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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
Sponsor:
Collaborator:
Eli Lilly and Company
Information provided by (Responsible Party):
Eli Lilly and Company ( Loxo Oncology, Inc. )

Study Description
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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.

Condition or disease Intervention/treatment Phase
Non-Small Cell Lung Cancer Medullary Thyroid Cancer Colon Cancer Any Solid Tumor Drug: LOXO-292 Phase 1 Phase 2

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 875 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : May 2, 2017
Estimated Primary Completion Date : February 28, 2025
Estimated Study Completion Date : February 28, 2026

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: LOXO-292
Phase 1 - Multiple doses of LOXO-292 (selpercatinib) Phase 2 - The maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D)
 Drug: LOXO-292
Oral LOXO-292
Other Names:
  • Selpercatinib
  • LY3527723


Outcome Measures
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Primary Outcome Measures :
  1. 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

  2. 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

  3. 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)


Secondary Outcome Measures :
  1. 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)

  2. 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)

  3. 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

  4. 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)

  5. 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)

  6. 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)

  7. 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)

  8. 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)

  9. 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)

  10. 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)

  11. 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)

  12. 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

  13. 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)

  14. 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)

  15. 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)


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03157128


Contacts
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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

Locations
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Sponsors and Collaborators
Loxo Oncology, Inc.
Eli Lilly and Company
Investigators
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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
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Loxo Oncology, Inc.
ClinicalTrials.gov Identifier: NCT03157128    
Other Study ID Numbers: 17477
J2G-OX-JZJA ( Other Identifier: Eli Lilly and Company )
LOXO-RET-17001 ( Other Identifier: Loxo Oncology, Inc. )
2017-000800-59 ( EudraCT Number )
First Posted: May 17, 2017    Key Record Dates
Last Update Posted: March 4, 2024
Last Verified: March 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Eli Lilly and Company ( Loxo Oncology, Inc. ):
LOXO-292
KIF5B-RET
M918T
CCDC6-RET
RET-PTC1
NCOA4-RET
RET-PTC
RET-PTC3
RET-PTC4
PRKAR1A-RET
RET-PTC2
GOLGA5-RET
RET-PTC5
ERC1-RET
KTN1-RET
 RET-PTC8
HOOK3-RET
PCM1-RET
TRIM24-RET
RET-PTC6
TRIM27-RET
TRIM33-RET
RET-PTC7
AKAP13-RET
FKBP15-RET
SPECC1L-RET
TBL1XR1-RET
BCR-RET
FGRF1OP-RET
RFG8-RET
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Colonic Neoplasms
Thyroid Neoplasms
Carcinoma, Neuroendocrine
Thyroid Diseases
Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Endocrine System Diseases
 Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Endocrine Gland Neoplasms
Head and Neck Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Adenocarcinoma