A Study of Selpercatinib (LOXO-292) in Participants With Advanced Solid Tumors, RET Fusion-Positive Solid Tumors, and Medullary Thyroid Cancer (LIBRETTO-001) (LIBRETTO-001)

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ClinicalTrials.gov Identifier: NCT03157128

Recruitment Status : Recruiting

First Posted : May 17, 2017

Last Update Posted : March 4, 2024

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Sponsor:

Collaborator:

Eli Lilly and Company

Information provided by (Responsible Party):

Eli Lilly and Company ( Loxo Oncology, Inc. )

Tracking Information

First Submitted Date ^ICMJE

May 9, 2017

First Posted Date ^ICMJE

May 17, 2017

Last Update Posted Date

March 4, 2024

Actual Study Start Date ^ICMJE

May 2, 2017

Estimated Primary Completion Date

February 28, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures ^ICMJE

Phase 1: MTD [ Time Frame: The first 28 days of treatment (Cycle 1) ]
Incidence rate and category of dose limiting toxicities (DLTs) during the first 28-day cycle of LOXO-292 (selpercatinib) treatment
Phase 1: RP2D [ Time Frame: The first 28 days of treatment (Cycle 1) and every cycle (28 days) for approximately 12 months (or earlier if the participant discontinues from the study) ]
Phase 1: RP2D
Phase 2: Objective Response Rate [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, and 7 days after the last dose (for up to 2 years) in participants who have not progressed. ]
As assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or Response Assessment in Neuro-Oncology (RANO), as appropriate to tumor type, as assessed by independent review committee (IRC)

Original Primary Outcome Measures ^ICMJE

Maximum tolerated dose (MTD) [ Time Frame: The first 28 days of treatment (Cycle 1) ]

Change History

Current Secondary Outcome Measures ^ICMJE

Phase 1: Number of Participants with a Treatment-Related Adverse Event(s) (TRAE[s]) [ Time Frame: From the time of informed consent, for approximately 24 months (or earlier if the participant discontinues from the study), and through Safety Follow-up (28 days after the last dose) ]
Phase 1: Number of Participants with a TRAE(s)
Phase 1: Number of Participants with an Abnormal Laboratory or Physical Exam Result(s) [ Time Frame: From the time of informed consent, for approximately 24 months (or earlier if the participant discontinues from the study), and through Safety Follow-up (28 days after the last dose) ]
Phase 1: Number of Participants with an Abnormal Laboratory or Physical Exam Result(s)
Phase 1: Overall Response Rate (ORR) based on RECIST 1.1 or RANO, as Appropriate to Tumor Type [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in participants who have not progressed ]
Phase 1: ORR based on RECIST 1.1 or RANO, as Appropriate to Tumor Type
Phase 2: ORR (by Investigator) [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in participants who have not progressed ]
Phase 2: ORR (by Investigator)
Phase 2: Best Change in Tumor Size from Baseline (by IRC and Investigator) [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in participants who have not progressed ]
Phase 2: Best Change in Tumor Size from Baseline (by IRC and Investigator)
Phase 2: Duration of Response (DOR; by IRC and Investigator) [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in participants who have not progressed ]
Phase 2: DOR (by IRC and Investigator)
Phase 2: Central Nervous System (CNS) ORR (by IRC) [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in participants who have not progressed ]
Phase 2: CNS ORR (by IRC)
Phase 2: CNS DOR (by IRC) [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in participants who have not progressed ]
Phase 2: CNS DOR (by IRC)
Phase 2: Time to Any and Best Response (by IRC and Investigator) [ Time Frame: every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in participants who have not progressed ]
Phase 2: Time to Any and Best Response (by IRC and Investigator)
Phase 2: CBR (by IRC and Investigator) [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in participants who have not progressed ]
Phase 2: CBR (by IRC and Investigator)
Phase 2: PFS (by IRC and Investigator) [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in participants who have not progressed ]
Phase 2: PFS (by IRC and Investigator)
Phase 2: Overall Survival (OS) [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in participants who have not progressed ]
Phase 2: OS
Phase 2: Percentage of Participants with any Serious Adverse Event (SAE[s]) [ Time Frame: From the time of informed consent, for approximately 24 months (or earlier if the participant discontinues from the study), and through Safety Follow-up (28 days after the last dose) ]
Phase 2: Percentage of Participants with any SAE(s)
Phase 1 and 2: Pharmacokinetics (PK): Area Under the Plasma Concentration-Time Curve of LOXO-292 (Selpercatinib) [ Time Frame: Cycle 1 Day 1 through Cycle 5 Day 1 (Cycle = 28 days) ]
Phase 1 and 2: PK: AUC of LOXO-292 (Selpercatinib)
Phase 1 and 2: PK: Maximum Concentration (Cmax) of LOXO-292 (Selpercatinib) [ Time Frame: Cycle 1 Day 1 through Cycle 5 Day 1 (Cycle = 28 days) ]
Phase 1 and 2: PK: Cmax of LOXO-292 (Selpercatinib)

Original Secondary Outcome Measures ^ICMJE

Recommended dose for further study [ Time Frame: The first 28 days of treatment (Cycle 1) and every cycle (28 days) for approximately 12 months (or earlier if the patient discontinues from the study) ]
Number of participants with adverse events as assessed by CTCAE v4.03 [ Time Frame: From the time of informed consent, for approximately 24 months (or earlier if the patient discontinues from the study), and through Safety Follow-up (28 days after the last dose) ]
Number of participants with serious adverse events [ Time Frame: From the time of informed consent, for approximately 24 months (or earlier if the patient discontinues from the study), and through Safety Follow-up (28 days after the last dose) ]
Number of patients with changes in clinical laboratory results compared to baseline [ Time Frame: Day 1 (baseline) , Day 8 and Day 15 of Cycle 1 and every cycle (28 days) beginning with Cycle 2, for approximately 24 months (or earlier if the patient discontinues from the study), and through Safety Follow-up (28 days after the last dose) ]
Number of patients with changes upon physical examination compared to baseline [ Time Frame: Day 1 (baseline) , Day 8 and Day 15 of Cycle 1 and every cycle (28 days) beginning with Cycle 2, for approximately 24 months (or earlier if the patient discontinues from the study), and through Safety Follow-up (28 days after the last dose) ]
Number of patients with changes in vital signs compared to baseline [ Time Frame: Day 1 (baseline) , Day 8 and Day 15 of Cycle 1 and every cycle (28 days) beginning with Cycle 2, for approximately 24 months (or earlier if the patient discontinues from the study), and through Safety Follow-up (28 days after the last dose) ]
Number of patients with changes in ECGs compared to baseline [ Time Frame: Day 1 (baseline) , Day 8 and Day 15 of Cycle 1 and every cycle (28 days) beginning with Cycle 2, for approximately 24 months (or earlier if the patient discontinues from the study), and through Safety Follow-up (28 days after the last dose) ]
Area under the plasma concentration time curve from 0 to 24 hours (AUC0-24) of LOXO-292 [ Time Frame: Days 1 and 8 of Cycle 1 and Day 1 of Cycles 3 and 5 ]
Maximum plasma concentration (Cmax) of LOXO-292 [ Time Frame: Days 1 and 8 of Cycle 1 and Day 1 of Cycles 3 and 5 ]
Time to maximum plasma concentration (Tmax) of LOXO-292 [ Time Frame: Days 1 and 8 of Cycle 1 and Day 1 of Cycles 3 and 5 ]
Terminal half-life (t1/2) of LOXO-292 [ Time Frame: Days 1 and 8 of Cycle 1 and Day 1 of Cycles 3 and 5 ]
Degree of Accumulation of LOXO-292 [ Time Frame: Days 1 and 8 of Cycle 1 and Day 1 of Cycles 3 and 5 ]
Overall response rate [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose, and every 12 weeks after the last dose (for up to 2 years) in patients who have not progressed. ]
As assessed by RECIST v1.1 or RANO, as appropriate to tumor type
Duration of reponse [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose, and every 12 weeks after the last dose (for up to 2 years) in patients who have not progressed ]
In patients with best overall response of complete response or partial response, as assessed by RECIST v1.1 or RANO, as appropriate to tumor type
Best change in tumor size from baseline [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose, and every 12 weeks after the last dose (for up to 2 years) in patients who have not progressed ]
Clinical benefit rate [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose, and every 12 weeks after the last dose (for up to 2 years) in patients who have not progressed ]
Proportion of patients with complete response, partial response, or stable disease for at least 6 months while on LOXO-292, as assessed by RECIST v1.1 or RANO, as appropriate to tumor type
Median duration of progression-free survival following initiation of LOXO-292 [ Time Frame: Up to 2 years ]
Median overall survival following initiation of LOXO-292 [ Time Frame: Up to 2 years ]

Current Other Pre-specified Outcome Measures

Not Provided

Original Other Pre-specified Outcome Measures

Changes in serum tumor marker calcitonin compared to baseline (medullary thyroid cancer patients) [ Time Frame: Day 1 of Cycle 1 (baseline), Day 1 of Cycle 2, then Day 1 of every odd numbered cycle starting with Cycle 3, and 7 days after the last dose, for approximately 24 months (or earlier if the patient discontinues from the study) ]
Changes in serum tumor marker CEA compared to baseline (medullary thyroid cancer patients) [ Time Frame: Day 1 of Cycle 1 (baseline), Day 1 of Cycle 2, then Day 1 of every odd numbered cycle starting with Cycle 3, and 7 days after the last dose, for approximately 24 months (or earlier if the patient discontinues from the study) ]
RET gene status in DNA from tumor tissue [ Time Frame: Up to 28 days prior to Day 1 of Cycle 1 and 7 days after the last dose, for approximately 24 months (or earlier if the patient discontinues from the study) ]
RET gene status in plasma circulating free tumor DNA (cfDNA) [ Time Frame: Up to 28 days prior to Day 1 of Cycle 1, Day 15 of Cycle 1 , Day 1 of Cycle 2, then approximately every 8 weeks for one year, then every 12 weeks, and 7 days after last dose, for approximately 24 months (or earlier if patient discontinues from study). ]

Descriptive Information

Brief Title ^ICMJE

A Study of Selpercatinib (LOXO-292) in Participants With Advanced Solid Tumors, RET Fusion-Positive Solid Tumors, and Medullary Thyroid Cancer (LIBRETTO-001)

Official Title ^ICMJE

A Phase 1/2 Study of Oral Selpercatinib (LOXO-292) in Patients With Advanced Solid Tumors, Including RET Fusion-Positive Solid Tumors, Medullary Thyroid Cancer, and Other Tumors With RET Activation (LIBRETTO-001)

Brief Summary

This is an open-label, first-in-human study designed to evaluate the safety, tolerability, pharmacokinetics (PK) and preliminary anti-tumor activity of selpercatinib (also known as LOXO-292) administered orally to participants with advanced solid tumors, including rearranged during transfection (RET)-fusion-positive solid tumors, medullary thyroid cancer (MTC) and other tumors with RET activation.

Detailed Description

This is an open-label, multi-center Phase 1/2 study in participants with advanced solid tumors, including RET fusion-positive solid tumors, MTC, and other tumors with RET activation. The trial will be conducted in 2 parts: Phase 1 (dose escalation - completed) and phase 2 (dose expansion). Participants with advanced cancer are eligible if they have progressed on or are intolerant to available standard therapies, or no standard or available curative therapy exists, or in the opinion of the Investigator, they would be unlikely to tolerate or derive significant clinical benefit from appropriate standard of care therapy, or they declined standard therapy. A dose of 160 milligrams (mg) twice a day (BID) has been selected as the recommended phase 2 dose (RP2D). Approximately 875 participants with advanced solid tumors harboring a RET gene alteration in tumor and/or blood will be enrolled to one of seven phase 2 cohorts:

Cohort 1: Advanced RET fusion positive solid tumor other than NSCLC or thyroid cancer for participants who progressed on or intolerant to first line therapy (open)
Cohort 2: Advanced RET fusion positive solid tumor other than NSCLC or thyroid cancer for treatment naïve participants (open)
Cohort 3: Advanced RET-mutant MTC participants who progressed on or intolerant to first line therapy (closed)
Cohort 4: Advanced RET-mutant MTC participants who are treatment naïve (closed)
Cohort 5: Advanced RET-altered solid tumor for participants other than NSCLC or thyroid cancer and RET-mutant MEN2 spectrum tumors (e.g. pheochromocytoma) otherwise ineligible for cohorts 1-4. See details in inclusion/exclusion criteria (open)
Cohort 6: Participants otherwise eligible for Cohorts 1-5 who discontinued another RET inhibitor due to intolerance may be eligible with prior Sponsor approval (closed)
Cohort 7: RET fusion positive early-stage non-small cell lung cancer (NSCLC) participants who are candidates for definitive surgery. Participants will receive selpercatinib in a neoadjuvant and adjuvant setting. Participants will be followed for disease recurrence for up to 5 years from the date of surgery (closed)

Study Type ^ICMJE

Interventional

Study Phase ^ICMJE

Phase 1
Phase 2

Study Design ^ICMJE

Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment

Condition ^ICMJE

Non-Small Cell Lung Cancer
Medullary Thyroid Cancer
Colon Cancer
Any Solid Tumor

Intervention ^ICMJE

Drug: LOXO-292

Oral LOXO-292

Other Names:

Selpercatinib
LY3527723

Study Arms ^ICMJE

Experimental: LOXO-292

Phase 1 - Multiple doses of LOXO-292 (selpercatinib) Phase 2 - The maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D)

Intervention: Drug: LOXO-292

Publications *

* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.

Recruitment Information

Recruitment Status ^ICMJE

Recruiting

Estimated Enrollment ^ICMJE

875

Original Estimated Enrollment ^ICMJE

105

Estimated Study Completion Date ^ICMJE

February 28, 2026

Estimated Primary Completion Date

February 28, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria ^ICMJE

Key Inclusion Criteria:

For Phase 1:

Participants with a locally advanced or metastatic solid tumor that:
Has progressed on or is intolerant to standard therapy, or
For which no standard therapy exists, or in the opinion of the Investigator, are not candidates for or would be unlikely to tolerate or derive significant clinical benefit from standard therapy, or
Decline standard therapy
Prior multikinase inhibitors (MKIs) with anti-RET activity are allowed
A RET gene alteration is not required initially. Once adequate PK exposure is achieved, evidence of RET gene alteration in tumor and/or blood is required as identified through molecular assays, as performed for clinical evaluation
Measurable or non-measurable disease as determined by RECIST 1.1 or RANO as appropriate to tumor type
Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2 or Lansky Performance Score (LPS) greater than or equal to (≥) 40 percent (%) (age less than [<] 16 years) with no sudden deterioration 2 weeks prior to the first dose of study treatment
Adequate hematologic, hepatic and renal function
Life expectancy of at least 3 months

For Phase 2: As for phase 1 with the following modifications:

For Cohort 1: Participants must have received prior standard therapy appropriate for their tumor type and stage of disease, or in the opinion of the Investigator, would be unlikely to tolerate or derive clinical benefit from appropriate standard of care therapy
Cohorts 1 and 2:
- Enrollment will be restricted to participants with evidence of a RET gene alteration in tumor
- At least one measurable lesion as defined by RECIST 1.1 or RANO, as appropriate to tumor type and not previously irradiated
Cohorts 3 and 4: Enrollment closed
Cohort 5:
- Cohorts 1-4 without measurable disease
- MCT not meeting the requirements for Cohorts 3 or 4
- MTC syndrome spectrum cancers (e.g., MTC, pheochromocytoma), cancers with neuroendocrine features/differentiation, or poorly differentiated thyroid cancers with other RET alteration/activation may be allowed with prior Sponsor approval
- cfDNA positive for a RET gene alteration not known to be present in a tumor sample
Cohort 6: Participants who otherwise are eligible for Cohorts 1, 2 or 5 who discontinued another RET inhibitor may be eligible with prior Sponsor approval
Cohort 7: Participants with a histologically confirmed stage IB-IIIA NSCLC and a RET fusion; determined to be medically operable and tumor deemed resectable by a thoracic surgical oncologist, without prior systemic treatment for NSCLC

Key Exclusion Criteria (Phase 1 and Phase 2):

Phase 2 Cohorts 1 and 2: an additional known oncogenic driver
Cohorts 3 and 4: Enrollment closed
Cohorts 1, 2 and 5: prior treatment with a selective RET inhibitor Notes: Participants otherwise eligible for Cohorts 1, 2, and 5 who discontinued another selective RET inhibitor may be eligible for Phase 2 Cohort 6 with prior Sponsor approval
Investigational agent or anticancer therapy (including chemotherapy, biologic therapy, immunotherapy, anticancer Chinese medicine or other anticancer herbal remedy) within 5 half-lives or 2 weeks (whichever is shorter) prior to planned start of LOXO-292 (selpercatinib). In addition, no concurrent investigational anti-cancer therapy is permitted Note: Potential exception for this exclusion criterion will require a valid scientific justification and approval from the Sponsor
Major surgery (excluding placement of vascular access) within 2 weeks prior to planned start of LOXO-292 (selpercatinib)
Radiotherapy with a limited field of radiation for palliation within 1 week of planned start of LOXO-292 (selpercatinib), with the exception of participants receiving radiation to more than 30% of the bone marrow or with a wide field of radiation, which must be completed at least 4 weeks prior to the first dose of study treatment
Any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 at the time of starting study treatment with the exception of alopecia and Grade 2, prior platinum-therapy related neuropathy
Symptomatic primary CNS tumor, metastases, leptomeningeal carcinomatosis, or untreated spinal cord compression. Participants are eligible if neurological symptoms and CNS imaging are stable and steroid dose is stable for 14 days prior to the first dose of LOXO-292 (selpercatinib) and no CNS surgery or radiation has been performed for 28 days, 14 days if stereotactic radiosurgery (SRS)
Clinically significant active cardiovascular disease or history of myocardial infarction within 6 months prior to planned start of LOXO-292 (selpercatinib) or prolongation of the QT interval corrected (QTcF) greater than (>) 470 milliseconds (msec)
- Participants with implanted pacemakers may enter the study without meeting QTc criteria due to nonevaluable measurement if it is possible to monitor for QT changes.
- Participants with bundle branch block may be considered for study entry if QTc is appropriate by a formula other than Fridericia's and if it is possible to monitor for QT changes.
Required treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers and certain prohibited concomitant medications
Phase 2 Cohort 7 (neoadjuvant treatment): Participant must not have received prior systemic therapy for NSCLC.

Sex/Gender ^ICMJE

Sexes Eligible for Study:

All

Ages ^ICMJE

12 Years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers ^ICMJE

Contacts ^ICMJE

Contact: There may be multiple sites in this clinical trial. 1-877-CTLILLY (1-877-285-4559) or

1-317-615-4559

ClinicalTrials.gov@lilly.com

Listed Location Countries ^ICMJE

Australia, Canada, Denmark, France, Germany, Hong Kong, Israel, Italy, Japan, Korea, Republic of, Singapore, Spain, Switzerland, Taiwan, United Kingdom, United States

Removed Location Countries

Administrative Information

NCT Number ^ICMJE

NCT03157128

Other Study ID Numbers ^ICMJE

17477
J2G-OX-JZJA ( Other Identifier: Eli Lilly and Company )
LOXO-RET-17001 ( Other Identifier: Loxo Oncology, Inc. )
2017-000800-59 ( EudraCT Number )

Has Data Monitoring Committee

U.S. FDA-regulated Product

Studies a U.S. FDA-regulated Drug Product:	Yes
Studies a U.S. FDA-regulated Device Product:	No

IPD Sharing Statement ^ICMJE

Plan to Share IPD:

Current Responsible Party

Eli Lilly and Company ( Loxo Oncology, Inc. )

Original Responsible Party

Same as current

Current Study Sponsor ^ICMJE

Loxo Oncology, Inc.

Original Study Sponsor ^ICMJE

Same as current

Collaborators ^ICMJE

Eli Lilly and Company

Investigators ^ICMJE

Study Director:

Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)

Eli Lilly and Company

PRS Account

Eli Lilly and Company

Verification Date

March 2024

^ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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