic/antidiarrheal medication in case of G3 and \<24 hours in case of G4 * G4 manageable constitutional symptom. |
| Phase 1: Recommended Phase 2 Dose (RP2D) | Cycle 1 (cycle length = 28 days) | Phase 1: RP2D |
| Phase 2: Objective Response Rate (ORR) Based on Independent Review Committee (IRC) Assessment | Approximately for up to 7 years 8 months | Objective Response Rate was defined as the percentage of participants with best overall response of confirmed response (CR), or Partial response (PR). Response was confirmed by a repeat assessment no less than 28 days. * CR is defined as disappearance of all target lesions. * PR is defined as at least a 30% decrease in the sum of diameter. |
5. Statistical Structure of the Primary Questions
LIBRETTO-001 illustrates why the phrase "primary endpoint" does not necessarily imply a single hypothesis test comparing two randomized groups. Its three registered primary endpoints address different statistical tasks.
| Phase | Endpoint | Statistical role |
|---|---|---|
| Phase 1 | Maximum Tolerated Dose | Dose-escalation decision based on dose-limiting toxicities during Cycle 1. |
| Phase 1 | Recommended Phase 2 Dose | Dose-selection decision for subsequent development. |
| Phase 2 | Objective Response Rate | Estimation of the proportion of participants with confirmed CR or PR based on IRC assessment. |
There is no randomized comparator in the registry-reported design, so an effect estimate such as a treatment hazard ratio versus control is not the natural primary quantity for this trial. The principal inferential quantities are instead dose-toxicity information and the response proportion, together with its statistical uncertainty.
6. Planned Analysis
ClinicalTrials.gov reports that results have been posted for all three registered primary endpoints, but the ClinicalTrials.gov record contains no formal statistical analyses. Consequently, the available data do not provide formal analysis estimates, confidence intervals, or p-values for the primary endpoints in the structured statistical-analysis field.
For the Phase 2 endpoint, the primary descriptive quantity would ordinarily be the observed proportion of participants with a confirmed response. An exact or otherwise prespecified confidence interval would normally accompany the response estimate to quantify its precision.
Phase 1: Maximum Tolerated Dose
The registered MTD rule is explicitly dose- and cohort-based. The highest dose level satisfying the stated Cycle 1 DLT rule would be identified as the MTD. The registry-reported definition specifies that none of the first 3 treated patients, or not more than 1 of the first 6 treated patients, may experience a DLT at that dose level.
Phase 1: Recommended Phase 2 Dose
The registry identifies RP2D as a primary endpoint but supplies only the endpoint label and its Cycle 1 time frame. The statistical interpretation is therefore a dose-selection decision rather than a conventional comparative hypothesis test.
Phase 2: Objective Response Rate
The registered endpoint is based on Independent Review Committee assessment and requires a confirmed CR or PR. Confirmation requires a repeat assessment no less than 28 days after the initial response assessment. The appropriate analysis would therefore distinguish confirmed responses from unconfirmed tumor changes and express the endpoint as a proportion.
7. Phase 1 Dose-Finding Logic
The MTD definition provides an unusually clear example of how an early-phase trial converts observed toxicity into a dose-selection rule. The decision is made using the first Cycle 1 experience at a dose level rather than by comparing long-term outcomes between randomized groups.
First 3 treated patients
The registered rule allows a dose level to satisfy the MTD definition when none of the first 3 treated patients experiences a DLT.
First 6 treated patients
The registered rule also allows a dose level when not more than 1 of the first 6 treated patients experiences a DLT.
DLT window
The primary endpoint is evaluated during Cycle 1, with a cycle length of 28 days.
Highest qualifying dose
The MTD is defined as the highest dose level satisfying the registered DLT rule.
8. Serious Adverse Events by Phase 1 Dose Group
The ClinicalTrials.gov record provides affected/at-risk counts for several Phase 1 dose groups. These counts are safety descriptions and should not be interpreted as efficacy results or as randomized treatment effects.
| Phase 1 dose group | Participants with serious AEs / participants at risk |
|---|---|
| 20 mg Selpercatinib QD | 4/6 |
| 20 mg Selpercatinib BID | 8/10 |
| 40 mg Selpercatinib BID | 9/16 |
| 60 mg Selpercatinib BID | 7/12 |
| 160 mg Selpercatinib QD | 1/1 |
| 80 mg Selpercatinib BID | 13/20 |
| 120 mg Selpercatinib BID | 11/19 |
9. Statistical Methods Explained
What is the statistical purpose of an MTD?
The MTD is a dose-selection endpoint. Instead of asking whether one treatment is better than another, the analysis asks how observed dose-limiting toxicity changes as dose level increases. The registered rule makes that decision explicit by defining the highest dose at which the specified number of early participants experience DLTs.
Why is Cycle 1 important for the MTD endpoint?
The registered MTD time frame is Cycle 1, with a cycle length of 28 days. Restricting the primary dose-limiting-toxicity decision to a defined observation window makes the escalation rule operational and reproducible. It also means that the MTD endpoint is not equivalent to cumulative toxicity over the entire study.
What does "not more than 1 of the first 6" mean?
It is a decision threshold, not a statement that 1 of 6 participants represents a universal acceptable toxicity rate. In the context of this specific registered rule, a dose level can meet the MTD definition when no more than 1 of the first 6 treated participants experiences a DLT.
Why is RP2D different from MTD?
MTD is explicitly defined in the registry as a toxicity-based endpoint. RP2D is a separate registered endpoint intended to identify the dose selected for Phase 2. The ClinicalTrials.gov record provides the RP2D label but do not provide its decision algorithm, so the two endpoints should not be treated as interchangeable.
How should ORR be interpreted in a single-group study?
ORR is the percentage of participants with a confirmed CR or PR according to the registered IRC-based definition. In a single-group design, the response proportion describes the observed activity in the studied population. Without a concurrent randomized control group, it does not by itself quantify a treatment effect relative to another intervention.
Why does response confirmation matter?
The registered ORR endpoint requires a confirmed response, with a repeat assessment no less than 28 days after the initial response assessment. Confirmation reduces the chance that a transient or uncertain imaging finding is classified as a definitive response under the primary endpoint.
Why should a confidence interval accompany ORR?
A response proportion calculated from a finite sample is subject to sampling variability. A confidence interval provides information about the precision of the estimated response proportion. The interval does not mean that individual participants have a probability equal to the interval endpoints of responding; it describes uncertainty about the population parameter under the chosen statistical framework.
10. Objective Response Rate: Statistical Interpretation
The registered Phase 2 ORR endpoint measures the percentage of participants whose best overall response is a confirmed response, specifically CR or PR, based on Independent Review Committee assessment.
ORR does not measure overall survival, progression-free survival, duration of treatment, or the probability that an individual participant will experience long-term clinical benefit. A response endpoint is a tumor-response measure, not a complete summary of all possible clinical outcomes.
The denominator used for an ORR calculation must follow the prespecified analysis population and evaluability rules. Using a different denominator can materially change the reported percentage. The ClinicalTrials.gov record does not provide a statistical-analysis record defining the denominator for the posted result, so no numerical ORR is reconstructed here.
11. Independent Review Committee Assessment
The Phase 2 primary endpoint is explicitly based on Independent Review Committee (IRC) Assessment. This is statistically important because the primary response classification is not simply an investigator-reported judgment.
Independent review can reduce the influence of investigator expectations on the primary tumor-response classification. For statistical interpretation, the important point is that the endpoint is defined by a prespecified assessment framework rather than by an informal statement that a tumor "responded."
12. What the Single-Group Design Changes Statistically
A single-group design changes the meaning of nearly every familiar clinical-trial statistic. In a randomized trial, a treatment effect is usually defined by the difference between concurrent treatment groups. In LIBRETTO-001, the primary Phase 2 response endpoint is instead a response proportion within the treated study population.
| Question | Randomized comparative trial | LIBRETTO-001 framework |
|---|---|---|
| Primary comparison | Usually treatment versus comparator | No concurrent comparator identified in registry-reported design |
| Typical effect measure | Risk ratio, risk difference, odds ratio, hazard ratio, etc. | Observed response proportion is central to the registered Phase 2 endpoint |
| Randomization | Balances prognostic factors in expectation | Not present in the registry-reported single-group design |
| Phase 1 objective | Usually not a comparative efficacy question | MTD and RP2D dose-selection endpoints |
| Reference population | Comparator arm provides a concurrent reference | External context would be needed for comparative interpretation |
13. Statistical Methodology
Binary endpoint estimation
The Phase 2 ORR endpoint is classified in the ClinicalTrials.gov record as a Binary primary endpoint. The fundamental quantity is the proportion of participants meeting the confirmed-response definition.
where R is the number of participants meeting the registered confirmed-response definition and N is the prespecified analysis denominator.
For a binary endpoint, an interval estimate should ordinarily accompany the point estimate. Exact binomial methods are one common approach when the sample size or observed proportion makes a normal approximation inappropriate, although the specific method should be taken from the prespecified statistical analysis plan when available.
Dose-escalation decision rules
The Phase 1 MTD endpoint uses an explicit rule based on observed DLTs among the first 3 or first 6 treated participants at a dose level. This is a form of rule-based early-phase dose finding: the statistical decision is driven by toxicity observations rather than a conventional two-arm hypothesis test.
Descriptive safety analysis
Serious adverse events are naturally summarized using counts and denominators, often accompanied by percentages. For this trial, the ClinicalTrials.gov record provides affected/at-risk counts for several dose groups. Those counts should be retained as descriptive safety information rather than converted into a comparative effect estimate.
Independent response assessment
For the Phase 2 endpoint, IRC assessment provides the basis for response classification. The response must also be confirmed by repeat assessment no less than 28 days after the initial assessment. Statistically, the confirmation rule defines which observations enter the binary response endpoint.
14. Multiplicity and Interim Analysis
The ClinicalTrials.gov record identifies three registered primary endpoints but do not provide a statistical-analysis record describing multiplicity adjustment, alpha allocation, interim-analysis boundaries, or a formal hypothesis-testing hierarchy.
Three primary endpoints
The registry identifies MTD, RP2D, and Phase 2 ORR as primary endpoints. They represent different development decisions rather than three interchangeable versions of the same outcome.
Multiplicity
No multiplicity procedure is reported in the ClinicalTrials.gov record. Therefore, no claim about familywise type I error control is made here.
Interim analysis
No interim-analysis method is reported in the ClinicalTrials.gov record. The Phase 1 dose rule itself should not automatically be labeled an interim efficacy analysis.
Formal p-values
No formal statistical analyses were posted. No p-value is therefore reported or reconstructed for the primary endpoints.
For a single-group binary endpoint, statistical significance may be assessed against an external or historical benchmark if a protocol specifies one. No such benchmark or null response rate is included in the ClinicalTrials.gov record, so a formal one-sample hypothesis test cannot be reconstructed from the available information.
15. Missing Data and Analysis Population
The ClinicalTrials.gov record does not specify a missing-data or imputation strategy for the Phase 2 ORR endpoint. This matters because response assessment requires adequate tumor evaluation, and the definition of the analysis denominator can influence the resulting response proportion.
| Issue | Statistical implication |
|---|---|
| Missing response assessment | Can affect which participants contribute to the ORR denominator. |
| Unconfirmed response | Does not satisfy the registered confirmed-response definition. |
| Repeat assessment | Required no less than 28 days after the initial response assessment for confirmation. |
| Analysis denominator | Must follow the prespecified endpoint population; the ClinicalTrials.gov record does not provide that denominator. |
No imputation method is stated in the ClinicalTrials.gov record. In particular, this page does not assume that missing assessments were counted as responses, nonresponses, or censored observations.
16. Bayesian Methods
No Bayesian method is identified in the ClinicalTrials.gov record. The registered endpoints and registry-reported design information do not specify a Bayesian prior, posterior probability criterion, Bayesian dose-escalation algorithm, or Bayesian response analysis.
That distinction is important because early-phase oncology studies can use Bayesian dose-finding methods, but the presence of a dose-escalation endpoint alone is not evidence that a Bayesian model was used. The registry-reported MTD definition is expressed as an explicit rule involving the first 3 or first 6 treated participants.
17. Stratification and Covariate Adjustment
The ClinicalTrials.gov record does not identify stratification factors, covariate-adjusted models, or prespecified subgroup-adjusted analyses. Because this is a single-group design, there is no randomized treatment comparison for which stratified treatment-effect estimation would ordinarily be required.
A response proportion summarizes observed activity in the studied population. It does not automatically establish how the intervention compares with an alternative treatment, because the study lacks a concurrent randomized comparator in the registry-reported design.
18. Trial Timeline
Study start
The registry identifies 2017-05-02 as the study start date.
Dose evaluation
The registered primary endpoints include MTD and RP2D, both evaluated over Cycle 1, with a cycle length of 28 days.
Objective response assessment
The registered Phase 2 primary endpoint is ORR based on Independent Review Committee assessment, with a time frame of approximately up to 7 years 8 months.
Primary completion
The registry identifies 2025-02-14 as the primary completion date.
ACTIVE_NOT_RECRUITING
the ClinicalTrials.gov record identifies the current status as ACTIVE_NOT_RECRUITING.
19. How to Read the Phase 1 Safety Data
The serious-adverse-event counts illustrate a central issue in early-phase dose-finding: the denominator can be very small. For example, the ClinicalTrials.gov record reports 1/1 for the 160 mg Selpercatinib QD group. A proportion calculated from 1 participant is necessarily unstable as an estimate of a broader dose-level safety rate.
Affected/at-risk counts should always be read together with the denominator. A count of 1/1 means that the affected count equals the registry-reported at-risk count for that group; it does not establish a population-level serious-adverse-event probability.
The listed Phase 1 groups differ in both dose and number of participants. Simple comparison of their affected/at-risk fractions would not by itself provide a controlled estimate of a dose-response relationship.
The registry-reported serious-adverse-event field and the registered MTD endpoint are not interchangeable. MTD is defined using DLT criteria during Cycle 1, whereas the registry-reported safety field reports serious adverse events by arm.
20. What This Trial Does Not Establish From the Supplied Statistical Record
- No randomized treatment effect: the registry-reported design is single-group, so no concurrent randomized comparator effect is available.
- No numerical ORR is reconstructed: the registry indicates results are posted, but the registry-reported statistical-analysis array contains no ORR estimate.
- No formal p-value is reconstructed: no statistical-analysis entry supplies a hypothesis test or p-value.
- No confidence interval is reconstructed: the ClinicalTrials.gov record does not contain the numerical interval associated with the posted primary endpoint result.
- No MTD result is inferred: dose-group safety counts do not establish the registered MTD without the complete dose-escalation decision record.
- No RP2D result is inferred: the ClinicalTrials.gov record identifies RP2D as a primary endpoint but do not provide the selected result.
- No multiplicity adjustment is assumed: the ClinicalTrials.gov record does not specify an alpha-control strategy.
- No Bayesian method is assumed: the ClinicalTrials.gov record does not identify a Bayesian analysis.
21. Limitations
- Single-group design: without a concurrent randomized comparator, observed response cannot be interpreted as a randomized treatment effect.
- Incomplete structured statistical-analysis data: the ClinicalTrials.gov record indicates that results have been posted but provide no formal statistical analyses.
- Incomplete safety string: the registry-reported serious-adverse-event field ends during an additional 160 mg Selpercatinib entry, so the complete arm-level safety inventory cannot be reconstructed from the registry-reported text.
- Small early-phase denominators: several reported Phase 1 safety groups contain relatively few participants, limiting precision of simple event-rate descriptions.
- No registry-reported multiplicity framework: the record identifies three registered primary endpoints but does not supply an error-control hierarchy.
- No registry-reported missing-data strategy: the ClinicalTrials.gov record does not specify how missing response assessments were handled.
- No registry-reported subgroup framework: the available data do not identify prespecified covariate adjustment or formal subgroup interaction testing.
22. Why This Trial Matters Statistically
LIBRETTO-001 is useful as a statistical teaching case because it illustrates a different branch of clinical-trial methodology from the conventional randomized phase 3 model. The study combines early-phase dose selection with a later binary response endpoint in a single-group framework.
| Concept | How it appears in LIBRETTO-001 |
|---|---|
| Early-phase dose finding | MTD and RP2D are registered primary endpoints. |
| Rule-based toxicity decision | MTD uses the specified first-3 / first-6 DLT rule. |
| Cycle-specific safety window | MTD and RP2D use Cycle 1, with a cycle length of 28 days. |
| Binary endpoint | Phase 2 ORR is classified as Binary in the ClinicalTrials.gov record. |
| Confirmed response | CR or PR must be confirmed by repeat assessment no less than 28 days later. |
| Independent assessment | ORR is based on Independent Review Committee assessment. |
| Single-group inference | Observed response proportions do not automatically represent comparative treatment effects. |
| Small-sample safety data | Several listed dose groups have small denominators. |
| Multiplicity | Three registered primary endpoints are present, but no registry-reported multiplicity method is identified. |
| Missing data | The ClinicalTrials.gov record does not identify an imputation or missing-response strategy. |
23. Related Tutorials
Learn more about the methods used in this trial:
24. Related Calculators
25. Sources
- ClinicalTrials.gov: LIBRETTO-001, NCT03157128.
- Linked publication: PubMed record: PMID 39983053.
- Linked publication: PubMed record: PMID 39471424.
- Linked publication: PubMed record: PMID 39094065.
- Linked publication: PubMed record: PMID 39085487.
- Linked publication: PubMed record: PMID 38661071.
The numerical and endpoint information presented on this page is restricted to the registry-reported LIBRETTO-001 trial data. The linked PubMed records are provided as registry-linked publication resources; no additional numerical trial results from those publications are incorporated into this page.
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26. Record Summary
LIBRETTO-001 provides a useful example of how statistical methodology changes across clinical-development phases. Its registered primary endpoints combine a Cycle 1 dose-toxicity decision for MTD, a Phase 1 dose-selection endpoint for RP2D, and a Phase 2 confirmed objective-response endpoint based on Independent Review Committee assessment. Because the registry-reported design is single-group and the structured statistical-analysis array contains no entries, the available record supports a detailed explanation of the statistical framework but does not support reconstruction of numerical primary endpoint estimates, confidence intervals, or p-values.