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

Non-Small Cell Lung Cancer Clinical Trial

— LIBRETTO-001  

Official title:

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03157128
• Other study ID #: 17477
• Secondary ID: J2G-OX-JZJALOXO-
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: May 2, 2017
• Est. completion date: February 28, 2026

Study information

• Verified date: March 2024
• Source: Eli Lilly and Company
• Contact: There may be multiple sites in this clinical trial. 1-877-CTLILL
• Phone: 1-317-615-4559
• Email: ClinicalTrials.gov[@]lilly.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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)

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 875
• Est. completion date: February 28, 2026
• Est. primary completion date: February 28, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Any Solid Tumor
• Carcinoma, Neuroendocrine
• Carcinoma, Non-Small-Cell Lung
• Colon Cancer
• Colonic Neoplasms
• Lung Neoplasms
• Medullary Thyroid Cancer
• Non-Small Cell Lung Cancer
• Thyroid Diseases
• Thyroid Neoplasms

Intervention

Drug:
• LOXO-292
Oral LOXO-292

Locations

Country	Name	City	State
Australia	Peter MacCallum Cancer Centre	Melbourne	Victoria
Australia	Royal North Shore Hospital	St. Leonards	New South Wales
Canada	BC Cancer Vancouver	Vancouver	British Columbia
Denmark	Rigshospitalet	Copenhagen	København Ø
France	Institut Bergonié - Centre Régional de Lutte Contre Le Cancer de Bordeaux et Sud Ouest	Bordeaux
France	Centre Leon Berard	Lyon Cedex 08
France	APHM Hôpital de la Timone	Marseille
France	Institut du Cancer de Montpellier - Val d'aurelle	Montpellier Cedex 5
France	Hôpital Européen Georges Pompidou	Paris	Cedex 15
France	Gustave Roussy	Villejuif Cedex
Germany	Universitätsklinikum Köln	Köln	Nordrhein-Westfalen
Germany	Universitätsklinikum Würzburg A. ö. R.	Würzburg	Bayern
Hong Kong	Prince of Wales Hospital	Hong Kong	Shatin, New Territories
Israel	Soroka Medical Center - Pediatric Outpatient Clinic	Beer-Sheva
Israel	Hadassah Medical Center	Jerusalem
Israel	Shaare Zedek Medical Center	Jerusalem	Yerushalayim
Israel	Sheba Medical Center	Tel Hashomer	Ramat Gan
Italy	Istituto Nazionale dei Tumori	Milano	Lombardie
Japan	Hyogo Cancer Center	Akashi	Hyogo
Japan	National Cancer Center Hospital	Chuo-ku	Tokyo
Japan	National Hospital Organization Kyushu Cancer Center	Fukuoka
Japan	Kanazawa University Hospital	Kanazawa	Ishikawa
Japan	National Cancer Center Hospital East	Kashiwa	Chiba
Japan	Japanese Foundation for Cancer Research	Koto	Tokyo
Japan	Tominaga Hospital	Nagaizumi-cho,Sunto-gun	Shizuoka
Japan	Nagoya University Hospital	Nagoya	Aichi
Japan	Okayama University Hospital	Okayama
Japan	Osaka City General Hospital	Osaka
Japan	Kindai University Hospital	Osaka Sayama-shi	Osaka
Japan	Hokkaido University Hospital	Sapporo	Hokkaido
Japan	Tottori University Hospital	Yonago	Tottori
Korea, Republic of	National Cancer Center	Goyang-si	Gyeonggi-do
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam	Kyonggi-do
Korea, Republic of	Asan Medical Center	Seoul	Seoul-teukbyeolsi [Seoul]
Korea, Republic of	Samsung Medical Center	Seoul	Seoul-teukbyeolsi [Seoul]
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Singapore	National Cancer Centre Singapore	Singapore
Spain	Hospital Universitari Vall d'Hebron	Barcelona	Barcelona [Barcelona]
Spain	Hospital Madrid Norte Sanchinarro	Madrid
Spain	Hospital Universitario Fundación Jiménez Díaz	Madrid
Switzerland	Kantonsspital Luzern	Luzern 16	Luzern
Taiwan	Taichung Veterans General Hospital	Taichung
Taiwan	National Taiwan University Hospital	Taipei
United Kingdom	Royal Marsden Hospital	Sutton	Surrey
United States	University of Michigan	Ann Arbor	Michigan
United States	Emory University	Atlanta	Georgia
United States	University of Maryland Medical Center	Baltimore	Maryland
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	University of North Carolina	Chapel Hill	North Carolina
United States	University of Chicago Medicine-Comprehensive Cancer Center	Chicago	Illinois
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Ohio State University Hospital	Columbus	Ohio
United States	University of Texas Southwestern Medical Center at Dallas	Dallas	Texas
United States	Sarah Cannon Research Institute at HealthOne	Denver	Colorado
United States	City of Hope National Medical Center	Duarte	California
United States	USO-Virginia Cancer Specialists, PC	Fairfax	Virginia
United States	START Midwest	Grand Rapids	Michigan
United States	University of Texas MD Anderson Cancer Center	Houston	Texas
United States	Mayo Clinic in Florida	Jacksonville	Florida
United States	University of California - San Diego	La Jolla	California
United States	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada
United States	UCLA Medical Center	Los Angeles	California
United States	University of Wisconsin-Madison Hospital and Health Clinic	Madison	Wisconsin
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Yale Cancer Center	New Haven	Connecticut
United States	Ochsner Clinic Foundation	New Orleans	Louisiana
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	NYU Langone	New York	New York
United States	Hoag Memorial Hospital Presbyterian	Newport Beach	California
United States	Irvine Medical Center	Orange	California
United States	Memorial Hospital Pembroke	Pembroke	Florida
United States	Thomas Jefferson University	Philadelphia	Pennsylvania
United States	University of Pennsylvania Hospital	Philadelphia	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Mayo Clinic	Rochester	Minnesota
United States	Washington University Medical School	Saint Louis	Missouri
United States	Huntsman Cancer Institute	Salt Lake City	Utah
United States	UCSF Medical Center at Mission Bay	San Francisco	California
United States	Kaiser Permanente	Santa Clara	California
United States	Mayo Clinic of Scottsdale	Scottsdale	Arizona
United States	Kaiser Permanente Medical Center	Vallejo	California
United States	Johns Hopkins University	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Loxo Oncology, Inc.	Eli Lilly and Company

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Phase 1: MTD	Incidence rate and category of dose limiting toxicities (DLTs) during the first 28-day cycle of LOXO-292 (selpercatinib) treatment	The first 28 days of treatment (Cycle 1)
Primary	Phase 1: RP2D	Phase 1: RP2D	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)
Primary	Phase 2: Objective Response Rate	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)	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.
Secondary	Phase 1: Number of Participants with a Treatment-Related Adverse Event(s) (TRAE[s])	Phase 1: Number of Participants with a TRAE(s)	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)
Secondary	Phase 1: Number of Participants with an Abnormal Laboratory or Physical Exam Result(s)	Phase 1: Number of Participants with an Abnormal Laboratory or Physical Exam Result(s)	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)
Secondary	Phase 1: Overall Response Rate (ORR) based on RECIST 1.1 or RANO, as Appropriate to Tumor Type	Phase 1: ORR based on RECIST 1.1 or RANO, as Appropriate to Tumor Type	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
Secondary	Phase 2: ORR (by Investigator)	Phase 2: ORR (by Investigator)	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
Secondary	Phase 2: Best Change in Tumor Size from Baseline (by IRC and Investigator)	Phase 2: Best Change in Tumor Size from Baseline (by IRC and Investigator)	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
Secondary	Phase 2: Duration of Response (DOR; by IRC and Investigator)	Phase 2: DOR (by IRC and Investigator)	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
Secondary	Phase 2: Central Nervous System (CNS) ORR (by IRC)	Phase 2: CNS ORR (by IRC)	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
Secondary	Phase 2: CNS DOR (by IRC)	Phase 2: CNS DOR (by IRC)	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
Secondary	Phase 2: Time to Any and Best Response (by IRC and Investigator)	Phase 2: Time to Any and Best Response (by IRC and Investigator)	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
Secondary	Phase 2: CBR (by IRC and Investigator)	Phase 2: CBR (by IRC and Investigator)	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
Secondary	Phase 2: PFS (by IRC and Investigator)	Phase 2: PFS (by IRC and Investigator)	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
Secondary	Phase 2: Overall Survival (OS)	Phase 2: OS	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
Secondary	Phase 2: Percentage of Participants with any Serious Adverse Event (SAE[s])	Phase 2: Percentage of Participants with any SAE(s)	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)
Secondary	Phase 1 and 2: Pharmacokinetics (PK): Area Under the Plasma Concentration-Time Curve of LOXO-292 (Selpercatinib)	Phase 1 and 2: PK: AUC of LOXO-292 (Selpercatinib)	Cycle 1 Day 1 through Cycle 5 Day 1 (Cycle = 28 days)
Secondary	Phase 1 and 2: PK: Maximum Concentration (Cmax) of LOXO-292 (Selpercatinib)	Phase 1 and 2: PK: Cmax of LOXO-292 (Selpercatinib)	Cycle 1 Day 1 through Cycle 5 Day 1 (Cycle = 28 days)