A Study of Selpercatinib (LY3527723) in Participants With Advanced Solid Tumors Including RET Fusion-positive Solid Tumors, Medullary Thyroid Cancer and Other Tumors With RET Activation (LIBRETTO-321)

• ClinicalTrials.gov Identifier: NCT04280081
• Recruitment Status: Active, not recruiting
• First Posted: February 21, 2020
• Results First Posted: June 2, 2022
• Last Update Posted: June 2, 2022
• Sponsor: Loxo Oncology, Inc.
• Collaborator: Eli Lilly and Company
• Information provided by (Responsible Party): Eli Lilly and Company ( Loxo Oncology, Inc. )

Study Description

Brief Summary:

The reason for this study is to see if the study drug selpercatinib is safe and effective in participants in China with rearranged during transfection (RET) fusion-positive solid tumors, medullary thyroid cancer (MTC) and other tumors with RET activation.

Condition or disease	Intervention/treatment	Phase
Solid Tumor; Medullary Thyroid Cancer	Drug: Selpercatinib	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 77 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study of Oral Selpercatinib (LOXO-292) in Patients With Advanced Solid Tumors, Including Rearranged in Transfection (RET) Fusion-Positive Solid Tumors, Medullary Thyroid Cancer and Other Tumors With RET Activation
• Actual Study Start Date: March 16, 2020
• Actual Primary Completion Date: March 25, 2021
• Estimated Study Completion Date: November 20, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Selpercatinib; Selpercatinib 160 milligrams (mg) administered orally twice daily (BID).	Drug: Selpercatinib; Administered orally; Other Names: LY3527723; LOXO-292

Outcome Measures

Primary Outcome Measures :

1. Primary Analysis Set: Overall Response Rate (ORR): Percentage of Participants With Complete Response (CR) or Partial Response (PR) as Assessed by Independent Review Committee (IRC) [ Time Frame: Date of First Dose to Disease Progression or Death (up to 12 Months) ]
   ORR is the summary measure of best overall response (BOR) as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. BOR is defined as the best response designation for each participant that is recorded between the date of the first dose of selpercatinib and the date of documented disease progression per RECIST 1.1 or the date of subsequent therapy, whichever occurs first, and subsequently confirmed. BOR will be categorized as complete response (CR), partial response (PR). CR is defined as Disappearance of all target lesions. Any pathologic nodes (whether target or non-target lesions) must have a reduction in short axis diameter (SAD) to less than 10 mm. PR At least 30% decrease in the sum of the diameters (SOD) (LD for non-nodal lesions and SAD for nodal lesions) of target lesions, taking as reference the baseline sum LD.
2. Enrolled Population: Overall Response Rate (ORR): Percentage of Participants With Complete Response (CR) or Partial Response (PR) as Assessed by IRC [ Time Frame: Date of First Dose to Disease Progression or Death (Up to 12 months) ]
   ORR is the summary measure of best overall response (BOR) as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. BOR is defined as the best response designation for each participant that is recorded between the date of the first dose of selpercatinib and the date of documented disease progression per RECIST 1.1 or the date of subsequent therapy, whichever occurs first, and subsequently confirmed. BOR will be categorized as complete response (CR), partial response (PR). CR is defined as Disappearance of all target lesions. Any pathologic nodes (whether target or non-target lesions) must have a reduction in short axis diameter (SAD) to less than 10 mm. PR At least 30% decrease in the sum of the diameters (SOD) (LD for non-nodal lesions and SAD for nodal lesions) of target lesions, taking as reference the baseline sum LD.

Secondary Outcome Measures :

1. Enrolled Population: Duration of Response (DoR) as Assessed by IRC [ Time Frame: Date of CR or PR to Date of Disease Progression or Death Due to Any Cause (Up to 11 Months) ]
   DOR is defined as the number of months from the start date of PR or CR (whichever response is recorded first), and subsequently confirmed, to the date of disease progression or death, whichever occurs earlier.
2. Enrolled Population: Time to Response (TTR) as Assessed by IRC [ Time Frame: Date of First Dose to First Occurrence of Confirmed Tumor Response (Up to 6 months) ]
   TTR is defined as the number of months elapsed between the date of the first dose of selpercatinib and the first documentation of objective response (CR or PR, whichever occurs earlier) that is subsequently confirmed.
3. Enrolled Population: Time to Best Response (TTBR) as Assessed by IRC [ Time Frame: Date of First Dose to First Occurrence of PR (If Subject's Best Overall Response [BOR] is PR) or CR (If Subject's BOR is CR) (Up to 8 months) ]
   TTR is defined as the number of months elapsed between the date of the first dose of selpercatinib and the first documentation of objective response (CR or PR, whichever occurs earlier) that is subsequently confirmed.
4. Enrolled Population: Clinical Benefit Rate (CBR): Percentage of Participants Who Achieve CR, PR, or Stable Disease (SD) With a Duration of At Least 16 or More Weeks as Assessed by IRC [ Time Frame: Baseline through Disease Progression or Death Due to Any Cause (Up to 12 Months) ]
   CBR based on the percentage of participants with best overall response of CR, PR, or stable disease (SD) lasting 16 or more weeks following initiation of selpercatinib as assessed by IRC. CR is defined as disappearance of all target lesions. Any pathologic nodes (whether target or non-target lesions) must have a reduction in short axis diameter (SAD) to less than 10 mm. PR is defined as at least a 30% decrease in the sum of the diameters (SOD) (LD for non-nodal lesions) and SAD for nodal lesions) of target lesions, taking as reference the baseline sum LD. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.
5. Enrolled Population: Progression Free Survival (PFS) as Assessed by IRC [ Time Frame: Baseline to Progressive Disease or Death from Any Cause (Up to 12 Months) ]
   PFS is defined as the number of months elapsed between the date of the first dose and the earliest date of documented disease progression or death (whatever the cause). Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest sum on study) for target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5.0 mm. Progressive disease for non-target lesion is defined as the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.
6. Enrolled Population: Overall Survival (OS) [ Time Frame: Baseline to Date of Death from Any Cause (Up to 12 Months) ]
   OS is defined as the number of months elapsed between the date of the first dose and the date of death (whatever the cause). Participants who are alive or lost to follow-up as of the data cutoff date will be right-censored.
7. Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve (AUC) of Selpercatinib [ Time Frame: PK: Cycle 1 Day 1: Predose, 1 h, 2, h, 4 h, 8 h, 12 h postdose PK: Cycle 1 Day 8: Predose, 1 h, 2, h, 4 h, 8 h postdose ]
   Serial blood samples for intensive PK monitoring will be collected for 12 participants.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Participants with a locally advanced or metastatic solid tumor.
• Evidence of a RET gene alteration in tumor and/or blood.
• Measurable or non-measurable disease as determined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2, with no sudden deterioration 2 weeks prior to the first dose of study treatment.
• Archived tumor tissue sample available for cohort 1 and 2.
• Cohorts 1 and 2: failed or intolerant to standard of care.
• Cohorts 1-2: enrollment will be restricted to participants with evidence of a RET gene alteration in tumor (i.e., not just blood). However, a positive germline DNA test for a RET gene mutation as defined in the protocol is acceptable in the absence of tumor tissue testing for participants with MTC.
• Cohorts 1-2: at least one measurable lesion as defined by RECIST v1.1 and not previously irradiated (unless progressive disease for the irradiated lesion[s] has been radiographically documented).

Exclusion Criteria:

• Cohorts 1-2, an additional validated oncogenic driver that could cause resistance to selpercatinib treatment if known.
• Prior treatment with a selective RET inhibitor(s) (including investigational selective RET inhibitor(s), such as BLU-667, RXDX-105, etc).
• Are currently enrolled in any other clinical study involving an investigational product or any other type of medical research judged not to be scientifically or medically compatible with this study.
• Any unresolved toxicities from prior therapy greater than common terminology criteria for adverse events (CTCAE) Grade 1 except where otherwise noted in this eligibility criteria at the time of starting study treatment with the exception of alopecia and Grade 2, prior platinum therapy-related neuropathy.
• Symptomatic primary central nervous system (CNS) tumor, symptomatic CNS metastasis, leptomeningeal carcinomatosis, or untreated spinal cord compression.
• Clinically significant active cardiovascular disease or history of myocardial infarction within 6 months prior to planned start of selpercatinib or prolongation of the QT interval corrected for heart rate using Fridericia's formula (QTcF) > 470 milliseconds.
• History of Human Immunodeficiency Virus (known HIV 1/2 antibodies positive); participants with unknown HIV status do not need to be tested.
• History of active hepatitis B (known positive hepatitis B surface antigen [HbsAg] and quantitative hepatitis B DNA greater than the upper limit of detection of the assay) or C (known positive hepatitis C antibody and quantitative hepatitis C RNA greater than the upper limit of detection of the assay); participants with unknown hepatitis B/hepatitis C status do not need to be tested.
• Active uncontrolled systemic bacterial, viral, or fungal infection or serious ongoing intercurrent illness, such as hypertension or diabetes, despite optimal treatment. Screening for chronic conditions is not required.
• Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of the study drug.
• Uncontrolled symptomatic hyperthyroidism or hypothyroidism
• Uncontrolled symptomatic hypercalcemia or hypocalcemia.
• Concurrent use of drugs known to prolong QTc.
• Pregnancy or lactation. Breast-feeding should be interrupted when selpercatinib is started; breast-feeding can be resumed 3 months after discontinuation of selpercatinib.
• Active second malignancy other than minor treatment of indolent cancers with prior sponsor approval.

Contacts and Locations

Locations

China, Guangdong

Nanfang Affiliated Hospital South Medical University

Guangzhou, Guangdong, China, 510515

China, Guangzhou

The First Affiated Hospital Of Guangzhou Medical Collage

Guangzhou, Guangzhou, China, 510120

China, Hunan

Hunan Cancer Hospital

Changsha, Hunan, China, 410013

China, Jilin

Jilin Province Tumor Hospital

Changchun, Jilin, China, 130012

China, Shandong

Jinan Central Hospital

Jinan, Shandong, China, 250013

China, Shanghai/China

Shanghai Chest Hospital

Shanghai, Shanghai/China, China, 200030

China, Zhejiang

Zhejiang Cancer Hospital

Hang Zhou, Zhejiang, China, 310022

First Affiliated Hosp of College of Med, Zhejiang University

Hangzhou, Zhejiang, China, 310003

Zhejiang Provincial People's Hospital

Hangzhou, Zhejiang, China, 310014

China

Beijing Cancer Hospital

Beijing, China, 100142

Fudan University Shanghai Cancer Center

Shanghai, China, 200032

Shanghai East Hospital

Shanghai, China, 200433

Tianjin Medical University Cancer Institute & Hospital

Tianjin, China, 300060

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; Eli Lilly and Company

  Study Documents (Full-Text)

Documents provided by Eli Lilly and Company ( Loxo Oncology, Inc. ):

Study Protocol  [PDF] February 1, 2021

Statistical Analysis Plan  [PDF] April 25, 2021

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Zheng X, Ji Q, Sun Y, Ge M, Zhang B, Cheng Y, Lei S, Shi F, Guo Y, Li L, Chen L, Shao J, Zhang W, Gao M. Efficacy and safety of selpercatinib in Chinese patients with advanced RET-altered thyroid cancers: results from the phase II LIBRETTO-321 study. Ther Adv Med Oncol. 2022 Aug 29;14:17588359221119318. doi: 10.1177/17588359221119318. eCollection 2022.

Lu S, Cheng Y, Huang D, Sun Y, Wu L, Zhou C, Guo Y, Shao J, Zhang W, Zhou J. Efficacy and safety of selpercatinib in Chinese patients with advanced RET fusion-positive non-small-cell lung cancer: a phase II clinical trial (LIBRETTO-321). Ther Adv Med Oncol. 2022 Jul 28;14:17588359221105020. doi: 10.1177/17588359221105020. eCollection 2022.

• Responsible Party: Loxo Oncology, Inc.
• ClinicalTrials.gov Identifier: NCT04280081
• Other Study ID Numbers: 17492; J2G-GH-JZJK ( Other Identifier: Eli Lilly and Company )
• First Posted: February 21, 2020
• Results First Posted: June 2, 2022
• Last Update Posted: June 2, 2022
• Last Verified: May 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)
• Time Frame: Data are available 6 months after the primary publication and approval of the indication studied in the US and EU, whichever is later. Data will be indefinitely available for requesting.
• Access Criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.
• URL: http://vivli.org/

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Eli Lilly and Company ( Loxo Oncology, Inc. ):

Non-Small Cell Lung Cancer; NSCLC; Targeted Therapy; Medullary Thyroid Carcinoma; Thyroid Cancer; RET Alteration; MTC

Additional relevant MeSH terms:

Thyroid Neoplasms; Carcinoma, Neuroendocrine; Brain Stem Neoplasms; Thyroid Diseases; Neoplasms; Endocrine System Diseases; Endocrine Gland Neoplasms; Neoplasms by Site; Head and Neck Neoplasms; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Infratentorial Neoplasms; Brain Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases