A Study of Selpercatinib (LOXO-292) in Participants With Advanced Solid Tumors, RET Fusion-Positive Solid Tumors, and Medullary Thyroid Cancer (LIBRETTO-001)
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 |
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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:
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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)
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Cohort 2: Advanced RET fusion positive solid tumor other than NSCLC or thyroid cancer for treatment naïve participants (open)
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Cohort 3: Advanced RET-mutant MTC participants who progressed on or intolerant to first line therapy (closed)
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Cohort 4: Advanced RET-mutant MTC participants who are treatment naïve (closed)
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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)
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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)
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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
Arms and Interventions
Arm | Intervention/Treatment |
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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:
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Outcome Measures
Primary Outcome Measures
- 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
- 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
- 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
- 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)
- 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)
- 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
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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
- 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)
- 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)
- 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
Key Inclusion Criteria:
For Phase 1:
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Participants with a locally advanced or metastatic solid tumor that:
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Has progressed on or is intolerant to standard therapy, or
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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
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Decline standard therapy
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Prior multikinase inhibitors (MKIs) with anti-RET activity are allowed
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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
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Measurable or non-measurable disease as determined by RECIST 1.1 or RANO as appropriate to tumor type
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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
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Adequate hematologic, hepatic and renal function
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Life expectancy of at least 3 months
For Phase 2: As for phase 1 with the following modifications:
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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
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Cohorts 1 and 2:
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Enrollment will be restricted to participants with evidence of a RET gene alteration in tumor
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At least one measurable lesion as defined by RECIST 1.1 or RANO, as appropriate to tumor type and not previously irradiated
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Cohorts 3 and 4: Enrollment closed
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Cohort 5:
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Cohorts 1-4 without measurable disease
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MCT not meeting the requirements for Cohorts 3 or 4
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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
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cfDNA positive for a RET gene alteration not known to be present in a tumor sample
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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
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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):
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Phase 2 Cohorts 1 and 2: an additional known oncogenic driver
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Cohorts 3 and 4: Enrollment closed
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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
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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
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Major surgery (excluding placement of vascular access) within 2 weeks prior to planned start of LOXO-292 (selpercatinib)
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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
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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
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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)
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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)
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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.
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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.
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Required treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers and certain prohibited concomitant medications
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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 | |
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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.- 17477
- J2G-OX-JZJA
- LOXO-RET-17001
- 2017-000800-59