A Study to Test the Safety of the Investigational Drug Selitrectinib in Children and Adults That May Treat Cancer

A Phase 1 Study of the TRK Inhibitor Selitrectinib (BAY 2731954) in Adult and Pediatric Subjects With Previously Treated NTRK Fusion Cancers

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.

Study Overview

• Status: Completed
• Conditions: Solid Tumors Harboring NTRK Fusion
• Intervention / Treatment: Drug: Selitrectinib (BAY2731954)

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.

• Study Type: Interventional
• Enrollment (Actual): 81
• Phase: Phase 1

Expanded Access

No longer available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2031
      • Sydney Children's Hospital
  • Victoria
    • Parkville, Victoria, Australia, 3052
      • Royal Children's Hospital Melbourne
• Belgium
  • Edegem, Belgium, 2650
    • UZ Antwerpen
• Denmark
  • Copenhagen, Denmark, 2100
    • Finsen Centre
• France
  • Paris, France, 75248
    • Institut Curie - Ulm - Paris
  • Villejuif, France, 94805
    • Institut Gustave Roussy - Département de Médecine Oncologique
• Germany
  • Baden-Württemberg
    • Heidelberg, Baden-Württemberg, Germany, 69120
      • Universitätsklinikum Heidelberg
• Ireland
  • Dublin, Ireland, D24NR0A
    • Tallaght Hospital
• Italy
  • Lombardia
    • Milano, Lombardia, Italy, 20133
      • Fondazione IRCCS Istituto Nazionale dei Tumori
• Singapore
  • Singapore, Singapore, 169610
    • National Cancer Center Singapore
• Spain
  • Barcelona, Spain, 08023
    • Ciutat Sanitaria i Universitaria de la Vall d'Hebron
  • Madrid, Spain, 28040
    • Fundacion Jimenez Diaz (Clinica de la Concepcion)
• United States
  • California
    • La Jolla, California, United States, 92093
      • Univ.of California-San Diego Moores Cancer Center
    • Los Angeles, California, United States, 90095
      • UCLA Jonsson Comprehensive Cancer Center
    • Palo Alto, California, United States, 94304
      • Stanford Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Children's Healthcare of Atlanta
  • Illinois
    • Zion, Illinois, United States, 60099
      • Midwestern Regional Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02114-2696
      • Massachusetts General Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan-Kettering Cancer Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57105
      • Avera Cancer Institute
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute
  • Texas
    • Houston, Texas, United States, 77030-4000
      • University of Texas MD Anderson Cancer Center
  • Virginia
    • Norfolk, Virginia, United States, 23502
      • Virginia Oncology Associates
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cancer participants <12 years; A Rolling-6 dose escalation design will be used. The starting dose for participants age < 12 years will be 25% below the highest dose level cohort divided by 1.73 m^2 cleared by the Safety Review Committee (SRC) for subjects age 12 years and older.	Drug: Selitrectinib (BAY2731954); Selitrectinib is administered as capsules or liquid formulation.; Other Names: Loxo-195
Experimental: Cancer participants ≥12 years; A 3+3 dose escalation design will be used to determine the maximum tolerated dose (MTD)/recommended dose for further study, enrolling 3 to 6 participants per cohort with a starting dose level of 100 mg twice daily (BID).	Drug: Selitrectinib (BAY2731954); Selitrectinib is administered as capsules or liquid formulation.; Other Names: Loxo-195

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum tolerated dose (MTD)	Up to 42 days
Recommended dose	Up to 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events		Up to 56 months
Severity of adverse events	Severity is assessed using CTCAE version 4.03	Up to 56 months
Duration of adverse events		Up to 56 months
Number of subjects with safety-relevant changes in clinical parameters or vital signs after drug administration		Up to 56 months
Severity of safety-relevant changes in clinical parameters or vital signs after drug administration		Up to 56 months
Overall response rate (ORR) in subjects with NTRK fusion cancer previously treated with TRK inhibitor determined by investigator	ORR is determined by the investigator using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.	Up to 56 months
Overall response rate (ORR) in subjects with primary central nervous system (CNS) malignancies determined by investigator	ORR is determined by the treating investigator using the Response Assessment in Neuro-Oncology (RANO) criteria.	Up to 56 months
Maximum concentration (Cmax) of BAY2731954 in plasma		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)
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)		At defined time points for different cohort, up to 10 hours post-dose

Collaborators and Investigators

• Sponsor: Bayer

Publications and helpful links

General Publications

• 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.

Helpful Links

• Click here to find information about studies related to Bayer Healthcare products conducted in Europe.
• Click here to find further information and, after study completion, the study results according to Bayer's transparency standards

Study record dates

Study Major Dates

• Study Start (Actual): July 3, 2017
• Primary Completion (Actual): April 11, 2022
• Study Completion (Actual): January 30, 2023

Study Registration Dates

• First Submitted: June 30, 2017
• First Submitted That Met QC Criteria: July 10, 2017
• First Posted (Actual): July 12, 2017

Study Record Updates

• Last Update Posted (Actual): March 26, 2024
• Last Update Submitted That Met QC Criteria: March 25, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Children; Advanced cancer; Solid Tumor; Metastatic cancer; NTRK1; NTRK2; NTRK3; Neurotrophic tyrosine receptor kinase (NTRK); Fusion Positive
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Selitrectinib
• Other Study ID Numbers: 20810; LOXO-EXT-17005 (Other Identifier: Loxo Oncology, Inc.); 2017-004246-20 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

IPD Plan Description

Availability of this study's data will later be determined according to Bayer's commitment to the EFPIA/PhRMA "Principles for responsible clinical trial data sharing". This pertains to scope, timepoint and process of data access. As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014.

Interested researchers can use www.vivli.org to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the member section of the portal.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No