A Study of Oral LOXO-292 (Selpercatinib) in Pediatric Participants With Advanced Solid or Primary Central Nervous System (CNS) Tumors (LIBRETTO-121)

• ClinicalTrials.gov Identifier: NCT03899792
• Recruitment Status: Recruiting
• First Posted: April 2, 2019
• Last Update Posted: March 7, 2024
• Sponsor: Loxo Oncology, Inc.
• Collaborator: Eli Lilly and Company
• Information provided by (Responsible Party): Eli Lilly and Company ( Loxo Oncology, Inc. )

Tracking Information

• First Submitted Date: February 6, 2019
• First Posted Date: April 2, 2019
• Last Update Posted Date: March 7, 2024
• Actual Study Start Date: June 13, 2019
• Estimated Primary Completion Date: December 15, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 10, 2021)

• To Determine the Safety of Oral LOXO-292 in Pediatric Participants with Advanced Solid Tumors: Dose Limiting Toxicities (DLTs) [ Time Frame: During the first 28-day cycle of LOXO-292 treatment ]
  For Phase 1
• To Determine the Safety of Oral LOXO-292 in Pediatric Participants with Primary CNS Tumors: DLTs [ Time Frame: During the first 28-day cycle of LOXO-292 treatment ]
  For Phase 1
• Overall Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 per Independent Review Committee (IRC) [ Time Frame: Baseline to Progressive Disease or Death due to any cause (Estimated up to 12 months) ]
  For Phase 2
• ORR Based on Response Assessment in Neuro-Oncology (RANO) per IRC [ Time Frame: Baseline to Progressive Disease or Death due to any cause (Estimated up to 12 months) ]
  For Phase 2

Original Primary Outcome Measures (submitted: April 1, 2019)

• To determine the safety of oral LOXO-292 in pediatric patients with advanced solid tumors: Dose limiting toxicities (DLTs) [ Time Frame: During the first 28-day cycle of LOXO-292 treatment ]
  For Phase 1
• To determine the safety of oral LOXO-292 in pediatric patients with primary central nervous system (CNS) tumors: Dose limiting toxicities (DLTs) [ Time Frame: During the first 28-day cycle of LOXO-292 treatment ]
  For Phase 1
• ORR based on RECIST 1.1 per IRC [ Time Frame: Baseline to Progressive Disease or Death due to any cause (Estimated up to 12 months) ]
  For Phase 2
• ORR based on RANO per IRC [ Time Frame: Baseline to Progressive Disease or Death due to any cause (Estimated up to 12 months) ]
  For Phase 2

Current Secondary Outcome Measures (submitted: February 10, 2021)

• Plasma Concentrations of LOXO-292 [ Time Frame: Days 1 and 8 of Cycle 1, Day 1 of Cycle 3 and Day 8 after Intra-participant Dose Escalation (each cycle is 28 days) ]
  Phase 1
• Area Under the Concentration-Time Curve from 0 to 24 hours (AUC0-24) of LOXO-292 [ Time Frame: Days 1 and 8 of Cycle 1, Day 1 of Cycle 3 and Day 8 after Intra-participant Dose Escalation (each cycle is 28 days) ]
  Phase 1 and Phase 2
• Maximum Concentration (Cmax) of LOXO-292 [ Time Frame: Days 1 and 8 of Cycle 1, Day 1 of Cycle 3 and Day 8 after Intra-participant Dose Escalation (each cycle is 28 days) ]
  Phase 1 and Phase 2
• Time to Maximum Concentration (Tmax) of LOXO-292 [ Time Frame: Days 1 and 8 of Cycle 1, Day 1 of Cycle 3 and Day 8 after Intra-participant Dose Escalation (each cycle is 28 days) ]
  Phase 1 and Phase 2
• Recommended LOXO-292 Dose for Phase 2 (MTD) [ Time Frame: Cycle 1 (28 days) ]
  For Phase 1
• To Assess the Preliminary Anti-Tumor Activity of LOXO-292 in Pediatric Participants with Tumors Harboring an Activating RET Alteration as Determined by ORR Based on RECIST v1.1 [ Time Frame: Baseline to Progressive Disease or Death due to any cause (Estimated up to 12 months) ]
  For Phase 1
• Changes from Baseline in Pain Measures as Measured by Wong Baker Faces scales. Wong-Baker Faces Pain Scale includes pictures of facial expressions with correlating scores of 0 being 'no hurt' and 10 being 'hurts worst'. [ Time Frame: Up to 24 months ]
  For Phase 1
• Changes from Baseline in Health Related Quality of Life Measures as Measured by Pediatric Quality of Life (PedsQoL) Inventory Core. PedsQoL includes a list of problems with scores of 0 being 'never a problem' and 4 being 'almost always a problem'. [ Time Frame: Up to 24 months ]
  For Phase 1
• Objective Response Rate as Assessed by RECIST v1.1, as Assessed by Investigator [ 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. ]
  For Phase 2
• Objective Response Rate as Assessed by RANO, as Assessed by Investigator [ 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. ]
  For Phase 2
• Duration of Response (DOR) as Assessed by Investigator [ 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. ]
  For Phase 2
• Duration of Response (DOR) as Assessed by the IRC [ 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. ]
  For Phase 2
• Progression Free Survival (PFS) as Assessed by Investigator [ 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. ]
  For Phase 2
• PFS as Assessed by IRC [ 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. ]
  For Phase 2
• Overall survival (OS) [ 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. ]
  For Phase 2
• Clinical Benefit Rate (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. ]
  For Phase 2
• Clinical Benefit Rate (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. ]
  For Phase 2
• Frequency of Adverse Events (AEs) [ Time Frame: From the time of informed consent, for approximately 24 months (or earlier if the participants discontinues from the study), and through Safety Follow-up (28 days after the last dose) ]
  For Phase 2
• To Evaluate the Concordance of Prior Molecular that Detected a RET Alteration within the Participant's Tumor with Diagnostic Tests Being Evaluated by Sponsor [ Time Frame: 6 months ]
  For Phase 2
• Phase 2: Post-Operative Stage on Participants Treated with LOXO-292 [ Time Frame: Up to 3 years ]
  Tumor stage is described according to the Tumor, Node, Metastasis (TNM)Classification of malignant tumors of the Union for International Cancer Control (UICC)
• Phase 2: Surgical Margin Status in Participants Treated with LOXO-292 [ Time Frame: Up to 3 years ]
  Tumor margins after surgery are classified into four groups using the International Cancer Control (UICC)-R classification and the Intergroup Rhabdomyosarcoma Staging (IRS) systems: 1) Complete tumor resection with histologically free margins, 2) Macroscopic resection but invaded margins on histology, 3)Macroscopic residual tumor and 4) Distant metastatic tumor.
• Descriptive Analysis of Pretreatment Surgical Plan [ Time Frame: Up to 3 years ]
  For Phase 2
• Descriptive Analysis of Post-Treatment Plans [ Time Frame: Up to 3 years ]
  For Phase 2

Original Secondary Outcome Measures (submitted: April 1, 2019)

• Plasma concentrations of LOXO-292 [ Time Frame: Days 1 & 8 of Cycle 1, Day 1 of Cycle 3 and Day 8 after Intra-patient Dose Escalation (each cycle is 28 days) ]
  Phase 1
• AUC0-24 of LOXO-292 [ Time Frame: Days 1 & 8 of Cycle 1, Day 1 of Cycle 3 and Day 8 after Intra-patient Dose Escalation (each cycle is 28 days) ]
  Phase 1 & Phase 2
• Cmax of LOXO-292 [ Time Frame: Days 1 & 8 of Cycle 1, Day 1 of Cycle 3 and Day 8 after Intra-patient Dose Escalation (each cycle is 28 days) ]
  Phase 1 & Phase 2
• Tmax of LOXO-292 [ Time Frame: Days 1 & 8 of Cycle 1, Day 1 of Cycle 3 and Day 8 after Intra-patient Dose Escalation (each cycle is 28 days) ]
  Phase 1 & Phase 2
• Recommended LOXO-292 Dose for Phase 2 (Maximum Tolerated Dose [MTD]) [ Time Frame: Cycle 1 (28 days) ]
  For Phase 1
• To assess the preliminary anti-tumor activity of LOXO-292 in pediatric patients with tumors harboring an activating RET alteration as determined by ORR based on RECIST v1.1 [ Time Frame: Baseline to Progressive Disease or Death due to any cause (Estimated up to 12 months) ]
  For Phase 1
• Changes from baseline in pain measures as measured by Wong Baker Faces scales. Wong-Baker Faces Pain Scale includes pictures of facial expressions with correlating scores of 0 being 'no hurt' and 10 being 'hurts worst'. [ Time Frame: Up to 24 months ]
  For Phase 1
• Changes from baseline in health related quality of life measures as measured by Pediatric Quality of Life Inventoy Core. PedsQoL includes a list of problems with scores of 0 being 'never a problem' and 4 being 'almost always a problem'. [ Time Frame: Up to 24 months ]
  For Phase 1
• Objective Response Rate as assessed by RECIST v1.1, as assessed by investigator [ 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 patients who have not progressed. ]
  For Phase 2
• Objective Response Rate as assessed by RANO, as assessed by investigator [ 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 patients who have not progressed. ]
  For Phase 2
• Duration of response (DOR) as assessed by the Investigator [ 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 patients who have not progressed. ]
  For Phase 2
• Duration of response (DOR) as assessed by the IRC [ 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 patients who have not progressed. ]
  For Phase 2
• Progression free survival (PFS) as assessed by the Investigator [ 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 patients who have not progressed. ]
  For Phase 2
• Progression free survival (PFS) as assessed by the IRC [ 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 patients who have not progressed. ]
  For Phase 2
• Overall survival (OS) [ 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 patients who have not progressed. ]
  For Phase 2
• Clinical Benefit Rate (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 patients who have not progressed. ]
  For Phase 2
• Clinical Benefit Rate (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 patients who have not progressed. ]
  For Phase 2
• Frequency of AEs [ Time Frame: From the time of informed consent, for approximately 24 months (or earlier if the patient discontinues from the study), and through Safety Follow-up (28 days after the last dose) ]
  For Phase 2
• To evaluate the concordance of prior molecular profiling that detected a RET alteration within the subject's tumor with diagnostic tests being evaluated by the Sponsor [ Time Frame: 6 months ]
  For Phase 2
• Phase 2: Post-operative stage on patients treated with LOXO-292. [ Time Frame: Up to 3 years ]
  Tumor stage is described according to the TNM Classification of malignant tumors of the Union for International Cancer Control (UICC).
• Phase 2: Surgical margin status in patients treated with LOXO-292. [ Time Frame: Up to 3 years ]
  Tumor margins after surgery are classified into four groups using the International Cancer Control (UICC)-R classification and the Intergroup Rhapdomyosarcoma Staging (IRS) systems: 1) Complete tumor resection with histologically free margins, 2) Macroscopic resection but invaded margins on histology, 3)Macroscropic residual tumor and 4) Distant metastatic tumor.
• Descriptive analysis of pretreatment surgical plan [ Time Frame: Up to 3 years ]
  For Phase 2
• TDescriptive analysis of post-treatment plans [ Time Frame: Up to 3 years ]
  For Phase 2

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Oral LOXO-292 (Selpercatinib) in Pediatric Participants With Advanced Solid or Primary Central Nervous System (CNS) Tumors
• Official Title: A Phase 1/2 Study of the Oral RET Inhibitor LOXO 292 in Pediatric Patients With Advanced RET-Altered Solid or Primary Central Nervous System Tumors
• Brief Summary: This is an open-label, multi-center Phase 1/2 study of oral LOXO-292 in pediatric participants with an activating rearranged during transfection (RET) alteration and an advanced solid or primary CNS tumor.
• Detailed Description: This study includes 2 parts: phase 1 (dose escalation) and phase 2 (dose expansion). In phase 1, participants will be enrolled using a rolling 6 dose escalation scheme. The starting dose of LOXO-292 is equivalent to the adult recommended phase 2 dose of 160 milligrams (mg) twice a day (BID). Once the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) is identified, participants will be enrolled to one of four phase 2 dose expansion cohorts depending on tumor histology and tumor genotype. Cycle length will be 28 days.
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Medullary Thyroid Cancer
• Infantile Myofibromatosis
• Infantile Fibrosarcoma
• Papillary Thyroid Cancer
• Soft Tissue Sarcoma

Intervention

Drug: LOXO-292

Oral LOXO-292

Other Names:

• Selpercatinib
• LY3527723

Study Arms

Experimental: LOXO-292

Phase 1- Dose Escalation and determination of MTD; multiple dose levels of LOXO-292 to be evaluated; Phase 2 - The MTD/recommended dose from Phase 1

Intervention: Drug: LOXO-292

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: September 5, 2023): 50
• Original Estimated Enrollment (submitted: April 1, 2019): 100
• Estimated Study Completion Date: May 31, 2029
• Estimated Primary Completion Date: December 15, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Advanced or metastatic solid or primary CNS tumor which has failed standard of care therapies
• Evidence of an activating RET gene alteration in the tumor and/or blood
• Measurable or non-measurable disease
• Karnofsky (participants 16 years and older) or Lansky (participants younger than 16) performance score of at least 50
• Participant with primary CNS tumors or cerebral metastases must be neurologically stable for 7 days prior and must not have required increasing doses of steroids within the last 7 days
• Adequate hematologic, hepatic and renal function.
• Ability to receive study drug therapy orally or via gastric access
• Willingness of men and women of reproductive potential to observe conventional and effective birth control

Exclusion Criteria:

• Major surgery within two weeks prior to planned start of LOXO-292
• Clinically significant, uncontrolled cardiac, cardiovascular disease or history of myocardial infarction within 6 months prior to planned start of LOXO-292
• Active uncontrolled systemic bacterial, viral, fungal or parasitic infection
• Clinically significant active malabsorption syndrome
• Pregnancy or lactation
• Uncontrolled symptomatic hyperthyroidism or hypothyroidism (i.e. the participant required a modification to current thyroid medication in the 7 days before start of LOXO-292)
• Uncontrolled symptomatic hypercalcemia or hypocalcemia
• Known hypersensitivity to any of the components of the investigational agent, LOXO-292 or Ora-Sweet® SF and OraPlus®, for participants who will receive LOXO-292 suspension
• Prior treatment with a selective RET inhibitor(s) (including investigational selective RET inhibitor[s])

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 6 Months to 21 Years (Child, Adult)
• Accepts Healthy Volunteers: No

Contacts

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

• Listed Location Countries: Australia, Canada, Denmark, France, Germany, Italy, Japan, Korea, Republic of, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT03899792
• Other Study ID Numbers: 17493; J2G-OX-JZJJ ( Other Identifier: Eli Lilly and Company ); LOXO-RET-18036 ( Other Identifier: LOXO Oncology, Inc. ); 2019-000212-28 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Eli Lilly and Company ( Loxo Oncology, Inc. )
• Original Responsible Party: Same as current
• Current Study Sponsor: Loxo Oncology, Inc.
• Original Study Sponsor: Same as current
• Collaborators: 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

• PRS Account: Eli Lilly and Company
• Verification Date: March 2024