Clinical trial NCT03215511: A Study to Test the Safety of the Investigational Drug Selitrectinib in Children and Adults That May Treat Cancer
Official title: A Phase 1 Study of the TRK Inhibitor Selitrectinib (BAY 2731954) in Adult and Pediatric Subjects With Previously Treated NTRK Fusion Cancers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumors Harboring NTRK Fusion
Keywords: Solid Tumor
Metastatic cancer
Advanced cancer
Neurotrophic tyrosine receptor kinase (NTRK)
NTRK1
NTRK2
NTRK3
Fusion Positive
Children
Lead sponsor: Bayer
Sponsor class: INDUSTRY
First posted: 2017-07-12
Enrollment: 81
Sex: ALL
Minimum age (years): 1
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This research study is done to test the safety of the new drug selitrectinib in children and adults with cancer having a change in a particular gene (NTRK1, NTRK2 or NTRK3). The drug may treat cancer by interfering with the effect of the NTRK genes on cancer growth. The study also investigates how the drug is absorbed and processed in the human body, and how well and for how long the cancer responds to the drug. This is the first study to test selitrectinib in humans with cancer, for whom no other effective therapy exists.

Detailed description: The primary objective is to determine the recommended dose for further study of oral selitrectinib with previously treated neurotrophic tyrosine kinase (NTRK) cancers in 2 patient groups: a) aged 12 years and older and b) younger than 12 years. Secondary objectives of Phase I are to characterize the pharmakokinetic properties of the test drug, its safety and tolerability, and to assess the objective response rate (ORR) of NTRK-tumors.

Eligibility criteria: Inclusion Criteria:

* Advanced solid tumor for which, in the opinion of the investigator, no other standard therapy offers greater benefit.
* A solid tumor diagnosis in the setting of:

  * a) a documented NTRK fusion and a clinical history of relapse following a response to a prior TRK inhibitor
  * b) a documented NTRK fusion unresponsive to a prior TRK inhibitor
  * c) a documented NTRK fusion and a clinical history of intolerance to a prior TRK inhibitor
* NTRK gene fusions will be identified in a CLIA-certified (or equivalently-accredited diagnostic) laboratory. If such a report cannot be provided, other available certifications/accreditations are required and need to be documented. Patients with infantile fibrosarcoma (IFS) or congenital mesoblastic nephroma (CMN) may be enrolled based on an ETV6+ FISH test without identifying NTRK3.
* Performance Status: Eastern Cooperative Oncology Group (ECOG) score ≤ 2 in adults or Karnofsky Performance Status (KPS) Score≥50% (age ≥ 16 years) or Lansky Performance Score (LPS) ≥ 40% (age \< 16 years).
* Life expectancy of at least 3 months.
* Adequate hematologic, hepatic and renal function.
* Patients with stable central nervous system (CNS) primary tumor, brain metastases, or treated spinal cord compression are eligible if neurological symptoms have been stable for 7 days prior to the first dose of selitrectinib.
* Ability to receive study drug orally or by enteral administration

Exclusion Criteria:

* Prior exposure to second generation TRK inhibitor (e.g. selitrectinib, repotrectinib \[TPX-0005\]), taletrectinib \[DS-6501b/AB-106\]). Exception is in case patient presented intolerance to the second generation TRK inhibitor agent and the duration of exposure was less than 28 days. No previous treatment with selitrectinib is allowed.
* Concurrent treatment with a strong CYP3A4 inhibitor or inducer, consumption of grapefruit juice or Seville oranges, or drugs associated with QT prolongation.
* Clinically significant active cardiovascular disease or history of myocardial infarction within 3 months prior to planned start of selitrectinib, or prolongation of QT interval corrected for heart rate (QTc interval) \>480 milliseconds within past 6 months
* Major surgery within 7 days of enrollment
* Uncontrolled systemic bacterial, fungal or viral infection.
* Pregnancy or lactation.
* Known hypersensitivity to selitrectinib or Ora-Sweet® SF and OraPlus® for patients receiving liquid formulation.

Primary outcomes:
measure: Maximum tolerated dose (MTD)
timeFrame: Up to 42 days
measure: Recommended dose
timeFrame: Up to 12 months
Secondary outcomes:
measure: Incidence of adverse events
timeFrame: Up to 56 months
measure: Severity of adverse events
timeFrame: Up to 56 months
measure: Duration of adverse events
timeFrame: Up to 56 months
measure: Number of subjects with safety-relevant changes in clinical parameters or vital signs after drug administration
timeFrame: Up to 56 months
measure: Severity of safety-relevant changes in clinical parameters or vital signs after drug administration
timeFrame: Up to 56 months
measure: Overall response rate (ORR) in subjects with NTRK fusion cancer previously treated with TRK inhibitor determined by investigator
timeFrame: Up to 56 months
measure: Overall response rate (ORR) in subjects with primary central nervous system (CNS) malignancies determined by investigator
timeFrame: Up to 56 months
measure: Maximum concentration (Cmax) of BAY2731954 in plasma
timeFrame: Predose, 0.25, 0.5, 1, 2, 4, 6, 8 hours post-dose on Day 1, predose, 0.5, 1, 2, 4 post-dose on Day 8 of Cycle 1 (cycle length 28 days)
measure: Area under the concentration versus time curve of BAY2731954 in plasma (AUC (0-10), AUC(0-12) for BID dosing and AUC(0-24) for QD dosing)
timeFrame: At defined time points for different cohort, up to 10 hours post-dose
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: Univ.of California-San Diego Moores Cancer Center
state: California
city: Los Angeles
country: United States
facility: UCLA Jonsson Comprehensive Cancer Center
state: California
city: Palo Alto
country: United States
facility: Stanford Cancer Center
state: California
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta
state: Georgia
city: Zion
country: United States
facility: Midwestern Regional Medical Center
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Sioux Falls
country: United States
facility: Avera Cancer Institute
state: South Dakota
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Norfolk
country: United States
facility: Virginia Oncology Associates
state: Virginia
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Sydney
country: Australia
facility: Sydney Children's Hospital
state: New South Wales
city: Parkville
country: Australia
facility: Royal Children's Hospital Melbourne
state: Victoria
city: Edegem
country: Belgium
facility: UZ Antwerpen
city: Copenhagen
country: Denmark
facility: Rigshospitalet - Kræftbehandling
city: PARIS cedex 5
country: France
facility: Institut Curie - Ulm - Paris
city: Villejuif Cedex
country: France
facility: Institut Gustave Roussy - Département de Médecine Oncologique
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
state: Baden-Württemberg
city: Dublin
country: Ireland
facility: Tallaght Hospital
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori
state: Lombardia
city: Singapore
country: Singapore
facility: National Cancer Center Singapore
city: Barcelona
country: Spain
facility: Ciutat Sanitaria i Universitaria de la Vall d'Hebron
city: Madrid
country: Spain
facility: Fundacion Jimenez Diaz (Clinica de la Concepcion)
Study officials:
References:
citation: O'Reilly EM, Hechtman JF. Tumour response to TRK inhibition in a patient with pancreatic adenocarcinoma harbouring an NTRK gene fusion. Ann Oncol. 2019 Nov 1;30(Suppl_8):viii36-viii40. doi: 10.1093/annonc/mdz385. Epub 2019 Dec 24.