Clinical trial NCT03899792: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Medullary Thyroid Cancer
Infantile Myofibromatosis
Infantile Fibrosarcoma
Papillary Thyroid Cancer
Soft Tissue Sarcoma
Keywords: Loxo
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
RET-PTC9
ACBD5-RET
MYH13-RET
CUX1-RET
KIAA1468-RET
FRMD4A-RET
SQSTM1-RET
AFAP1L2-RET
PPFIBP2-RET
EML4-RET
PARD3-RET
G533C
C609F
C609G
C609R
C609S
C609Y
C611F
C611G
C611S
C611Y
C611W
C618F
C618R
C618S
C620F
C620R
C620S
C630R
C630Y
D631Y
C634F
C634G
C634R
C634S
C634W
C634Y
K666E
E768D
L790F
V804L
V804M
A883F
S891A
R912P
CLIP1-RET
Y806C
RET fusion
RET alteration
RET mutation
RET rearrangement
RET translocation
Neoplasms by Site
Neoplasms
Non-Small Cell Lung Cancer
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Cancer of Lung
Cancer of the Lung
Lung Cancer
Neoplasms, Lung
Neoplasms, Pulmonary
Pulmonary Cancer
Pulmonary Neoplasms
Respiratory Tract Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Medullary Thyroid Cancer
Papillary Thyroid Cancer
Thyroid Diseases
Thyroid Neoplasms
Cancer of the Thyroid
Cancer of Thyroid
Neoplasms, Thyroid
Thyroid Adenoma
Thyroid Cancer
Thyroid Carcinoma
Endocrine System Diseases
Endocrine Gland Neoplasms
Head and Neck Neoplasms
Thoracic Neoplasms
CNS tumor
Primary CNS tumor
Colonic Neoplasms
Cancer of Colon
Cancer of the Colon
Colon Cancer
Colon Neoplasms
Colonic Cancer
Neoplasms, Colonic
Malignant tumor of Breast
Mammary Cancer
Mammary Carcinoma, Human
Mammary Neoplasm, Human
Neoplasms, Breast
Tumors, Breast
Human Mammary Carcinoma
Malignant Neoplasm of Breast
Breast Carcinoma
Breast Tumors
Cancer of the Breast
Breast Neoplasms
Breast Cancer
RET Inhibitor
MTC
NSCLC
Soft tissue sarcoma
Infantile Myofibromatosis
Infantile Fibrosarcoma
Lead sponsor: Eli Lilly and Company
Sponsor class: INDUSTRY
Collaborators: name: Loxo Oncology, Inc.
First posted: 2019-04-02
Enrollment: 50
Sex: ALL
Minimum age (years): 6
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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\[s\])

Primary outcomes:
measure: To Determine the Safety of Oral LOXO-292 in Pediatric Participants with Advanced Solid Tumors: Dose Limiting Toxicities (DLTs)
timeFrame: During the first 28-day cycle of LOXO-292 treatment
measure: To Determine the Safety of Oral LOXO-292 in Pediatric Participants with Primary CNS Tumors: DLTs
timeFrame: During the first 28-day cycle of LOXO-292 treatment
measure: Overall Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 per Independent Review Committee (IRC)
timeFrame: Baseline to Progressive Disease or Death due to any cause (Estimated up to 12 months)
measure: ORR Based on Response Assessment in Neuro-Oncology (RANO) per IRC
timeFrame: Baseline to Progressive Disease or Death due to any cause (Estimated up to 12 months)
Secondary outcomes:
measure: Plasma Concentrations of LOXO-292
timeFrame: 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)
measure: Area Under the Concentration-Time Curve from 0 to 24 hours (AUC0-24) of LOXO-292
timeFrame: 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)
measure: Maximum Concentration (Cmax) of LOXO-292
timeFrame: 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)
measure: Time to Maximum Concentration (Tmax) of LOXO-292
timeFrame: 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)
measure: Recommended LOXO-292 Dose for Phase 2 (MTD)
timeFrame: Cycle 1 (28 days)
measure: 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
timeFrame: Baseline to Progressive Disease or Death due to any cause (Estimated up to 12 months)
measure: 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'.
timeFrame: Up to 24 months
measure: 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'.
timeFrame: Up to 24 months
measure: Objective Response Rate as Assessed by RECIST v1.1, as Assessed by Investigator
timeFrame: 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.
measure: Objective Response Rate as Assessed by RANO, as Assessed by Investigator
timeFrame: 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.
measure: Duration of Response (DOR) as Assessed by Investigator
timeFrame: 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.
measure: Duration of Response (DOR) as Assessed by the IRC
timeFrame: 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.
measure: Progression Free Survival (PFS) as Assessed by Investigator
timeFrame: 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.
measure: PFS as Assessed by IRC
timeFrame: 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.
measure: Overall survival (OS)
timeFrame: 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.
measure: Clinical Benefit Rate (by Investigator)
timeFrame: 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.
measure: Clinical Benefit Rate (by IRC)
timeFrame: 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.
measure: Frequency of Adverse Events (AEs)
timeFrame: 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)
measure: To Evaluate the Concordance of Prior Molecular that Detected a RET Alteration within the Participant's Tumor with Diagnostic Tests Being Evaluated by Sponsor
timeFrame: 6 months
measure: Phase 2: Post-Operative Stage on Participants Treated with LOXO-292
timeFrame: Up to 3 years
measure: Phase 2: Surgical Margin Status in Participants Treated with LOXO-292
timeFrame: Up to 3 years
measure: Descriptive Analysis of Pretreatment Surgical Plan
timeFrame: Up to 3 years
measure: Descriptive Analysis of Post-Treatment Plans
timeFrame: Up to 3 years
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Childrens Hospital of Los Angeles
state: California
city: Aurora
country: United States
facility: The Children's Hospital for Cancer and Blood Disorders
state: Colorado
city: Orlando
country: United States
facility: Nemours Children's Health
state: Florida
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota Hospital
state: Minnesota
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center at Dallas
state: Texas
city: Houston
country: United States
facility: Texas Childrens Hospital
state: Texas
city: Seattle
country: United States
facility: Seattle Children's Hospital Research Foundation
state: Washington
city: Westmead
country: Australia
facility: The Children's Hospital at Westmead
state: New South Wales
city: Melbourne
country: Australia
facility: Royal Children's Hospital
state: Victoria
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Villejuif Cedex
country: France
facility: Gustave Roussy
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
state: Baden-Württemberg
city: Milan
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori
state: Lombardia
city: Sapporo
country: Japan
facility: Hokkaido University Hospital
state: Hokkaido
city: Chuo-ku
country: Japan
facility: National Cancer Center Hospital
state: Tokyo
city: Hiroshima
country: Japan
facility: Hiroshima University Hospital
city: Kyoto
country: Japan
facility: Kyoto University Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
state: Korea
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
state: Barcelona [Barcelona]
city: London
country: United Kingdom
facility: University College Hospital - London
state: Greater London
Study officials:
affiliation: Eli Lilly and Company
name: 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)
role: STUDY_DIRECTOR
References: