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

Sponsor
Loxo Oncology, Inc. (Industry)
Overall Status
Recruiting
CT.gov ID
NCT03157128
Collaborator
Eli Lilly and Company (Industry)
875
85
1
88
10.3
0.1

Study Details

Study Description

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
Phase 1/Phase 2

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

Study Type:
Interventional
Anticipated 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
Anticipated Primary Completion Date :
Mar 21, 2024
Anticipated Study Completion Date :
Sep 1, 2024

Arms and Interventions

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

    Primary Outcome Measures

    1. Phase 1: MTD [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 [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 [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]) [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) [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 [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) [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) [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) [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) [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) [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) [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) [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) [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) [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]) [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) [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) [Cycle 1 Day 1 through Cycle 5 Day 1 (Cycle = 28 days)]

      Phase 1 and 2: PK: Cmax of LOXO-292 (Selpercatinib)

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    12 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Locations

    Site City State Country Postal Code
    1 Mayo Clinic of Scottsdale Scottsdale Arizona United States 85259
    2 City of Hope National Medical Center Duarte California United States 91010-0269
    3 University of California - San Diego La Jolla California United States 92161
    4 UCLA Medical Center Los Angeles California United States 90095
    5 Hoag Memorial Hospital Presbyterian Newport Beach California United States 92663
    6 Irvine Medical Center Orange California United States 92868
    7 UCSF Medical Center at Mission Bay San Francisco California United States 94115
    8 Kaiser Permanente Santa Clara California United States 95051
    9 Kaiser Permanente Medical Center Vallejo California United States 94589
    10 Sarah Cannon Research Institute at HealthOne Denver Colorado United States 80218
    11 Yale Cancer Center New Haven Connecticut United States 06510
    12 Johns Hopkins University Washington District of Columbia United States 20016
    13 Mayo Clinic in Florida Jacksonville Florida United States 32224
    14 Memorial Hospital Pembroke Pembroke Florida United States 33028
    15 Emory University Atlanta Georgia United States 30322
    16 University of Chicago Medicine-Comprehensive Cancer Center Chicago Illinois United States 60637
    17 Ochsner Clinic Foundation New Orleans Louisiana United States 70121
    18 University of Maryland Medical Center Baltimore Maryland United States 21201
    19 Massachusetts General Hospital Boston Massachusetts United States 02114
    20 Dana-Farber Cancer Institute Boston Massachusetts United States 02215
    21 University of Michigan Ann Arbor Michigan United States 48109
    22 START Midwest Grand Rapids Michigan United States 49546
    23 Mayo Clinic Rochester Minnesota United States 55905
    24 Washington University Medical School Saint Louis Missouri United States 63110
    25 Comprehensive Cancer Centers of Nevada Las Vegas Nevada United States 89169
    26 Roswell Park Cancer Institute Buffalo New York United States 14263-0002
    27 NYU Langone New York New York United States 10016
    28 Memorial Sloan Kettering Cancer Center New York New York United States 10065
    29 University of North Carolina Chapel Hill North Carolina United States 27599-7305
    30 Cleveland Clinic Foundation Cleveland Ohio United States 44195
    31 Ohio State University Hospital Columbus Ohio United States 43210
    32 Oregon Health and Science University Portland Oregon United States 97239
    33 University of Pennsylvania Hospital Philadelphia Pennsylvania United States 19104
    34 Thomas Jefferson University Philadelphia Pennsylvania United States 19107
    35 Sarah Cannon Research Institute SCRI Nashville Tennessee United States 37203
    36 Vanderbilt University Medical Center Nashville Tennessee United States 37232-6307
    37 University of Texas Southwestern Medical Center at Dallas Dallas Texas United States 75390-9063
    38 University of Texas MD Anderson Cancer Center Houston Texas United States 77030
    39 Huntsman Cancer Institute Salt Lake City Utah United States 84112
    40 Virginia Cancer Specialists, PC Fairfax Virginia United States 22031
    41 University of Wisconsin-Madison Hospital and Health Clinic Madison Wisconsin United States 53792
    42 Royal North Shore Hospital St. Leonards New South Wales Australia 2065
    43 Peter MacCallum Cancer Centre Melbourne Victoria Australia 3000
    44 BC Cancer Vancouver Vancouver British Columbia Canada V5Z 4E6
    45 Rigshospitalet Copenhagen København Ø Denmark 2100
    46 Hôpital Européen Georges Pompidou Paris Cedex 15 France 75908
    47 Institut Bergonié - Centre Régional de Lutte Contre Le Cancer de Bordeaux et Sud Ouest Bordeaux France 33076
    48 Centre Leon Berard Lyon Cedex 08 France 69373
    49 APHM Hôpital de la Timone Marseille France 13385
    50 Institut du Cancer de Montpellier - Val d'aurelle Montpellier Cedex 5 France 34298
    51 Gustave Roussy Villejuif Cedex France 94805
    52 Universitätsklinikum Würzburg A. ö. R. Würzburg Bayern Germany 97080
    53 Universitätsklinikum Köln Köln Nordrhein-Westfalen Germany 50937
    54 Prince of Wales Hospital Hong Kong Shatin, New Territories Hong Kong
    55 Sheba Medical Center Tel Hashomer Ramat Gan Israel 5265601
    56 Shaare Zedek Medical Center Jerusalem Yerushalayim Israel 9103102
    57 Soroka Medical Center - Pediatric Outpatient Clinic Beer-Sheva Israel 8410101
    58 Hadassah Medical Center Jerusalem Israel 91120
    59 Istituto Nazionale dei Tumori Milano Lombardie Italy 20133
    60 Nagoya University Hospital Nagoya Aichi Japan 466-8560
    61 National Cancer Center Hospital East Kashiwa Chiba Japan 277-8577
    62 Hokkaido University Hospital Sapporo Hokkaido Japan 060-8648
    63 Hyogo Cancer Center Akashi Hyogo Japan 673-8558
    64 Kanazawa University Hospital Kanazawa Ishikawa Japan 920-8641
    65 Kindai University Hospital Osaka Sayama-shi Osaka Japan 589 8511
    66 Shizuoka Cancer Center Nagaizumi Shizuoka Japan 411-8777
    67 National Cancer Center Hospital Chuo-ku Tokyo Japan 104-0045
    68 Japanese Foundation for Cancer Research Koto Tokyo Japan 135-8550
    69 Tottori University Hospital Yonago Tottori Japan 683-8504
    70 National Hospital Organization Kyushu Cancer Center Fukuoka Japan 811-1395
    71 Okayama University Hospital Okayama Japan 700-8558
    72 Osaka City General Hospital Osaka Japan 534-0021
    73 National Cancer Center Goyang-si Gyeonggi-do Korea, Republic of 10408
    74 Seoul National University Bundang Hospital Seongnam Kyǒnggi-do Korea, Republic of 13620
    75 Asan Medical Center Seoul Seoul-teukbyeolsi [Seoul] Korea, Republic of 05505
    76 Samsung Medical Center Seoul Seoul-teukbyeolsi [Seoul] Korea, Republic of 06351
    77 Severance Hospital, Yonsei University Health System Seoul Korea, Republic of 03722
    78 National Cancer Centre Singapore Singapore Singapore 169610
    79 Hospital Universitari Vall d'Hebron Barcelona Barcelona [Barcelona] Spain 8035
    80 Hospital Universitario Fundación Jiménez Díaz Madrid Spain 28040
    81 Hospital Madrid Norte Sanchinarro Madrid Spain 28050
    82 Kantonsspital Luzern Luzern 16 Luzern Switzerland 6000
    83 Taichung Veterans General Hospital Taichung Taiwan 40705, ROC
    84 National Taiwan University Hospital Taipei Taiwan 10002
    85 Royal Marsden Hospital Sutton Surrey United Kingdom SM2 5PT

    Sponsors and Collaborators

    • Loxo Oncology, Inc.
    • Eli Lilly and Company

    Investigators

    • 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

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Loxo Oncology, Inc.
    ClinicalTrials.gov Identifier:
    NCT03157128
    Other Study ID Numbers:
    • 17477
    • J2G-OX-JZJA
    • LOXO-RET-17001
    • 2017-000800-59
    First Posted:
    May 17, 2017
    Last Update Posted:
    Aug 8, 2022
    Last Verified:
    Aug 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Loxo Oncology, Inc.
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Aug 8, 2022